The Physiology and Ecology of Puberty Modulation by Primer Pheromones

ADVANCES IN THE STUDY OF BEHAVIOR. VOL. 16

The Physiology and Ecology of Puberty Modulation by Primer Pheromones JOHN G . VANDENBERGHAND DAVIDM. COPPOLA DEPARTMENT OF ZOOLOGY NORTH CAROLINA STATE UNIVERSITY RALEIGH, NORTH CAROLINA

1. Introduction .................... 11. Acceleration of Puberty.. ......................................... A. Effect of Males . . . . ................

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111. Inhibition of Puberty . . .

B . Control Mechanisms A. Puberty Modulation in M i c e . . ..................................

B . Speculations on the Adaptive Significance of Puberty Pheromones. . . . .

C. Highway Island Populations .................... ory Theory . . . . . . . . . . . . . VI. Age at First Reproduction in Terms o A. Ecological Determinants of Age at First Reproduction. . . . . . B . A New Hypothesis of Puberty Pheromone Function.. . . . . . . . . . . . . . . . VII. Conclusions . . . . . . . . . . ....

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81 88 92 96 101

I. INTRODUCTION With a chemical sense dulled by selection for visual and auditory senses and abused by such pleasures as tobacco and alcohol, investigators have overlooked the rich world of chemical communication until recently. This article cannot pretend to make up for human evolutionary pathways or for our pleasures. We do hope, however, to explore one small portion of the growing literature on chemical communication in animals, namely, how chemical substances may have evolved as messengers to modulate the onset of puberty in the house mouse. Before discussing the selection pressures that resulted in such messengers or the use to which they are put in natural populations, we must first describe the 71

Copyright 8 1986 by Academic Press. Inc. All right?of reproduelion in any form reserved.

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pheromones involved and what we know about them from several years of laboratory experimentation, Although the awareness of olfaction and observations of the chemical senses extend back to early biological investigations (McCartney, 1968), the recent surge of interest began in the 1950s and grew out of studies on insect communication. Karlson and Luscher (1959) proposed the term “pheromone” for substances that are secreted externally by an animal and cause a specific reaction in another individual of the same species. The result of the stimulus can be either the prompt release of a specific behavior or a more long-term physiological or developmental change. Pheromones can exert their effect after oral or olfactory reception. Substances that induce short-term behavioral responses are termed signalling pheromones and those having a more prolonged effect on physiological state, usually reproduction, or development, are termed priming pheromones. Several compounds have been identified that seem to serve as signals of reproductive state. Dimethyl disulfide, a compound present in hamster vaginal secretions, attracts males to receptive females (Singer et al., 1976; O’Connell et al., 1981) although other, more complex, compounds may be involved in actually inducing males to mount estrous females (Singer e? al., 1980). Methyl-p-hydroxybenzoate may similarly signal estrus in the bitch (Goodwin et al., 1979). A blend of aliphatic acids of vaginal origin may serve to attract male rhesus monkeys to females (Michael et al., 1967; Keverne, 1976). Some of the claims that a specific chemical or blend of chemicals serve as a pheromone having signalling function have been criticized (Goldfoot, 1981;Johnston, 1983). Although there is general agreement that chemical signals are important in animal communication, additional research is necessary to clarify their role in the life of animals. One promising area being pursued is the development of a new technique for computerized reocgnition of patterns of substances in complex chemosignals. Isolation and identification of such complex chemosignals from the tamarin, Saguinus fuscicollis, a South American monkey, has been attempted (Preti e?al., 1976). These small monkeys use the secretions of highly specialized scent glands along with urine and genital discharge to mark their environment. Such marks convey information concerning species identification, gender, reproductive status, and social status. Concentration profiles of these marks suggest that the animals have “scent prints” for such characteristics. Using analysis by a pattern recognition method, preliminary results suggest that the relationship between a few highly volatile components may encode the chemical messages (Smith, 1984). These studies and others recently reviewed by Johnston (1983) reveal the progress being made to understand the role of signalling pheromones in the lives of mammals. Among priming pheromones, studies have focused almost exclusively on reproduction. These studies grew out of the discoveries of Hilda Bruce and Wesley

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Whitten. Bruce (1959) demonstrated that exposure of a recently inseminated female mouse to a male other than her stud causes the blockage of pregnancy in a high number of cases. Whitten (1959) showed that if adult female mice are densely grouped, most will go into an anestrous state; upon exposure to a male, estrous cyclicity is restored in a synchronous manner. Urine has been shown to convey the message in both the effect discovered by Bruce (Bruce and Parrott, 1960) and that discovered by Whitten (Marsden and Bronson, 1964). Considerable additional work has been done in recent years on adult mammalian reproductive functions and their control by pheromones (McClintock, 1981; 1983). In this article we will focus on the role of priming pheromones in controlling sexual maturation in juvenile animals. 11. ACCELERATION OF PUBERTY

A.

EFFECTOF MALES

Under typical rearing conditions in the laboratory, juvenile female mice are reared separately from males after weaning. When the assumed age of maturity is reached, commonly 60 days, the investigator or animal caretaker mates the females with males. Pregnancies occur in a high proportion of females. Given the mode of rearing this is an appropriate procedure. If, however, juvenile females are housed with adult males from weaning, sexual maturity occurs at a much earlier age (Castro, 1967; Vandenbergh, 1967). Females housed in groups of six to eight with an adult male display vaginal estrus beginning at 37 days of age, about 20 days earlier than females housed in an all-female group (Vandenbergh, 1967). Chemical signals from the male were suspected as the stimulus to the female because work on adult females showed that the male effect on estrous cyclicity and pregnancy blockage could be attributed to cues in male urine (Marsden and Bronson, 1964). These results were extended to juveniles when bedding soiled by males was shown to accelerate puberty (Vandenbergh, 1969). Urine was shown to contain the stimulus accelerating puberty in subsequent studies (Cowley and Wise, 1972; Colby and Vandenbergh, 1974; Drickamer and Murphy, 1978). The pheromone in urine is remarkably potent. Diluting the male urine in water at 1: 10 actually enhanced the effect; at 1:lOO the affect was retained but at higher dilutions the effect declined (Drickamer, 1982a; Wilson et al., 1980). Even a minute dose of male urine is capable of accelerating puberty. Drickamer (1984a) found that female puberty was accelerated by a dose as low as O.OOO1 ml of male urine. In our laboratory, chemical cues from the male are able to induce only about 50 to 70% of the acceleration of puberty resulting from the physical presence of

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T

FIG. 1. Mean acceleration of first vaginal estrus ( 2 1 SE) in days compared to the control for female mice under four treatment conditions. The means for mice exposed to neonatally androgenized (NA) females male bedding and intact males were not significantly different from each other but were significantly different from the other two treatment means. The means for the females exposed to male bedding alone or NA females alone were not significantly different. All treatment means were significantly different from the control (Drickamer, 1974).

+

an adult male; the remainder of the stimulus is presumably provided by tactile or other signals requiring the physical presence of the male (Vandenbergh et al., 1972; Drickamer, 1974). Drickamer (1974) combined two lines of inquiry to design a clever experiment to rest the role of tactile stimulation. Female mice injected with testosterone shortly after birth display malelike behavior as adults even if additional androgens are not given after puberty. Thus, he could create a female mouse with female chemical signals that showed malelike behavior. When juvenile females were caged with such neonatally androgenized females the results shown in Fig. 1 were obtained. These results show that exposure of juvenile females to male bedding material results in an intermediate age of pubertal onset in comparison to that obtained after exposure to a male or the control condition of a female living alone in a cage. Females showing malelike behavior induced as much acceleration as soiled bedding and, when exposure to such females was combined with the soiled bedding from males, juvenile females responded with puberty as early as noted

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when adult males were placed in the cage with juvenile females. The interactive effect between physical stimulation and chemical signals on puberty acceleration was confirmed by Bronson and Maruniak (1975). Thus, although the focus of this article is on pheromonal influences on puberty, the reader should be aware that pheromones may explain only part of the effect, at least on puberty acceleration.

B. CONTROLMECHANISMS The most immediate and direct control over production of the puberty-accelerating pheromone operates via control of androgen levels. Castration results in the disappearance of the pheromone from urine within 2 weeks. An injection of testosterone proprionate restores pheromonal potency within 60 hours and a dose-dependent response to testosterone occurs in the range of 5 to 250 mg testosterone proprionate injected every other day (Lombardi et al., 1976). An age-related reduction in the potency of the male’s acceleratory pheromone has been reported by Wilson and Harrison (1983) that reflects age-dependent changes in testosterone. More work needs to be done on the interaction between age and production of the pheromone because Wilson and Harrison did not measure androgens and because the effect of age on reproductive performance of male mice is not consistent (Bronson and Desjardins, 1981). If the puberty-accelerating pheromone is androgen dependent, then environmental factors influencing androgen production could indirectly affect pheromone production. The first factor tested in this regard was the social environment. Lombardi and Vandenbergh (1977) reasoned that social subordination could result in loss of pheromonal potency since decreased androgen output follows loss of social status. To test this assumption, previously isolated male mice were paired with trained fighter mice for 1 week. Urine was then collected for a subsequent 8 days from both the dominant, successful fighters and the subordinate mice. When juvenile females were exposed to urine from the dominant male mice, their onset of puberty was significantly accelerated in comparison to females exposed to urine from subordinate males or females exposed to water as a control substance (Lombardi and Vandenbergh, 1977). In addition to social stimuli, environmental factors such as food quality and photoperiod can influence pheromonal acceleration of female puberty. When comparing the relative effects of dietary protein and male stimulation on female sexual maturation, Vandenbergh et al. (1972) showed that both diet and male stimuli significantly influenced sexual maturation of female mice. Diet contributed about 5% and male stimuli about 47% of the variance. Drickamer (1982b) has recently shown that the potency of male urine to accelerate puberty and the effectiveness of the female’s receptor system vary with time of day. Urine collected from male mice maintained on 12 hours of light

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per day was most effective in accelerating puberty when collected at 0600, the start of the lights-on period. Interestingly, females also displayed the greatest responsivity to the male acceleratory pheromone at 0600. In our laboratory we have attempted to isolate and identify the puberty-accelerating pheromone. The androgen dependency of the pheromone suggested that the active material was either a metabolic degradation product of testosterone or a secondary product under the control of androgen. The hypothesis that the material was an androgen catabolite was rejected when urine was found to retain its activity following extraction with ether or dialysis. The component was heat labile and the active fraction could be salted out of urine with ammonium sulfate (Vandenbergh et af.,1975). This and other unpublished data led us to suggest that the active material was related to the protein fraction of urine. Rodent urine contains remarkably high levels of protein (Parfentjev, 1932; Finlayson et al., 1965), so this notion is feasible. In another series of chemical separations (Vandenbergh et af.,1976) we were able to show that further purification of the active components could be obtained by gel chromatography. The active fraction eluted at a position corresponding to MW 860 on a Sephadex G-15 column. This fraction containing the pubertyaccelerating pheromone yielded positive reactions for peptides. The possibility that the material could be a low-molecular-weightpeptide leads to some interesting speculation relating pheromones to hypothalmic releasing factors. Could priming pheromones that regulate reproductive events within a population be analogous to hypothalamic releasing factors that regulate reproductive events within an individual? To date, these ideas remain conjectural and will remain so until we have a more clear understanding of priming pheromones and their role in populations. Genetic as well as environmental factors influence the pheromonal regulation of puberty in female mice. Drickamer (1981a) selected female mice for rapid or slow sexual maturation. Within three generations the stocks attained puberty at significantly different ages. Females in the line selected for early puberty reached first estrus at a mean of 28 days of age and the line selected for late puberty matured at 46 days of age. The stock of mice that was randomly bred attained puberty at 35 to 36 days of age. Among early maturing females, exposure to male stimuli did not result in an additional acceleration of puberty (Drickamer, 1981a). At least for the strain tested (ICR/Alb), selection had apparently taken the females to the earliest possible time for breeding, about 28 days. Yet, selection for early puberty had not fixed the trait. Selection for early puberty in the fast maturing line could be reversed within eight generations of selection for slow maturation (Drickamer, 1983). Females in each of the lines selected for early puberty showed normal reproductive characteristics in such measures as fertility, litter size, and weight. Stimuli from female mice typically suppress the rate of sexual maturation of

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other females, as we shall see later in this article. An important exception to this principle has been discovered by Drickamer and Hoover (1979). They found that puberty in juvenile females exposed to urine from pregnant or lactating females occurred 4 to 5 days earlier in comparison to juvenile females exposed to water or urine from a nonpregnant adult female. Little has been done to follow up on this interesting finding except for recent studies of Drickamer (1984b,c) demonstrating circadian rhythm and timing effects of urine from lactating females. We do not know what endocrine variables present during pregnancy and lactation influence the production of the acceleratory signal and the identity of the signal remains unknown. The phenomenon deserves additional attention in view of the interesting implications of this effect on selective stimulation of a female’s own offspring or Drickamer and Hoover’s idea that pregnant and lactating females may signal other females in a population that prevailing conditions are favorable for reproduction. Why, in an evolutionary sense, females should show such altruism is discussed later. 111. INHIBITION OF PUBERTY A.

EFFECTSOF GROUPED FEMALES

Many biological functions operate as a result of opposing stimulatory and inhibitory control mechanisms. The neuromuscular system is a prime example. The regulation of puberty in several species seems to be under similar stimulatory and inhibitory control. We have described in previous pages how puberty is stimulated by pheromones from the male and from reproductively active females. Here we turn to the inhibitory side of the coin. As we will discuss later in this article, puberty inhibition may be more important than puberty acceleration under natural conditions. The potential importance of puberty inhibition prompted us to list the mammals in which this phenomenon is reported based on references brought to our attention by R. Levin (personal communication). Table I lists eight species of rodents and primates in which puberty suppression has been reported. In other mammals, particularly canids, there is also evidence of suppression of the subordinate females in a group but evidence of ovarian or endocrine suppression at the time of puberty is not yet available (McClintock, 1983). The most complete information on social suppression of puberty has been assembled by Drickamer and his associates working with the house mouse. The puberty-inhibition effect first came to light when it was found that grouped female mice exposed to a male attained puberty 7 to 10 days later on the average than females exposed singly to a male (Vandenbergh et al., 1972). This delay could only be due to the suppressive effects of interactions between the females.

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MAMMALSIN WHICH PUBERTY Species

TABLE I IS SUPPRESSED BY STIMULI FROM

Measure of puberty

FEMALES Reference

Mus musculus (house mouse)

First estrus delayed 5-7 days

Peromyscus leucopus (prairie deer mouse) Microtus californicus (California vole) M . ochrogaster (prairie vole) Nofomys alexis (hopping mouse) Meriones unguiculatus (Mongolian gerbil) Callithrix jaccus (common marmoset) Sanguinus fuscicollus (saddle-back tamarin)

Vaginal introitus delayed at 40 days Delayed pregnancy

Vandenbergh et a / . ( 1972); Cowley and Wise (1972); Mclntosh and Drickamer ( 1977) Lombardi and Whitsett ( 1980) Batzli et a / . (1977)

Delayed pregnancy and uterine weight decrease First estrus delayed 25 days

Batzli et al. (1977); Carter and Getz . ( 1984) Breed (1976)

Suppression of breeding in daughters Suppression of ovulation in subordinate females Suppression of ovulation in daughters

Payman and Swanson ( 1980) Abbott and Hearn (1978); Abbott (1984) Katz and Epple ( I 980)

Drickamer (1977) confirmed this by showing that soiled bedding taken from cages of grouped females inhibited puberty in juvenile females. Mclntosh and Drickamer (1977) then showed that voided urine from grouped females inhibits puberty but urine of isolated females was without effect. Interestingly, when urine was collected directly from the bladder of either grouped or isolated females and tested, urine collected from both sources induced puberty delay. This finding suggests that bladder urine contains a puberty-inhibiting pheromone in female mice regardless of social stimuli. Only when females are grouped is it possible for the puberty-inhibiting pheromone to be passed through the urethras. This further suggests that the urethra contains a gating mechanism for the pheromone. In a figurative sense, grouping opens the gate. A crucial experiment showing the involvement of the urethra was conducted by McIntosh and Drickamer (1977). They showed that urine from grouped females incubated with homogenized urethras from isolated females lost its ability to inhibit puberty. The puberty-inhibiting pheromone is potent at very low doses (Drickamer, 1984a). A daily dose of 0.001 ml urine from grouped females produced a significant delay of puberty when applied to the noses of juvenile females. A dose of O.OOO1 ml gave intermediate results and 0.00001 ml was without effect. Among other factors known to affect the potency of the puberty-inhibiting pheromone are the number of females in the group and the duration of residence in the group (Coppola and Vandenbergh, 1985). Grouping six females in a standard

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mouse cage for 2 weeks induced production of the inhibiting pheromone whereas 3 weeks was necessary to produce a similar effect for groups of two or four females. When removed from a group, females lost their ability to produce the pheromone within 10 days. The persistence of the puberty-inhibiting pheromone in the environment may be important for understanding its role in regulating wild populations. Coppola and Vandenbergh (1985) demonstrated that after 7 days on a glass plate urine from grouped females no longer retained its ability to inhibit puberty. This indicates the relative volatility or instability of the puberty-delaying pheromone in contrast to the stability of the puberty-accelerating pheromone (Vandenbergh et al., 1976). Similarly, the heritability of the traits responsible for producing or regulating the puberty-inhibiting pheromone is important for understanding its role under natural circumstances. This issue has not been explored. But, Drickamer (1981a) has shown that female mice can be selected for early or late puberty. Only three to four generations are required to produce a significant delay in puberty. Puberty in such slow-maturing females could be accelerated by male stimuli but not further inhibited by urine from grouped females (Drickamer, 1981b).

B.

CONTROLMECHANISMS

Although little is known about the juvenile responses to the puberty-inhibiting pheromone, some knowledge has been acquired about the mechanisms controlling its production. The endocrine changes involved in the production of the puberty-inhibiting pheromone or in the urethral gating mechanism have been investigated. Ovariectomy fails to interfere with the excretion of the puberty-inhibiting pheromone produced by grouped females (Drickamer et al., 1978). Yet the stage of the estrous cycle seems to have some effect on excretion of the pubertyinhibiting pheromone. Juvenile females exposed to urine collected only from the estrous females in a group attained estrus 4.5 days earlier than those exposed to urine from grouped females not in estrus, and at about the same time as untreated females (Drickamer, 1982~). Production of the puberty-inhibiting pheromone occurs when females are group housed or when singly housed females are exposed to the soiled bedding of grouped females (Drickamer, 1982~).Thus, chemical communication among the females in the group is responsible for the production of the pheromone. This chemical communication was shown to be interrupted by removal of the vomeronasal organ from grouped females (Lepri, Wysocki, and Vandenbergh, 1985). This experiment indicates that the vomeronasal organ is involved as a receptor for the production of the puberty-inhibiting pheromone in addition to its reception by juvenile females.

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AND PHYSIOLOGICAL RESPONSEMECHANISMS IV. SENSORY

Chemical stimuli such as the priming pheromones that modify female puberty are present in the air or in fluids that convey them to target recipients. Females must receive these signals to induce the endocrine changes that result in accelerated or delayed puberty. Evidence is accumulating that the vomeronasal organ is the primary receptor of the puberty-accelerating pheromone and may be involved in the production of the puberty-inhibiting pheromone. Kaneko et al. (1980) severed the vomeronasal nerves at the level of the olfactory bulb in juvenile female mice. One olfactory bulb was removed, thus destroying the adjacent vomeronasal nerves and allowing the vomeronasal nerves on the contralateral side to be viewed and severed. This procedure resulted in deafferentationof the vomeronasal organ while leaving one olfactory bulb intact. Such females could presumably smell males through their intact olfactory bulb but not detect them via the vomeronasal organ. Upon exposure to males such females failed to show uterine weight increase in comparison to control females. A more critical experiment by Lomas and Keverne (1982) further identified the vomeronasal organ as the site of reception of the puberty-accelerating pheromone. They cauterized the vomeronasal organs of juvenile females and found that such vomeronasalectomized females with their main olfactory bulbs intact were incapable of responding to soiled bedding material from adult males. Identification of the vomeronasal organ as the receptor of the puberty-accelerating pheromone produced by the male is but the first step in explaining the mechanism translating a chemical stimulus into its physiological effect. The most direct effect of pheromonal stimulation reported is that of Dluzen et al. (198 1). Working with female prairie voles (Microtus ochrogasrer), they showed that a 185% increase in luteinizing hormone-releasing hormone (LHRH) occurred in that portion of the olfactory bulb containing projections from the vomeronasal organs within 60 min after a single exposure to a drop of male vole urine. If we assume that the sharp increase in LHRH resulting from male chemical stimuli in voles is similar to what occurs in house mice, it would effectively explain the rise in blood levels of luteinizing hormone (LH) in female house mice 1 hr after exposure to a male as reported by Bronson and Desjardins (1974). Within 12 hr after male exposure, female estradiol levels are increased 100-fold and at 60 hr an LH surge occurs (Bronson and Desjardins, 1974). Uterine weight sharply increases to peak about 48 hr after male exposure as a consequence of these endocrine changes. While considerable progress has been made in understanding the reception of and physiological response to the puberty-accelerating pheromone, little is known about the puberty-inhibiting pheromone. Evidence implicating components of the complex chemosensory system of rodents is difficult to obtain

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because disruption of olfactory receptors or tracts results in disturbance of gonadal function through direct effects on other portions of the CNS or its neuroendocrine secretion (Meredith, 1983). The endocrine responses to female chemosignals that inhibit puberty also remain undiscovered although work in our laboratory is currently focused on this issue. The potential importance of puberty inhibition by pheromones to the regulation of natural populations of rodents as described later in this article heightens the need for information of the physiological response mechanisms involved. V.

PUBERTY REGULATION IN NATURAL POPULATIONS

A. PUBERTY MODULATION IN MICE Puberty modulation is frequently observed in natural (Southwick, 1958; Crowcroft and Rowe, 1957), seminatural (Lidicker, 1976), and laboratory populations (Christian, 1956; Christian et al., 1965) of house mice in response to high densities. Delayed puberty at high population densities has been cited as one of the factors dampening further population growth (Christian, 1978). This phenomenon, along with other deficits in reproductive output which are observed at high population densities, are considered part of a “general adaptive syndrome” (Selye, 1946). Puberty modulation has also been frequently observed in response to urinary pheromones in house mice. In contrast to the puberty delay observed at high population densities, almost all the information on pheromonal modulation of puberty has come from laboratory studies. Delayed puberty caused by urinary pheromones has also been implicated in the regulation of house mouse populations (Drickamer, 1981b,c). A few attempts (Bronson, 1979; Bronson and Coquelin, 1980; Drickamer, 1981c) have been made at articulating the potential causal relationships between primer pheromones, age at first reproduction, and demographics. However, little effort has been made to integrate the large body of theoretical literature on this subject into a cogent theoretical framework in which to study the causal relationships mentioned above. The remainder of this article is intended as a first attempt at this difficult but necessary task. If what follows does nothing more than incite more rigorous considerations of this topic then we will have achieved our primary purpose. B.

SPECULATIONS ON PHEROMONES

THE

ADAFTIVESIGNIFICANCE OF PUBERTY

Whenever robust and repeatable effects on the reproductive system of any animal are widely found in response to some ambient cue, speculations invari-

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ably come forth concerning the adaptive significance of these effects. The effects of the priming pheromones on puberty regulation are no exception. In this section we discuss the hypotheses put forward to date explaining the potential functional utility of the puberty pheromones in wild populations. Relevant empirical and theoretical results will be considered for each hypothesis. The emphasis here will be on puberty pheromones in the house mouse but inferences drawn from this discussion may apply to other aspects of the primer pheromone system of the mouse and to the growing number of other species in which primer pheromones have been found (Table I). Two provisos should be stated at the outset of this discussion. First, some of the hypotheses listed below could be invoked to explain the function of puberty acceleration and delay by pheromones in other species. However, we feel that such unifying schemes are unwarranted given our present lack of knowledge about how or even if primer pheromones work in nature. Moreover, the social contexts in which the primer pheromones of other species, particularly some microtine rodents (Getz et al., 1983), have their effect in the laboratory are different from those for the house mouse. Indeed, profound life-history differences exist among the species in which primer pheromones have been demonstrated. Given fundamental differences in reproductive biology, such as induced versus reflex ovulation, it seems unlikely that primer pheromones having similar proximate effects across different genera in the laboratory have the same causation in evolutionary terms. Second, the speculative nature of this discussion must be emphasized. With the exception of two studies to be discussed below, there is no evidence that primer pheromones have any influence on the reproduction of naturally occuring populations. A major goal of this article is to reaffirm the need for field studies designed to illuminate the role of pheromones in natural populations. Bronson’s (1979) comments are particularly appropriate in this regard: “Where one finds the most sophisticated behavioral and physiological information (pheromone biology) one also finds a total lack of hard data about its functional utility in wild populations.”

I . Puberty Acceleration There is little disagreement concerning the functional utility of the pubertyacceleratory chemosignal of the house mouse. Obvious advantages accrue to both the sender (male) and receiver (female) of a chemical signal which coordinates their reproductive efforts using chemical cues (Bronson, 1979; Vandenbergh, 1980). Male mice encountering dispersing young females could bring on their pubertal ovulations using pheromonal and tactile cues within 36-60 hr, thereby expediting the colonization of new habitats. The rapidity with which a “weed” species such as the house mouse can colonize unexploited habitats is of critical importance. This intuitively appealing hypothesis begs the question of

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why female mice do not come into reproductive condition as early as physiologically possible and remain that way throughout their short lives. The answer to this question must be presented in terms of the interaction between acceleration by the male and delay by females which serves to schedule attainment of reproductive competence of the female only after dispersal from the natal site. The interplay between male-originating and female-originating cues will be discussed below. There is no direct evidence that the puberty-acceleratory phenomenon demonstrated in the laboratory works in natural populations. Only one published report (Massey and Vandenbergh, 1980) exists that directly addresses the question of acceleratory pheromone production in the field. The results from this study will be discussed below in a separate section summarizing the efforts to study primer pheromones in the field. Indirect evidence for the utility of the acceleratory substances abounds in the large number of reports documenting the great colonizing ability of the house mouse (see Bronson, 1979, for review). Despite the lack of field data, it should be mentioned that acceleration of female puberty by male presence and or male chemosignals has been found in a diverse array of captive animals (Vandenbergh, 1983). Whatever selective advantage, if any, this mechanism imparts, it is a robust and widespread phenomenon that will undoubtedly be found in more species as studies in this area continue. 2 . Puberty Delay The functional utility of the puberty-delaying chemosignal is more obscure than that of puberty acceleration. It is difficult to explain why a so-called “rselected” animal such as the house mouse would ever benefit from delaying puberty and thereby presumably decrease its reproductive output. Only recently has puberty delay by social cueing received the attention that puberty acceleration has had since its discovery. Whatever the function of socially cued puberty delay, it has now been found in several species (Table I), albeit in response to a variety of different social contexts. The following hypotheses have been put forward implicitly or explicitly to explain “why” puberty delay in young female mice occurs in response to chemical cues from grouped females. The first hypothesis is that puberty delay is a laboratory artifact; a result of the close quarters or unnaturally high densities of the laboratory or a quirk of artificial selection. Though this hypothesis to our knowledge has never been stated explicitly to explain the existence of the delay of puberty by pheromones, parsimony requires that the simplest explanations be falsified before proffering more complicated ones. Moreover, Bronson (1979) has made a strong case against any adaptive significance for the Bruce and Lee-Boot effects, pointing out that the requisite social contexts are rare or absent in nature.

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The available evidence does not support the idea that puberty delay through pheromonal cueing is a laboratory artifact. Three lines of evidence call for an alternate view. First, the delayed puberty of females resulting from such a specific stimulus as a urinary cue argues for a signalling function that must have some adaptive value. If delayed puberty is an artifactual response to this cue then what is the proper response? The only other known response of female mice to grouped female urine is estrus suppression (Whitten, 1959). As Bronson (1979) and Bronson and Coquelin (1980) point out, it is far more difficult to conceptualize any adaptive function for the mutual suppression of adults than for delay of puberty in young females. Second, the social context in which puberty delay by pheromones is manifested in the laboratory is known to occur in the field. The social organization of wild mice has been described as consisting of deme territories with one dominant male and several adult females and their young (Anderson, 1970; Selander, 1970). Females born into these demes live in a pheromonal environment dominated by chemical cues from a male, that is most probably their father, and a group of females. Drickamer (l982a) has shown that grouped female urine has precedence over male urine in its action on prepubertal females. However, adult females are easily released from intrafemale suppression of estrus by the presence of a male or his odors. This difference in the interactive effects of the maleand female-emanating cues, depending on the age of the recipient, again argues for puberty delay as the evolved trait and mutual estrus suppression of adult females as the artifact because groups of females living together in the absence of a male would be a rare and ephemeral circumstance in nature. The last line of evidence opposing the notion that pheromonal delay of puberty is an artifact comes from field studies of house mouse populations. These studies, which will be discussed below, verify the production of delay pheromone in nature as a result of increasing female interaction rate. The second hypothesis proposes that the delay pheromone of the house mouse played an adaptive role as a mechanism for intrinsic population control (Drickamer, 1974, 1980). The rationale behind this hypothesis stems from the fact that in a polygynous species, such as the house mouse in which females presumably mate at sexual maturity, female age at puberty is tantamount to generation time. Since generation time influences a population’s intrinsic rate of increase, any factor that increases generation time slows population growth. Thus, delay of puberty in female mice due to a pheromone produced by females living at high densities, should curtail further population growth through its effect on the intrinsic rate of increase. Indirect evidence from a number of field and laboratory studies supports the intrinsic population control hypothesis. A suite of reproductive deficits has been described in studies on enclosed laboratory and seminatural populations of mice (reviewed by Christian and Davis, 1964). Most notable among these deficits is severe inhibition of reproductive maturation. Whether the pubertal inhibition

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observed in asymptotic populations has an olfactory basis has never been studied in the house mouse and studies done on Perornyscus are conflicting (Rogers and Beauchamp, 1976; Terman, 1968). In the laboratory, the graded production or release of the delay pheromone in response to increasing the number of females housed together (Drickamer, 1982c; Coppola and Vandenbergh, 1985) reveals the sensitivity of this phenomenon to density (also see Section V,C). Any mechanism that evolved to dampen population growth, thereby preventing a population from overshooting its carrying capacity, would be expected to track density. The delay-pheromone production or release appears to do this. In the laboratory and field work done to date the causal relationships between pheromones, puberty delay, and population changes have not been addressed. The need for such studies is obvious. The population control hypothesis, however, suffers from a fundamental theoretical weakness: its reliance on the theory of group selection. If puberty is delayed in wild females in response to a pheromone that is produced in increasing amounts as female densities increases, then the effect of this delay will be a diminution of the intrinsic rate of increase: a dampening of population growth. Thus, population dampening could be an effect of puberty delay by pheromones in mice but evolutionary causation is not so easily invoked. Pubertal delay for the purpose of population regulation can hardly be explained on the basis of individual selection, if this physiological response benefits the population at the price of the individual. Such a hypothesis requires the theory of group selection put forward by Wynne-Edwards ( 1962). While the rise and fall of the theory of group selection is an interesting and important chapter in evolutionary ecology it is beyond the scope of this discussion. Most ecologists now agree that reliance on the operation of group selection is more indicative of a theory’s frailty than its vitality, particularly if plausable alternate theories can be advanced to explain the same phenomena in the framework of individual selection (Williams, 1966). Whether more recent group- or kin-selection models (Wilson, 1980) can salvage the population control hypothesis remains to be seen. More information on the characteristics of mouse populations will be required to decide whether they meet the restrictive requirements of these models. Finally, some of the empirical evidence from natural or seminatural populations fails to demonstrate population regulation below environmental carrying capacities. Newsome and Crowcroft ( 1971) provided particularly compelling evidence against the notion that mice control their own numbers below or near the carrying capacity of their environment. In a study done on house mice living in stacked wheat they captured over 500 individuals from one stack in a few hours. Several sick and severely underweight mice were caught leaving the stack every hour. The fact that these animals could be restored to health by feeding points to chronic starvation as the cause of their poor conditions. The third hypothesis concerning the functional role of pheromonal delay of

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puberty was proposed by Bronson (1979). He envisions the delay-pheromone phenomenon as a mechanism affording prepubertal females protection against pregnancy before dispersal. It seems reasonable that dispersing female mice should breed as soon as possible after establishing a suitable home. Though puberty in females can be induced by a male as early as 27 days of age even if he is the female’s father (Bronson and Macmillan, 1979), the antagonism of the male’s acceleratory action by pheromones from female litter mates could delay reproduction until the young females have time to disperse. Upon finding a home in a male territory, tactile and urinary cues from the male can cause the young female to ovulate within 36-60 hr (Bronson, 1983). Bronson’s logical hypothesis has a number of underlying assumptions that must also be considered if we are to properly evaluate its feasibility. The most obvious assumption of this hypothesis is that pregnancy before dispersal has a significant penalty associated with it. An obvious cost of reproduction before dispersal could result from insemination of a young female by her father, which presumably produces inferior young due to inbreeding depression. The effects of inbreeding depression in the house mouse are known from controlled genetic studies of this phenomenon (i.e., Bowman and Falconer, 1960); however, inbreeding has several advantages (see Moore and Ali, 1984). The extent to which wild mice inbreed is unknown. Pregnancy may also prevent or limit dispersal. The promotion of outcrossing is not the only potential advantage of dispersal. The avoidance of competition for environmental resources with parents and siblings may also drive dispersal. Indeed, the majority of polygynous mammals that have been studied do not meet the predictions of a dispersal model driven by the benefits of outcrossing (Dobson, 1982; Moore and Ali, 1984). House mice may be an exceptional case among polygynous mammals given at least one report of predominant female dispersal (Myers, 1974); however, typical male-dominated dispersal has been reported in other studies (Lidicker, 1976; Rowe et af., 1963). Bronson ( 1979) has suggested that perhaps nonpregnant females can travel greater distances than pregnant females. This may confer an advantage to females that disperse before pregnancy. Only meager and equivocal evidence exists on the reproductive condition of dispersing house mice (Myers, 1974; Lidicker, 1976; Newsome, 1969). Moreover, almost no information exists on the fate of dispersers versus nondispersers in natural populations (Gaines and McClenaghan, 1980), much less the influence of reproductive state on dispersal success. A proper evaluation of Bronson’s assumption regarding the penalty of pregnancy before dispersal in the house mouse or any other small mammal awaits more data on the reproductive condition of female dispersers in general and the interaction between reproductive conditions and dispersal costs. Another assumption of Bronson’s hypothesis is that the puberty-delay pheromone is an intersibling signal produced in the context of a family group to

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promote mutual dispersal of females before reproductive maturity. Several laboratory studies address this assumption. Drickamer has found that urine from groups of females will delay the puberty of young females irrespective of the donor’s age or relatedness to the urine recipients in both wild and domestic strains of house mice (1982c, 1984d). Whether the age and genetic relatedness of grouped females alters the ability of their urine to override the acceleratory effect of males remains to be seen. In light of the house mouse’s ability to discriminate between the odors of individuals that differ only slightly in genetic relatedness (Yamazaki et al., 1979; Yamaguchi et al., 1981) it is hardly parsimonious to view the puberty-delay pheromone as a signal between siblings. It would seem more efficient to base any mechanisms designed to prevent pregnancy before dispersal on the presence of sibling or paternal odors. The fact that genetic relatedness does not influence pheromonal potency calls for a broader interpretation of this chemosignal’s function. Despite the apparent problems with some of the assumptions of Bronson’s hypothesis, it is an attractive idea that deserves further attention. However, it does not account for all of the empirical evidence on puberty delay by pheromones in the house mouse. One of the most striking deficits of this hypothesis is that it fails to account for the apparent density dependence of the puberty-delay pheromone. Urine from individually housed mice is not significantly different from water in its ability to delay puberty. However, the ability of equal amounts of urine from females living in groups to delay puberty in test females is directly related to group size (Drickamer, 1982c; Coppola and Vandenbergh, 1985). It is difficult to weave this finding into Bronson’s hypothesis. One of the few generalities that has emerged from studies on species for which adequate demographic data exist is that dispersal is density independent (Gaines and McClenaghan, 1980). If dispersal is density independent in the house mouse, then why should a pheromone designed to prevent pregnancy before dispersal be density dependent? In posing this question we should warn that density dependence in the laboratory is not necessarily analogous to density dependence in the field. For this reason we felt that it was important to examine the possible density dependence of the delay pheromone in natural populations (see Section V,C). If the delay pheromone functions as an inbreeding avoidance mechanism, then its release should be independent of density. The last hypothesis we will discuss holds that when reproduction has little or no chance of success due to limited food or low social position, delaying reproduction may be prudent. Postponing reproduction until times are better may be advantageous in the long run. This hypothesis, to our knowledge, has never been offered to explain the functioning of the delay pheromone in house mice. However, it is often invoked whenever reproductive curtailment is observed in response to increasing densities (Ricklefs, 1979, p. 579). At least two considera-

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tions detract from this explanation of puberty delay in response to pheromones in the house mouse. First, the delay occurs in response to a “chemical signal” produced by other individuals that need not be genetically related to the signal recipient (see above). It is difficult to envision the advantage to the signal sender of advertising to potentially unrelated females that conditions are unpropitious for reproduction. Of course, the so-called urinary pheromone involved in puberty delay may not be a specific compound that has evolved as a signal imparting “semantic” information (see Krebs and Dawkins, 1984) to would-be recipients. For instance, individual selection may have favored females that can detect the urinary metabolites of glucocorticoids that are secreted in response to social stress. This immutable response has been observed in a wide array of animals and is part of the “general adaptive syndrome” that presumably did not evolve as a pheromone production mechanism. Prepubertal females could benefit from information about the social environment contained in the urine of conspecifics by delaying puberty until conditions were better or until they could disperse to new habitats. It is of interest in this vein that the adrenals are necessary for the production or release of the delay pheromone and that glucocorticoid treatment of adrenalectomized females living in groups will restore the ability of their urine to delay puberty (Drickamer and Shiro, 1984f). Another problem with conceptualizing puberty delay in the house mouse as a mechanism to postpone reproduction until the environment improves is the short life span of mice in the wild. Survival estimates for mice in wild populations are consistently less than 1 month (Massey, 1980; Myers, 1974). A species that suffers such high mortality rates can ill afford the luxury of postponing reproduction. Moreover, the length of time puberty is delayed in the laboratory is typically between 5 to 10 days. It seems unlikely that the environment could rebound from resource depletion in such a short period.

C. HIGHWAYISLAND POPULATIONS Two experiments designed to determine the role of the puberty pheromones in nature have been conducted on mouse populations enclosed by highway cloverleaf sections. These habitats, termed “highway islands” (Massey and Vandenbergh, 1980), are excellent sites for the study of small mammal populations because of their relatively small size (0.3-0.7 ha) and virtual insularity. Several studies (Swihart and Slade, 1984; Wilkins, 1982; Kozel and Fleharty, 1979; Adams anc Geis, 1983) have demonstrated that roads are a strong barrier to rodent dispersal. In the studies that have included them, house mice were found to rarely cross even narrow unpaved roads (Kozel and Fleharty, 1979; Adams and Geis, 1982). In the initial study of highway island populations (Massey and Vandenbergh, 1980) very little emigration from or immigration onto the islands was observed. Over a 2-year period 6658 trap nights (available traps X nights

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N

'lo<

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FIG. 2. Schnabel population estimates and their 95% confidence limits for two populations of house mice confined to highway cloverleaf sections (redrawn from Massey and Vandenbergh, 1980).

open) were devoted to capturing mice on the islands and 5877 trap nights were devoted to trapping habitat adjacent to the islands. Only 1.5% of over 200 mice caught and marked migrated across the highway separating the islands from adjacent habitat (Massey and Vandenbergh, 1980). This figure represents one of the lowest migration rates ever observed for natural populations of the house mouse. In this initial 2-year study, two island populations were studied by semimonthly mark-recapture methods. The results of the Schnabel(l938) population estimates on each island for the first year of the study are shown in Fig. 2. Urine from resident mice was routinely collected from each population and brought back to the laboratory for bioassay. Preliminary studies demonstrated that urine from wild male and female mice kept in the laboratory had the same pheromonal effect on laboratory females as urine from laboratory males and females. Moreover, Drickamer (1979) has shown that laboratory-raised wild females respond to the puberty pheromones in the same way that laboratory females do. For these

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reasons the use of laboratory females in the bioassays or urine samples from the island populations seemed justified. Urine from wild male mice residing on the islands accelerated puberty in laboratory females irrespective of the season or population density at the time of collection (Massey and Vandenbergh, 1981). The degree of acceleration was consistent across time. Puberty was advanced an average of 7 days in test females as measured by age at first estrus. Urine from wild females collected on the islands in the spring (see Fig. 2) when the population densities on both islands were relatively low had no effect on the age of first vaginal estrus in test females. Only female urine taken in December from population 2 at its peak density delayed first estrus in test females. Female urine collected at the same time from population 1 had no effect on age at first estrus (Massey and Vandenbergh, 1980). Despite the fact that both populations were at their peak in December, the density estimate for population was over four times that of population 1. This observation provided the first evidence that wild female mice living under natural conditions produce a urinary component that delays pubertal onset in juvenile females coincident with density increases. However, the conclusions drawn from the initial highway island study were mitigated somewhat by the lack of replication and the differences in plant composition (Massey, 1982) between the two islands studied. For these reasons seasonal changes in vegetation could not be eliminated as a possible cause for the change in female urine. The next study utilized highway island populations to provide a test of the causal relationship between population density and delay pheromone release. The design was constrained by our ability to work with only four island populations at one time due to the large amount of labor involved in mark-recapture studies. The small number of islands available to us, along with the great floral diversity between islands, required the use of repeated measures. Two adjacent islands at each of two locations were studied by monthly mark-recapture trapping over a 6-month period. Acute population explosions were created on these islands by the introduction of 40 second- or third-generation female wild house mice that had been raised in the laboratory. Animals were introduced onto one island at each location three times during the study. A different island at each location received the interlopers for each introduction. This allowed us to compare treated and untreated islands at the same point in time and also to examine an individual island across time. Urine samples from resident females were collected for each island at monthly intervals during the 6- to 8-day trapping sessions. Three weeks separated the introduction of foreign females and the collections of urine samples from each island. This schedule was chosen because Drickamer (1983) has shown that laboratory females do not release the delay pheromone until after the tenth day of grouping. Moreover, recent studies in our laboratory (Coppola and Vanden-

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6

Before treatment

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T

3 weeks

after treatment

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after treatment

FIG. 3. Mean delay of first vaginal estrus (5 I SEM) in days compared to the control for female mice treated with urine from wild females living on highway cloverleaf sections. The SEMs represent the variation between cloverleaf sections treated alike. Urine collected before the artificial population explosion did not cause a significant delay in puberty compared to controls. However, urine collected 3 or 7 weeks after the explosion did cause a significant delay. The delays produced by urine collected 3 or 7 weeks after the explosion were not significantly different.

bergh, 1985) have shown that increasing the number of females per group will not shorten the length of time necessary for the initiation of pheromone release. The ability of the urine samples from the highway islands to delay puberty was assessed, as in the first field study, by our standard laboratory bioassay. The results of these assays are shown in Fig. 3 (Coppola and Vandenbergh, in preparation). Urine samples collected from the treated islands during the first trapping session after the introduction of foreign females caused an average delay of 5.3 days. Foreign females that were captured during this trapping session were selectively removed from the islands. This was done to bring the population density back down to the preintroduction levels. Urine samples collected from the islands at the next trapping session after the selected removal of foreign females also significantly delayed the puberty of test females albeit to a lesser extent than samples taken 3 weeks after the introductions. The average delay in

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first estrus was 2.7 days for this group of females. These samples were collected 7 weeks after the introduction of foreign females onto an island and 3 weeks after the selected removal. In contrast to the urine samples taken from the islands after introductions, the urine from wild female mice residing on untreated islands did not cause a significant increase in the age at first estrus of test females (Fig. 3). Density estimates for these untreated islands were low (Coppola and Vandenbergh, 1985). The association between low population density and lack of delay pheromone in the urine of wild female mice is consistent with the earlier study (Massey and Vandenbergh, 1980). The second study provides the first experimental evidence that the pubertydelaying pheromone of female mice is produced in response to acute increases in female density in nature. Moreover, rapid induction of pheromone release after artificial population increases and the decline in pheromonal potency after the populations were stabilized reveal the dynamic nature of this phenomenon. These results support an ecological interpretation of the puberty-delaying pheromone’s function and undermine this phenomenon’s designation as a laboratory artifact. We have also examined the fate of introduced females (Coppola and Vandenbergh, in preparation). Not surprisingly, these animals suffer a high mortality rate and only a small percentage become permanent residents of the islands. Future studies of the highway island populations should further clarify the role of the puberty pheromones in the biology of the house mouse. This experimental system will allow us to choose between alternative hypotheses of pheromonal influences on population dynamics, given the appropriate manipulations of demographic parameters on the islands. It is critical to our investigation that hypotheses concerning the puberty pheromones are based not only on empirical evidence obtained from laboratory experiments using domestic strains but also on theoretical results pertaining to the age of first reproduction and how it interacts with other life-history characters. In the next section we give a brief review of the theoretical literature on age at first reproduction and from it propose a new theoretical framework in which to study the puberty pheromones.

IN TERMS VI. AGEAT FIRSTREPRODUCTION OF LIFE-HISTORY THEORY

The importance of age at first reproduction as a life-history trait has been recognized by life-history theoreticians since the inception of this area of investigation. In his seminal paper on life-history phenomena, Cole (1954) emphasized the influence of age at first reproduction on the population growth rate r, also known as the Malthusian parameter. The growth rate r is the most common measure of fitness used in life-history studies (see Charlesworth, 1980). Lewon-

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tin (1965) used a simple simulation model to examine the sensitivity of the population growth rate to three life-history parameters: age at first reproduction, the age at which reproductive value starts to decline, and the age at last reproduction. He found that r was most sensitive to decreases in the age of first reproduction and relatively insensitive to equivalent decreases in the other two parameters. A decrease from 12 to 9.8 days in the age of first reproduction in his model system was equivalent to doubling the total progeny produced. Though the value of the population models used by Lewontin and Cole has been questioned because they do not incorporate reproductive costs (Bell, 1980), their conclusions concerning the importance of age at first reproduction to population dynamics have not been overturned. The analysis of a single trait such as age at first reproduction must recognize trade-offs that exist among the collage of traits that constitute a species’ life history. The mean and variance in age at first reproduction, litter size, size of young, number of lifetime litters, and interlitter interval represent the most important life-history traits. A life-history tactic consists of a given combination of these traits which has evolved in response to patterns of environmental variation. The time scale of environmental change governs whether the adaptive response in life history will be behavioral, physiological, developmental, or genetic (Horn and Rubenstein, 1984). Life-history traits have intricate developmental interactions which are a result of genetic segregation. Life-history tactics in general do not evolve as unitary characters nor do their component traits evolve autonomously (Rose, 1983). It appears that age at maturity is a trait that controls several important developmental pathways determining an organism’s size and shape (Gould, 1977; Alberch et af., 1979). This means that changes in age at sexual maturity will cause correlative changes in other important traits due to developmental interdependence. Unfortunately, very little is known about the coadaptation of age at first reproduction, litter size, longevity, and other lifehistory characters in mammals. Except for very broad comparisons, compelling data on age at maturity in mammals in the wild are unavailable. Therefore, the theoretical results that we are about to discuss have not yet been rigorously tested in an empirical way. A “general and reliable” theory of life-history evolution does not yet exist (see Steams, 1980, for discussion). The following hypotheses concerning the determinants of age at first reproduction are, by and large, the results of optimization arguments which ignore ontogeny and genetics. Theoreticians have tried to determine the age at maturity that will optimize some fitness measure such as r under different ecological conditions. In most cases the predictions have been more qualitative than quantitative. This methodology has been criticized because of its emphasis on the population instead of on the individual. A thorough discussion of this and other criticisms of current life-history theory is beyond the scope of this article (see Steams, 1976, 1980, for discussion); however, it seems prudent to view the results that follow with the same skepticism as any untested theory.

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ECOLOGICAL DETERMINANTS OF AGE AT FIRSTREPRODUCTION

The evolution of age at first reproduction and other life-history traits are influenced by temporal and spatial patterns of variation in important environmental variables such as temperature, food, breeding sites, and predators. Multiple evolutionary causes, possibly acting at the same time, can have the same influence on life history. In this section we will discuss the factors that favor early reproduction and those that favor late reproduction. We will also consider the conditions where we could expect an optimum age at first reproduction. 1 . Early Reproduction Natural selection should favor early and total investment by an individual in the maximum number of young that can possibly be produced whenever the environment provides abundant opportunities. In a rapidly growing population, age at first reproduction, a, will be driven to the physiological minimum by natural selection (Cole, 1954; Lewontin, 1965). Cole (1954) found that population growth rate r has much greater sensitivity to changes in a when birth rate is high. Therefore, a and birth rate should be under strong selection pressure in rapidly growing populations. Lewontin (1965) predicted that colonizing species such as the house mouse should show little genetic variance in a due to the selection pressure associated with repeated episodes of colonization. Meats (1971) showed that Lewontin’s results concerning the sensitivity of r to changes in a are not applicable at low values of r. Besides the need for a growing population, Cole (1954) showed that with other factors held constant the advantage of earlier a is greater for species with large versus small litter sizes and greater for species which reproduce once and die (semelparous) versus animals that reproduce repeatedly (iteroparous). Species which possess a combination of low a , many young, and semelparity have been termed r selected (MacArthur and Wilson, 1967) because this combination of traits is selected in environments favoring rapid population growth. Deterministic models, such as the ones mentioned above, seek to explain why r-selected traits should be found together. Stochastic models have also been created that offer different reasons for predicting the evolution of the same combinations of life-history traits. According to these models, earlier maturity should be favored in a fluctuating environment when adult mortality is variable and juvenile mortality or birth rate is not. Moreover, a short life span and many young should be selected along with small a as they were in the r-selection case (see Stearns, 1976, 1977, for discussion of these models). Adult mortality may fluctuate to a greater extent than juvenile mortality in a population which undergoes a series of colonizing episodes (Hirshfield and Tinkle, 1975). To further define the causal mechanisms underlying a trend of early age at first

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reproduction, we must define two important concepts-reproductive cost and reproductive value. Reproductive cost is the deleterious effect of present reproduction on future survival and/or fecundity. Reproductive value, a concept developed by Fisher (1930), is the average number of offspring a female of a given age can expect to have over the rest of her life, discounted back to the present. Earlier reproduction will be favored as reproductive cost, in terms of adult mortality, decreases (Schaffer, 1972; Schaffer and Elson, 1975). It will also be favored when the reproductive value an animal can accrue by not reproducing declines with age (Gadgil and Bossert, 1970). 2 . Delayed Reproduction Organisms might delay reproduction if the delay allows them to gain fecundity or produce better “quality” offspring. Many of the demographic or environmental factors that favor delayed reproduction are simply the opposite of those factors favoring early reproduction. Delayed reproduction would be selected for in a stable population at its carrying capacity (Cole, 1954; Lewontin, 1965) or in a declining population (Hamilton, 1966; Mertz, 1971). Selection in saturated environments which favors the ability to compete and avoid predators has been termed K selection (MacArthur and Wilson, 1967). Its correlated traits include later maturity, fewer large offspring, and longer life. Stochastic models predict that the suite of traits correlated with K selection, including delayed maturity, will be favored in fluctuating environments when juvenile mortality or birth rate fluctuates and adult mortality is stable (Steam, 1976, 1977). In a stable population where resources are limiting and competition high, variation in juvenile survival may be great, whereas adult survival is stable (Hirshfield and Tinkle, 1975).

The causal mechanisms which underlie a trend toward delayed reproduction are the opposite of those for a trend toward earlier reproduction. As reproductive cost increases in terms of adult mortality and as the reproductive value an organism can accrue by not reproducing increases with age, delayed reproduction will be favored (Gadgil and Bossert, 1970; Schaffer and Elson, 1975). Moreover, if reproductive success is contingent upon age, size, or social status, delayed reproduction is also favored (Geist, 1971). 3. Optimizing Age at First Reproduction

Bell (1980) analyzed the necessary and sufficient conditions for the existence of an optimum a in population models with different reproductive costs. Optimum a is the age at first reproduction such that another a results in lower fitness. Its existence is dependent upon certain reproductive costs. Bell defined actual fecundity cost, when fecundity increases with age and reproduction increases mortality, as the cost in fitness due to failing to realize greater future fecundity by present reproduction. He defined potential fecundity cost as the

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decrease in fecundity due to previous reproduction in a female age ( x ) compared to a female of the same age that had never reproduced. Bell showed that for an optimum a to exist it was necessary but not sufficient that present reproduction should cause a decrease in potential fecundity. Sufficient conditions exist if potential fecundity costs decline with age relative to the actual fecundity cost. His models assume that the population is stationary and that the annual rate of increase in actual fecundity is constant. If the first assumption is relaxed, optimal a will be smaller in growing populations and larger in decreasing populations (see Bell, 1980, for discussion of relaxation of second assumption). OF PUBERTY PHEROMONE FUNCTION B. A NEW HYPOTHESIS

Many organisms do not reproduce as soon as they are physiologically able to do so. However, few species delay reproduction into old age. The ecological factors that govern the timing of reproductive competency between the extremes mentioned above are of great interest to life-history ecologists. Unfortunately, the current state of life-history theory only allows us to draw vague and imprecise conclusions about the timing of reproductive maturity. Moreover, more than one evolutionary cause could be operating at the same time on age at first reproduction. Nevertheless, the theoretical results discussed in the previous section are relevant to hypotheses regarding the pheromonal control of puberty in the house mouse.

I , Alternative Maturation Rates Life-history theory has provided a basis for predictions with regard to age at first reproduction under different ecological conditions. Since the optimal a varies with the environmental conditions, organisms should be expected to develop at the maturational rate most appropriate for their environmental conditions. Biotic and abiotic cues are known to be involved in determining the proper rate of development. Egg diapause in some insects, which is often controlled by the mother during oogenesis (Smith-Gill, 1983), is a mechanism that suspends maturation when environmental conditions are harsh. This is an example where abiotic cues received by the mother cause her to influence the maturation of her young in an on-off manner. One example of biotic cueing which is particularly relevant to this discussion is the induction of diapause or metamorphosis in ant larvae by a pheromone from the queen (Brian, 1965). Another pertinent example is the synchronization of sexual maturation in some colonial insects through either acceleration or retardation of an individual’s development by fellow colony members (Butler, 1967). Kin selection explains the evolution of the cueing systems in these eusocial insects, but does not suffice to explain all examples of environmental cueing. Many more examples of environmental cueing of alternative developmental schedules are known and the advantages of these mechanisms are obvious (see Smith-Gill, 1983).

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There are problems with a schedule of sexual maturity keyed to age alone or size alone. An organism whose maturity is triggered by the attainment of a fixed size suffers a protracted delay in reproduction when the conditions are inhospitable and faces a risk of mortality proportional to the length of the delay. An organism whose maturity is triggered at a fixed age will be very small at the time of maturity when conditions are bad, and will have decreased fecundity if fecundity increases with age (see Steams, 1983, for discussion). The more predictable the changes in the environment, the greater the advantage of using environmental cues to time maturation (Smith-Gill, 1983). The activities of conspecifics are an important component of an animal’s environment. We should expect systems to have evolved whereby cues concerning the social milieu are used to modulate age at first reproduction and other life-history traits whose optimum may depend on the social environment. The insect pheromones mentioned above are examples of this kind of modulation. These mechanisms should be particularly advantageous when the social environment is highly unstable. 2.

Natural History of House Mice

House mice are known to exist in two distinct habitat types that profoundly affect the natural history of this species. One type of mouse population exists in and around human-made structures and lives commensally from stored grains and other food-stuffs humans unwillingly provide. This commensal type of population, which occurs commonly throughout the temperate and tropical zones, is characterized by a temporally stable and abundant food supply and a high population density of up to 10 mice/m2 in some cases (Bronson, 1979). The social organization in these populations is territorial with some hierarchial organization (Young et al., 1950). The other type of mouse population lives independent of human activities in various grassland habitats. This feral type of population is often characterized by temporal instability in food resources and can occur at densities as low as 1 mouse/ha (Justice, 1962; Meyers, 1974). The social organization of these feral populations is probably unstable and nonterritorial (Bronson, 1979). Intermale aggression and predominant juvenile dispersal seem to be characteristics of both types of mouse populations. It is important to note that the two types of mouse populations interact. Dispersers from commensal populations undoubtedly live in a feral setting at times, and feral mice, which appear to be quite nomadic, probably become commensal given the opportunity. It is difficult to conceive of a single mammal, save ourselves, that enjoys a wider diversity of habitats than the house mouse. Its plasticity and colonizing ability are legendary (see Bronson, 1979). It is instructive to consider what facets of house mouse biology afford this species so much ecological plasticity as evidenced by its near-global spread from its origins in Asia. Bronson (1979) has made a strong case for the importance of the pheromonal cueing system of house mice in aiding colonization through the synchronization of male and female

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reproductive effort and protection of females prior to dispersal (see discussion above). While we agree that priming pheromones play a key role in the house mouse’s colonizing ability, we view their function in terms of life-history considerations that might better explain the mouse’s ecological plasticity. 3. Pheromonal Triggering of Alternative Life-History Strategies

Life-history theory predicts that in growing populations with large population fluctuations or repeated colonization episodes, early maturity will be favored. The factors that favor early reproduction are the same factors that characterize feral house mouse populations. Moreover, in the absence of high interaction rates between females, such as in a newly founded population, the male acceleratory pheromone would stimulate females to mature early. Delayed maturity is favored in stable environments when the population is near equilibrium, and the social system is hierarchical. These factors characterize commensal populations of house mice. In this setting, female interaction rate will be high and the puberty delay pheromone will override the effect of the male and delay the puberty of young females. The fact that the puberty pheromones seem to affect age at maturity so as to increase fitness in different environmental circumstances leads us to view them as part of a mechanism affording the house mouse tremendous latitude with respect to its niche. There is little doubt that the recipient of the information contained in a chemical signal can benefit from this information by altering its behavior, sexual development, or reproductive investment according to current conditions. However, what advantage does the sender of the signal gain by this action? As we pointed out above in our discussion of the puberty-delaying pheromone, the signal may not have evolved as such at all. The urinary cues that make up the delay signal, in particular, may be metabolic by-products of the pituitary-adrenal response to social and environmental stress embodied in the general adaptive syndrome (Selye, 1946). Young mice could exploit this physiological mechanism by detecting these urinary by-products, thereby gaining information about the environment that could be used in timing reproductive competence and influencing other life-history characters. Much of our knowledge regarding the puberty pheromones supports our view that these cues influence the sexual maturation rate in order to increase fitness under different environmental circumstances, and that the delay “pheromone” may not be beneficial to the sender. Both the acceleratory and the delay signals are active in very small amounts (Drickamer, 1984a). The high sensitivity of females to the signal and the excess of the signal in the urine (Drickamer, 1984a) argue for its positive effect on the fitness of the recipients and also provide evidence that it is probably not produced solely as a chemosignal for the mutual benefit of sender and receiver. If this were the case, selection should favor smaller amounts of signal in the sender’s urine along with heightened sensitivity

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by the recipients, thereby reducing the cost of signal production (see Krebs and Dawkins, 1984). Of course, the excess pheromone in urine may afford the signal a more long-lasting effect once it is excreted. Drickamer and Hoover’s ( 1979) observation that urine from pregnant and lactating females accelerates puberty in young female mice fits into our scheme. The chemosignal from pregnant and lactating females would reveal to young female conspecifics that the environment is conducive to reproduction, an idea suggested by Drickamer and Hoover. No altruism in the production of this signal need be invoked if young conspecifics simply detect through olfaction the metabolic by-products of the normal physiological changes associated with pregnancy and lactation. The same argument would apply to the finding that estrous female urine accelerates young females (Drickamer, 1982~). In our laboratory, the puberty pheromones have an influence on the variance in age at sexual maturity as measured by vaginal cornification as well as on the mean age of puberty (unpublished data). In general, the male acceleratory substances decrease the variance in age at maturity in groups of females compared to water controls, and the delay pheromone increases the variance. Though research on the puberty pheromones has concentrated exclusively on their effects on the mean age at puberty, their effects on the variance in age at puberty in groups of females may be a critical factor in understanding the function of these pheromones. Life-history theory provides a framework in which to view the variance in onset of sexual maturity occasioned by the puberty pheromones. Under certain environmental circumstances, female mice might benefit from a “bet-hedging’’ strategy which would involve increasing the variance in age at puberty in their female offspring. Since there is a significant amount of interfemale variation in the effect of the puberty pheromones, it would be interesting in the context of this line of reasoning to know the contribution of maternal and genetic effect to this variation. Life-history theory is general enough to explain the possible function of the pheromonal influences on variance in age at puberty whereas the competing hypotheses enumerated above may be too restrictive to do so. Further evidence corroborating our view of puberty pheromone function was recently provided by Drickamer (1985). He showed that singly housed female mice produced the delay pheromone when placed on restricted diets. This work reveals a link between social and environmental circumstances that are unpropitious for breeding and pheromonal release by females. Life-history theory provides that delayed puberty is favored at high densities and during periods of low nutrient availability. The release of the delay pheromone in response to limited food does not appear to be consistent with Bronson’s (1979) dispersal hypothesis discussed above. We are not proposing that pheromones are the only or even most important cues that are used to schedule reproductive maturity in young female mice. Recent evidence from long-term studies of puberty modulation by pheromones in

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the controlled conditions of the laboratory demonstrated a marked circannual rhythm in the effectiveness of urine stimuli from male and female mice (Drickamer, 1984e). Young females from this study apparently were refractory to male stimuli from October through February and grouped female stimuli from May through August. Undoubtedly pheromones interact with other biotic and abiotic cues to aid in the proper timing of sexual maturation and possibly other life-history events. Our hypothesis does not explain all of the facts nor incorporate all of the theory relevant to age at first reproduction in the house mouse and further refinements are necessary. For instance, the recent finding (Lepri et af., 1985) that the vomeronasal organ may be necessary for the production of the delay signal argues for the evolution of the delay pheromone as a signal rather than a physiological response to nonspecific stressors.

VII. CONCLUSIONS In this article we have tried to bring together the empirical and theoretical information on the pheromones which accelerate and delay puberty in the house mouse. The difficulty of this task and a desire for brevity contrive to guarantee omissions in this work. If the list of physiological and empirical results discussed here is not exhaustive, we hope that the most important findings have been included. Life-history theory, its shortcomings notwithstanding, provides a rich backdrop against which to study the function of primer pheromones in house mice and for understanding primer pheromone function in general. It is now well established that chemical cues from conspecifics alter the timetable for puberty in the young of many species. This cueing system, at least regarding the delay of puberty, seems to serve the signal recipients while the signal senders are little affected. Unwitting release of metabolic correlates of physiological state rather than altruism may explain the presence of the delay pheromone. The benefits gained by the recipients of the puberty pheromones are most easily understood in terms of their life history. Life history provides predictions of the environmental circumstances, social or otherwise, favoring early or delayed maturity. The puberty pheromones appear to act as cues to the social environment that determine the maturational rate most appropriate for the conditions under which they are released. If our speculations are valid, then we should look for alterations in other lifehistory traits such as litter size and size of young in response to primer pheromones since the optima for these traits also depend on the environmental milieu. Another area that is in need of work, not only with respect to the puberty pheromones but also with respect to primer pheromones in general, is behavior

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related to pheromonal communication. We should know, for instance, whether a young female will investigate or avoid urine marks that will influence her puberty and if her choice is influenced by the social milieu or other factors in the environment. In the field, new techniques must be developed to study secretive species such as the house mouse. More information about demography, social structure, and dispersal of feral and commensal mice will be required to evaluate adequately the hypotheses discussed in this article. Life-history adaptations and behavioral adaptations undoubtedly interact to promote fitness despite the vagaries of the environment. Discovering the role of priming pheromones in this interactive process will require the melding of empirical and theoretical points of view. Acknowledgments We thank J. R. Walters, A. Massey, J. Cherry, and J. Lepri for their helpful comments on the manuscript. This work was supported by PHS Grant MH 30577 and NSF Grant BSR 8214558 to J.G.V. and appears as paper 9739 of the Journal Series of the North Carolina Agricultural Research Service, Raleigh, N.C. 27695.

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