Hormones and Development

CHAPTER 14

Hormones and Development Rachel Stark and Robbin Gibb University of Lethbridge, Lethbridge, AB, Canada

14.1 INTRODUCTION With the advances in science and technology made in the 20th century, it is remarkable that it was not until 1959 that a group of researchers began the pioneering studies in the field of sexual development. Phoenix and colleagues injected pregnant guinea pigs with testosterone and noted that while the male offspring seemed unaffected, the prenatal exposure of testosterone created females that were phenotypically male in characteristic but genetically female (Phoenix, Goy, Gerall, & Young, 1959). Thus, they published what is known today as the organizational/activational hypothesis of sexual differentiation. Phoenix and colleagues proposed that the androgens act at a specific time or times (critical period) during development to permanently alter the tissue. They suggested a dichotomy between organizational and activational effects. During the prenatal period the androgens acted to organize the tissue, meaning it prepared certain tissues in the body to respond differently to gonadal hormones in adulthood. Then, in adulthood, the gonadal hormones worked to activate the tissues, thus affecting sexual behavior (Arnold, 2009). Their belief that male hormones changed the brain was a new and very controversial idea that caused an explosion in the research of sexual differentiation (Wallen, 2009). Although this hypothesis has been adapted and changed over time, the main ideas that Phoenix and his colleagues proposed still hold true today. This chapter will focus on sexual differentiation, and how this differentiation affects both brain development and the behaviors that emerge. Factors that impact this development are also discussed. Finally, we delve into our current understanding of sexual differentiation and how this idea has changed over time.

14.2 GENETIC FACTORS INFLUENCING SEXUAL DIFFERENTIATION 14.2.1 Sex differences in gene expression Gonadal hormones are the defining factor in sexual differentiation of the body and brain, but where do these differences in hormones arise? What causes the gonads to become either testis or ovaries in the first place? This is where genetics plays an The Neurobiology of Brain and Behavioral Development DOI: http://dx.doi.org/10.1016/B978-0-12-804036-2.00014-5

r 2018 Elsevier Inc. All rights reserved.

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important role. Biological sex in humans is determined by the presence or absence of the Y sex chromosome. During gamete production in males, spermatocytes undergo division so that the gametes contain half the parents’ genetic material. This results in sperm that either possesses an X or a Y chromosome. The same process happens during female gamete production but since females possess two X chromosomes the gametes that are formed all contain an X chromosome. This gives rise to the typical XX female and XY male sex chromosomes once fertilization has occurred (Cheng & Mruk, 2010). Gonadal hormones function as secondary factors that act downstream of the primary factors, the X and Y chromosomes (Arnold, 2009). The expression of genes on the sex chromosomes influences the sexual differentiation of the brain, and sequentially behavior prior to the onset of gonadal hormone secretion. This suggests that there is a gene-hormone interaction (Davies & Wilkinson, 2006). The Ar gene encodes the androgen receptor and is found on the X chromosome. This receptor is critical for male development. Because it is found on the X chromosome, females carry and express this gene, but circulating progestins, expressed in high levels in females, inhibit the activity of the receptor. Acting as antiandrogen agents, progestins block the male typical mode of development (Raudrant & Rabe, 2003). The Ar gene provides a useful example for how genes may encode one mode of development but the interaction with hormones changes it. It is, therefore, important to understand the role sex-linked genes have on development (Fig. 14.1). The three mechanisms by which this may occur include X-linked gene dosage effects, X-linked imprinting, and Y-specific gene expression.

Figure 14.1 The organization/activation affects the sex chromosomes and hormones have on the brain. Adapted from McCarthy, M.M., & Arnold, A.P. (2011). Reframing sexual differentiation of the brain. Nature Neuroscience, 14(6), 677 683.

Hormones and Development

14.2.1.1 X-linked gene dosage Genetic females, as we have established, possess two X chromosomes. This puts females at risk of potentially fatal levels of gene product from the second X chromosome. A mechanism, called x-inactivation, has evolved to cope with this issue. In this process, one of the X chromosomes is condensed into a Barr body but not all of the genes on the inactivated chromosome are silenced. In fact, approximately 15% escape inactivation (Nieschlag, Werler, Wistuba, & Zitzamm, 2014). The escaped genes will be expressed in higher levels in females than in males, who only have one X chromosome. In other words, the genes that escape X-inactivation are more likely to be phenotypically expressed in females (Davies & Wilkinson, 2006). For example, color vision deficiencies like color blindness occur in about 8% of men (according to the National Eye Institute) while only .5% of the female population is affected. If a female is missing the functional gene on one chromosome, the other is able to compensate for this loss. Furthermore, women are able to express tetrachromacy (although this is fairly rare) as opposed to the normal trichromacy vision due to a double dosing effect (Jornda, Deeb, Bosten, & Mollon, 2010). This suggests that escaped genes may account for some of the sexually dimorphic differences seen between males and females. 14.2.1.2 X-linked imprinting Genomic imprinting involves the preferential expression of a subset of genes that are marked indicating parental origin. As such, some genes are preferentially expressed from either the paternal or maternal X chromosome (Reik & Walter, 2001). This process serves to sexually differentiate males and females as males inherit their X chromosome solely from their mother and females inherit an X chromosome from both parents. Genetic differences in females arise as the result of expression of the paternal X chromosome that would not occur in males, while the maternal X chromosome would be expressed in both sexes (Davis, Isles, Burgoyne, & Wilkinson, 2006). For example, females with Turner’s Syndrome (possessing only one X chromosome; discussed in more detail below) show stark differences depending on whether they received their X chromosome from their mother or father (Iwasa & Pomiankowski, 2001). As such, the parental origin and the preferential expression of genes have been shown to influence fundamental sex differences in the brain and behavior. 14.2.1.3 Y-specific gene expression The Y chromosome is functionally different from the X chromosome, mainly because it possesses a region that cannot recombine with the X chromosome during division. This nonrecombinant region (NRY) has genes on it that are specific to the Y chromosome and comprises 95% of the chromosome’s length. As a result, genes in this region are only expressed in males (Skaletsky et al., 2003). For example, the Sry gene

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is found on the mammalian Y chromosome and is known as the testis determining factor (Prokop et al., 2013). This gene is critical for male typical development of the testis and is another way in which genes account for sexual differentiation. Originally, it was thought that the Sry gene promoted the growth of the male reproductive tracts (Wollfian system) and eliminated the female reproductive tracts (Mu¨llerian system). This in turn caused the production of testosterone, which acts to masculinize and defeminize the tissues of the body, including the brain. Further research into the Sry gene has shown that the presence of a Y chromosome may play a larger role in brain development (McCarthy & Arnold, 2011). In one study, researchers created phenotypic female mice. The catch is that they had XY chromosomes. They did this by removing the Sry gene from the Y chromosome, and as a result these animals developed in the default female typical pattern (these animals will be denoted XY2). They furthered this research by mating these genetic XY2 females and found them to be fertile (Lovell-Badge & Robertson, 1990). More recent studies using the XY2 females showed that there may be sex differences in the brain due to the expression of genes found on either the X or Y chromosome. For example, it was demonstrated that when the Sry gene was present there were more dopaminergic neurons in the brain and further that the XY2 females had significantly lower numbers of dopaminergic neurons than the XY males. This is thought to be due to the absence of the Sry gene in the XY2 females (Carruth, Reisert, & Arnold, 2002). Lastly, research by Dewing et al. (2006) looked at expression of the Sry gene and its protein product. They found that there was increased expression of the Sry gene in the substantia nigra of the midbrain, the thalamus, and, although not to the same extent, throughout the cortex (Dewing et al., 2006).

14.2.2 Clinical populations One way in which to understand more about the function of the human body, aside of manipulations to animals (see Chapter 4: The Role of Animal Models in Studying Brain Development), is to study clinical populations. There are several different sexlinked gene abnormalities that have been pivotal in understanding the interactions between genes and hormones, and their effect on sexual differentiation of both the body and brain. 14.2.2.1 Triple X syndrome Triple X syndrome (XXX) is the addition of an X chromosome, with an incidence rate of 1/1000 females, that is a result of nondisjunction of the sex chromosomes during oogenesis. (Essentially, during gamete development the X chromosomes fail to separate.) As such, the extra chromosome has a maternal origin (May et al., 1990). The number of individuals affected may actually be significantly higher as majority of cases go undiagnosed because some individuals may experience only mild symptoms

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(Gustavson, 1999). Phenotypically, individuals with XXX tend to be tall and thin. Behaviorally, they show motor coordination difficulties, auditory processing disorders, psychological and personality disturbances, and an IQ 20 points below the control level. Anatomically, individuals with XXX have lower total brain volumes and larger ventricles with reported asymmetries. Some studies report reductions in amygdala volumes as well (Otter, Schrander-Stumpel, & Crufs, 2009). Most XXX females have normal ovarian and menstrual functions (Stagi et al., 2016) but occasionally cases of birth defects (such as overlapping digits) and some of ovarian and menstrual problems are reported in the literature. 14.2.2.2 Turner syndrome Turner syndrome (TS) is a sex chromosome disorder resulting from complete or partial loss of the X chromosome, affecting 1 in 2000 females. Nondisjunction in gamete development in either parents results in an individual with only one X chromosome, XO. This causes a reduction in X-linked gene dosing with the individual only expressing male typical levels of gene expression (Uematsu et al., 2002). Physical characteristics include short stature, infantilism, webbed neck, and cubitus valgus (an abnormal carrying position for the arm). Along with these physical signs are cognitive deficiencies including lowered performance IQ, and impairments in visuospatial skills, shortterm memory, attention, and social interactions (Nijhuis-van der Sanden, Eling, & Otten, 2003). MRI studies assessing anatomical features of individuals with TS have found smaller bilateral brain volumes in the hippocampus, caudate, lenticular, thalamic nuclei (all smaller in the right hemisphere), and the parieto-occipital regions (Murphy et al., 1993). Moreover, depending on the parental origin of the X chromosome certain symptoms are exaggerated. For example, individuals that inherited their X chromosome from their mother lack social awareness, flexibility, and scored lower on formal tests of social cognitive skills compared to individuals that received their X chromosome from their father (Skuse et al., 1997). 14.2.2.3 Klinefelters syndrome The most frequent type of congenital chromosomal disorders in males is Klinefelters syndrome (KS), with a prevalence rate of 1 in 426 to 1 in 1000 (Ngun et al., 2014). KS is characterized by an extra X chromosome (XXY) and as in females, the second X chromosome is silenced via X-inactivation and the escaped genes are the cause of the dosing affects that are seen in KS (Nieschlag, Werler, Wistuba, & Zitzamm, 2014). Typical symptoms are due to hypogonadism, mainly infertility and testosterone deficiencies as a result of X-linked dosing. Along with these symptoms are those of a more feminized phenotype including female typical distribution of adipose tissue, and absent or decreased facial hair. In addition, learning difficulties and a below normal verbal IQ have been reported (Bojesen, Juul, & Gravholt, 2003). To further

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understand the behavioral deficits observed, researchers have conducted MRI studies to evaluate the link between brain and behavior. Studies report enlargement of ventricular volume, and a bilateral reduction of cerebellar hemispheres, as well as a significant reduction in temporal lobe volume (Itti et al., 2006). 14.2.2.4 Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) occurs when there is a mismatch between gonadal hormones and sexual differentiation. CAH is the result of an autosomalrecessive inherited disorder caused by a mutation in the enzyme, 21-hydroxylase, which is involved in the pathway that converts precursor products into cortisol and aldosterone. In the case of CAH, these precursors are unable to form the respective corticosteroids and are metabolized into androgen. This disorder affects both males and females and occurs in 1 in 15,000 births (White, 2009). Females born with CAH tend to have ambiguous genitalia due to the high levels of androgens in utero, males at birth are harder to diagnose without blood tests and tend to go untreated depending on the severity (Merke & Bornstein, 2005). In the brain, CAH causes a decrease in amygdalar volume (Merke et al., 2003) and individuals affected with CAH have symptoms that range from mild to severe depending on the degree of corticosteroid deficiencies. Behaviorally, there are mixed reviews with some papers reporting increased IQ and some reporting decreased IQ (Nass & Baker, 1991; Wenzel et al., 1978). However, females with CAH are reported to have better spatial abilities, whereas males with CAH are reported to have poorer spatial abilities. This gives some insight into how the overabundance of androgens may act to organize the tissue of the developing fetus. Since the discovery in the 1950s that cortisone was an effective treatment for CAH, the lives of these patients have improved greatly. Screening is done at birth to detect CAH and treatment can begin (Hampson, Rovet, & Altmann, 1998). 14.2.2.5 Androgen insensitivity Androgen insensitivity (AI) is relatively rare, compared to the other disorders mentioned, with a population prevalence of 1 to 5 in 100,000. Individuals with AI are genetic males, XY. The main pathology of this disorder stems from the lack of functioning androgen receptors. The circulating androgens are at normal levels but the tissues lacking the functioning receptors cannot be activated by androgens and consequentially develop in a more female typical manner (Cohen-Bendahan, van de Beek, & Berenbaum, 2005). There are three categories of AI and they have a varying degree of effects on the body. The first is complete AI syndrome (CAIS), wherein the tissues of the body are insensitive to androgen (i.e., testosterone) and, consequently, the external genitalia differentiate in a female-typical direction. Therefore, CAIS individuals are generally raised as female and are not diagnosed until puberty when they

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fail to menstruate (Ehrhardt & Meyer-Bahlburg, 1979). The second type is mild AI syndrome (MAIS), this results from the mild impairment of the cells ability to respond to androgens. The male typical genitalia differentiate during fetal development but there is impaired development of secondary sexual characteristics during puberty and infertility (Zuccarello et al., 2008). Partial AI syndrome (PAIS) is the third type. Partial unresponsiveness to androgens results in impairments in the masculinization of the male genitalia during fetal development and impairments to male secondary sexual characteristics. Individuals with PAIS have ambiguous genitalia because not enough testosterone was available during pregnancy to fully complete the development in a typical manner (Hughes & Deeb, 2006). Since there is a spectrum in terms of the etiology of the disorder, there is a varying degree of cognitive sequelae. Impairments in visuospatial tasks and verbal comprehension have been reported (Imperato-McGlnley, Plchardo, Gautier, Voyer, & Bryden, 1991).

14.3 ENVIRONMENTAL FACTORS The relationship the environment has on development has been well established. Gonadal hormones are an important fetal secondary factor that has the potential to interact with environmental risk factors and experiences that may impact sexual development. Sexual differentiation is vulnerable to pre- and perinatal factors that may have estrogenic-like or antiandrogenic properties. These deviations can interfere with development and cause a masculinization or feminization of the brain and as a result, alter behavior. Here we will consider the effects of prenatal exposures, including maternal exposure to drugs, nutritional status, and environmental contaminants.

14.3.1 Drugs 14.3.1.1 Nicotine According to the Centers for Disease Control and Prevention (2016), an estimated 15% of US adults report daily smoking. Tobacco use is considered the largest preventable cause of death and disease. It costs an estimated $96 billion dollars in direct medical expenses and causes 443,000 smoking related deaths per year (Centers for Disease Control and Prevention, 2016). Females are particularly susceptible to developing tobacco-related morbidities and mortalities (Allen, Oncken, & Hatsukami, 2014). Resent research has also suggested that women who smoke have a much lower success rate of quitting (Piper et al., 2010). Thus, it has been estimated that 10% of women continue to smoke during pregnancy (Tong et al., 2013). Alongside a large body of literature indicating the negative impact on overall health, there is a growing evidence of the consequences of nicotine exposure on the developing brain. Women who smoke during pregnancy generally have children born with increased risk for sudden infant death syndrome, low birth weights, attentional

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and cognitive deficits (including learning and memory impairments), and an increased risk for developing ADHD (Ernst, Moolchan, & Robinson, 2001; Fried, Watkinson, & Gray, 1998). In rodent studies, prenatal exposure of nicotine reduces birth weight, increases locomotor activity, and causes poor performance in maze tasks and permanent changes to dendritic morphology (Ernst et al., 2001; Mychasiuk, Muhammad, Gibb, & Kolb, 2013). These results mimic the deficits observed in the human population and provide insight into the etiology of the effects of nicotine. In the brain, nicotine from tobacco products acts on nicotinic acetylcholine receptors (nAChR), which are ligand-gated channels that mediate the release of the neurotransmitter, acetylcholine (Ach). These receptors are expressed in the human brain during the first trimester. NAChR expression has also been reported to increase during critical periods of development, leaving the brain extremely susceptible to environmental factors (Dwyer, McQuown, & Leslie, 2009). Sex steroids play a role in the modulation of the nAChR. Specifically, progesterone and estradiol have been shown to increase the expression of the genes encoding the nAChR. While progesterone decreases activity of nAchRs, estradiol increases their activity (Centeno, Henderson, Pau, Bethea, 2006; Gangitano, Salas, Teng, Perez, & De Biasi, 2009; Jin & Steinbach, 2015; Ke & Lukas, 1996). These findings may shed some light on sex differences observed with nicotine use in adulthood such as low success for cessation in women, higher rates of cortisol during withdrawal, and subsequent higher rates of depression and anxiety during periods of nicotine abstinence (Cross, Linker, & Leslie, 2017).

14.3.1.2 Alcohol Alcohol can readily cross the placenta and as such, it has the potential for affecting fetal development. Prenatal alcohol exposure can result in fetal alcohol spectrum disorder (FASD), with a prevalence rate of 9/1000 births in North America (Thanh & Jonsson, 2010). FASD presents itself in clinical populations with growth retardation, impairments in cognition and self-regulation, and substance-use disorders (O’Connor & Paley, 2009). Prenatal exposure to alcohol has been shown to decrease testosterone surges, which can lead to feminization of the brain and other tissues in males. In females, prenatal alcohol exposure has been shown to cause delays in secondary sexual characteristics later in life, which has been linked to dysregulation of the hypothalamic pituitary adrenal (HPA) axis (see Chapter 16: Socioeconomic Status for more information). Furthermore, the symptoms seen with prenatal alcohol exposure may be exacerbated by the changes to the HPA axis in the mother, which acts as an additional perturbation to the developing fetus (Weinberg, Silwowska, Lan, & Hellemans, 2008). Alcohol consumption works to increase the activity of the HPA axis, thereby inducing a stress response in the body. However, chronic alcohol consumption causes the HPA axis to build up a tolerance to alcohol thereby reducing

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cortisol levels. This tolerance may negatively affect the ability of the HPA axis to respond to future stressors (Spencer & Hutchison, 1999). 14.3.1.3 Marijuana In 2015, the National Survey on Drug Use and Health found that approximately 20.5 million individuals 18 years of age or older were current users of marijuana, with 117.9 million individuals 12 years of age or older reporting marijuana use at least once in their lifetime (Center for Behavioral Health Statistics and Quality, 2016). Although controversy remains on the effects of chronic use on the brain, marijuana is the most commonly used illegal drug, and its use is on the rise among today’s youth (Leatherdale, Hammond, & Ahmed, 2008; Wilson et al., 2000). Individuals who begin smoking marijuana before the age of 17 have brain changes that include decreases in gray matter and increases white matter. Males who start smoking early have significantly higher global brain volumes. This has been hypothesized to be a result of the rapid growth observed in the brain during this period of adolescence (Wilson et al., 2000). Delta-9-tetrahydrocannabinol (THC) has been implicated in reducing circulating levels of estradiol and progesterone in females, and testosterone in males. In female rats, administration of THC has been shown to block ovulation. In rhesus monkeys, three weekly injections of THC are enough to disrupt normal menstrual cycling; an effect that lasts for several months. Similar clinical reports have been made in women who chronically use marijuana. In male rats, THC administration drastically lowers circulating levels of testosterone (Murphy, Mun˜oz, Adrian, & Villanu´a, 1998). THC freely crosses the blood brain barrier, the placenta, and is secreted in breast milk (Kumar et al., 1990). Individuals exposed to marijuana prenatally generally suffer from poor executive function, working memory, poor attention span, and altered acoustic profiles of their cries (Eyler & Behnke, 1999; Fried et al., 1998). In rodents, THC administered to pregnant dams increases reabsorption of pups, and perinatal exposure has been shown to decrease binding capabilities of dopamine receptors. Most striking in its effect is the demasculinization of male rats pre- or perinatally exposed to THC. This could be due to the interaction THC has on GnRH and therefore decreased circulating testosterone during development (Kumar et al., 1990). Imaging studies show functional abnormalities in individuals with THC dependence in the orbitofrontal cortex, insula, basal ganglia, anterior cingulate, with men showing greater activation in left brain regions while women show more activation in right brain regions (Franklin et al., 2002; Li, Kemp, Milivojevic, & Sinha, 2005). 14.3.1.4 Cocaine According to the National Institute on Drug Abuse, cocaine use has fallen in 2017 compared to 2007, with 1.5 million individuals 12 years of age or older reporting as

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current users (NIDA, 2015). Cocaine is highly addictive and individuals that have been abstinent show enhanced sensitivity to stress-induced drug/alcohol cue-related responses. Fox et al. (2006) showed that cocaine-dependent women have increased anxiety and negative emotion, along with increases in blood pressure when compared to men. Cocaine- dependent men have greater variability in psychological and physiological responses (Fox et al., 2006). Researchers have shown that during the first 28 days of cocaine abstinence, women have significantly higher levels of cortisol and progesterone indicating possible changes to the HPA axis (Sinha et al., 2007). Prenatal exposure to cocaine in rodents causes feminization of male genitalia. Vathy, Katay, and Mini (1993) found a significantly shorter ano-genital distance in male rat pups, while females remained unaffected. In adulthood, female rats prenatally exposed to cocaine showed an overall decrease in sexual behavior, while the exposed males had increased mounting and intromission behaviors. Anatomically, there were increases in dopamine and norepinephrine in males in the preoptic area, whereas no differences were found in the females (Vathy et al., 1993).

14.3.2 Diet Diet is important for overall health and proper development. Maternal and infant diet play a role in hormone levels in the mother, which in turn has an effect on the developing fetus, but formula choices may interfere with infant hormone levels. For example, there has been a major switch in Canada to use soy-based formula, around 20% in 1998. Soy-based formulas contain phytoestrogens; these compounds have estrogen like activity (although weakly so) and may provide doses of 4 11 mg/kg in infants consuming soy-based products. This dose range is much higher than that incurred by traditional Japanese diets (1 mg/kg; “Concerns for the use of soy-based formulas in infant nutrition.” 2009). These elevated doses may have effects on the developing male infant. Sharpe et al. (2002) found that when comparing marmoset monkeys hand fed with either soy-based formula or standard cow-based formula, males on the soy diet had significantly decreased testosterone levels. This demonstrates the importance of infant diet on development as it can disturb sex hormone production and/or function, thus leading to changes in the masculinization or feminization of the brain. The maternal diet plays an important role in the development of the fetus and in the newborn infant through nursing. Low-protein diets during pregnancy in rats result in females that have lower birth weights, and both male and female offspring that become obese in adulthood. Protein restriction after birth slowed the growth of both male and female offspring (Zambrano et al., 2006). Maternal obesity has been linked with lowered sperm counts and decreased sperm quality in male offspring. It has been hypothesized that maternal obesity results in increased fetal exposure to estrogens and

Hormones and Development

this may account for the sperm effects reported in this study (Ramlau-Hansen et al., 2007).

14.3.3 Environmental contaminants 14.3.3.1 Bisphenol A Bisphenol A (BPA) is used in the manufacturing of plastics and epoxy resins. Estimates on the amount of BPA used each year are upwards of 8 billion pounds, 100 tons of which may be released into the atmosphere (Vandenberg et al., 2010). BPA is a known endocrine disruptor and in the 1930s it was studied for its potential use as a synthetic estrogen. It binds both nuclear and plasma membrane bound estrogen receptors and can be found in detectable levels in urine, blood, amniotic fluid, placenta, and breast milk. The greater the exposure to BPA, the more severe the resulting symptoms (Maffini, Rubin, Sonnenschein, & Soto, 2006). In adolescents, studies have linked exposure of BPA to altered time of puberty, altered estrous cycles, prostate changes, and altered mammary gland development. BPA exposure in adults is linked to diabetes and cardiovascular disease. In women, increased exposure is correlated with recurrent miscarriages, and in men exposure is linked to decreased semen quality and sperm DNA damage (Rubin, 2011). With the substantial perturbations to the heath and development observed in children and adults, exposure during the prenatal period may be more deleterious. BPAs may have permanent organizational effects on the developing fetus. Mean BPA levels reports indicate that children have the highest amount of BPA in their urine as compared to adolescents who have higher levels than adults. This observation is important as it shows that exposure is increasing and that the younger generation is more at risk (Vandenberg et al., 2010). 14.3.3.2 Polychlorinated biphenyls Although the use of polychlorinated biphenyls (PCBs) has been banned, this class of contaminants has a long half-life and is still found in high levels in the environment. PCBs are fat-soluble and are therefore biomagnified through the food chain, with humans at the top. PCBs are readily transferred to newborns through lactation. The structural similarities of PCBs to thyroid hormones cause a decrease in circulating thyroid hormones in the body through negative feedback loops. This decrease has implications for brain development including consequences on cognitive function, behavioral responses, and decreased brain weights in rodents. PBCs have been correlated with early menarche, abnormal menstrual cycles, increased incidence of endometriosis, spontaneous abortion, fetal death, premature delivery, and low birth weights (Leon-Olea et al., 2014). In men, PCBs have been shown to decrease sperm motility, and to cause sex reversal (male to female) in some animal species with prenatal exposure (Guillette, Crain, Rooney, & Pickford, 1995). More subtly, PCB exposure has been shown to masculinize or defeminize the female hypothalamus whereas

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in males it has been shown to feminize or demasculinize the hypothalamus (Gore, Martien, Gagnidze, & Pfaff, 2014). Depending on the chemical makeup of the PCB, either an antagonistic or agonistic effect on androgen, progesterone, and estrogen receptors can result therefore confirming the mixed effects observed in both males and females (Hammers et al., 2006).

14.4 SEX DIFFERENCES IN THE BRAIN As previously discussed, the sex chromosomes have a large impact on sexual dimorphism via the expression of more genes in X-linked gene dosing, as well as the interactions between genes and hormone production. Here, we will discuss sex differences observed in the brain and the mechanisms that may account for these differences. Finally, we will delve into the implications these differences have on sex differences observed in individuals with neurological disorders.

14.4.1 Anatomical differences A meta-analysis performed by Ruigrok et al. (2014) looked at sex differences in brain structures reported in the literature since 1990. The Ruigrok study found that overall males are reported to have larger brain volumes by between 8% and 13%. With regard to specific brain regions, males appear on average, to have more gray matter in the bilateral amygdalae, hippocampi, putamen, and temporal poles. In addition, the left posterior and anterior cingulate gyri and multiple areas in the cerebellum were larger in males than females. Females, on the other hand, were found to have larger volumes at the right frontal pole, inferior and middle frontal gyri, anterior cingulate gyrus, planum temporale/parietal operculum, insular cortex, and Heschl’s gyrus. In addition, the bilateral thalami, precuneus, left parahippocampal gyrus, and lateral occipital cortex are reported to be larger in females (Ruigrok et al., 2014). 14.4.1.1 Sex differences in brain maturation It is well documented that as humans age, their brain develops and matures. Neurons begin developing in the prenatal period and as a child experiences the world they begin making synapses. Once puberty begins the number of neurons and synapses decrease remarkably. A loss of 100,000 synapses per second (synaptic pruning) is estimated to occur in adolescence. The last phase of brain development is the maturation and myelination of the brain, specifically the cortex. This process continues until at least 30 years of age (Kolb & Whishaw, 2015). Although this process is standard in all humans, sex differences are apparent. Females show more rapid brain growth than their male counterparts and attain their maximum brain volume about 5 years earlier. Myelination of the brain requires more time to complete in males relative to females (Lenroot, Gogtay, & Greenstein, 2007). These results suggest that behavioral

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development in males should also show delay in some domains and that brain plasticity associated with development persists over a longer time period in males. There is evidence of sex-specific changes to brain regions during brain maturation. A larger increase in hippocampal and striatal volume in females, and a larger increase in amygdala volume in males, this is thought to result from the activational effects brought on by the changes in hormones levels during puberty. In parallel, it has been shown that in primates that there are more androgen receptors in the amygdala and more estrogen receptors in the hippocampus (Neufang et al., 2009). Finally, in a diffusion tensor imaging study published in 2013 with more than 400 participants of each sex, it was noted that sex differences arise in brain connectivity with maturation. Adult females show greater interhemispheric connectivity than males whereas males show greater intrahemispheric connectivity than females (Fig. 14.2). These differences were not observed in children, adolescents, or even young adults. As a consequence, males demonstrate enhanced spatial processing, sensorimotor speed and a more modular brain, whereas females show enhanced attention, word and face memory, and a more integrated brain. Overall, these findings suggest that males are likely to complete a task in progress before moving on to another. In contrast, females are multitaskers (Ingalhalikar et al., 2013).

14.4.2 Biological differences Although sex chromosomes play a huge role in sexual differentiation, they are not the only genetic factor affecting sexual differentiation. In a recent study analyzing over 1100 postmortem brain samples from various brain regions (frontal cortex, occipital cortex, temporal cortex, intralobular white matter, hypothalamus, medulla, cerebral

Figure 14.2 Sex differences in brain connectivity: (A) male and (B) female brain. From Kolb, B., Teskey, G.C., & Whishaw, I.Q. (2016). An introduction to brain and behavior. NY: Worth Publishers.

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cortex, and spinal cord), originating from 137 individuals, it was discovered that 448 genes (2.6%) of the total genes expressed in the human central nervous system are differentially expressed based on sex (Trabzuni et al., 2013). Of these differentially expressed genes, over 85% were detected based on sex-biased splicing. Splicing is a posttranslational modification process where introns are removed from immature mRNA and the exons are then spliced back together to create the mature mRNA (Roy & Gilbert, 2006). This suggests that on top of gene differences, the mechanisms underlying the production of proteins are also different between the sexes. Most notable is the finding from Trabzuni et al. (2013) that 95% of genes with sex-biased splicing and 34% of genes with sex-biased expression were mapped to autosomes. This demonstrates that not all sex differences observed in the brain are due to differences in sex chromosomes alone. It appears that the other chromosomes are also important for observed differences. 14.4.2.1 Sex differences in HPA axis regulation The HPA axis is an important signaling cascade used to maintain homeostasis in living organisms. The HPA axis is designed to regulate internal and external stressors through the use of various hormones. The response starts in the hypothalamus with the release of corticotropin-releasing hormone (CRH), which acts on the pituitary to release adrenocorticotropic hormone (ACTH). ACTH then stimulates the release of adrenal glucocorticoids into the blood stream, which creates the body’s stress response. Finally, glucocorticoids act as negative feedback messengers in the brain to dissipate the stress response (Young, Korszun, Figueiredo, Banks-Solomon, & Herman, 2008). Animal studies of the development of the HPA axis have provided insight into the importance of the hypothalamic pituitary gonadal (HPG) axis and subsequent sex differences. A persistent observation is that female rats have a significantly higher response to stress, and therefore increased corticosterone secretion after stress, compared to males (Panagiotakopoulos & Neigh, 2014). It has been shown that male rats castrated after birth and reared under normal conditions, when supplemented with testosterone in adulthood show female typical patterns in response to stressors. This suggests that testosterone may have an organizational effect on the development of the HPA axis. In the human literature, sex differences in the HPA axis appear during development with the interaction between the HPA axis and the HPG axis. CRH has an inhibitory impact on the HPG axis directly (acts on specific brain structures) and indirectly (acts on neurotransmission), and has been shown to decrease testosterone levels in men and inhibit ovulation in females. And in a reciprocal fashion, the HPG axis can modulate CRH. For example, estrogen has been shown to increase transcription of the CRH gene whereas androgens have been shown to downregulate CRH gene transcription (Panagiotakopoulos & Neigh, 2014). Dahl et al. (1992) found that

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prepubescent boys and girls differ in their HPA axis response, with boys reaching higher peak values of cortisol 30 minutes later after CRH infusion than girls. In a study done with adults, response to CRH resulted in a greater increase in cortisol levels in women compared to men, suggestive of “activational” sex differences in the postpuberty period (Born, Ditschuneit, Schreiber, Dodt, & Fehm, 1995). To further the evidence of “organizational” effects on the HPA axis, Heim, Newport, Mletzko, Miller, and Nemeroff (2008) looked at early life stressors (for more information on early life stressors see Chapter 16: Socioeconomic Status) and found that women with childhood stress had an increased ACTH response to stress as adults compared to controls. Men with childhood stress, on the other hand, had increased cortisol levels in response to stress as an adult (Heim et al., 2008).

14.4.3 Differences in immunity Microglial cells comprise the brain’s immune system and play a critical role in the brain during injury, degeneration, and chronic stress (Ajami et al., 2007). More recently, research has uncovered other roles for microglia in the brain including plasticity, neurogenesis, apoptosis, and most notable for this discussion, sexual differentiation of the brain (Nimmerjahn, Kirchhoff, & Helmchen, 2005; Sierra et al., 2010; Lenz, Nugent, Hailyur, & McCarthy, 2013). During development, microglia begin populating the brain and by birth in rodents, there are already significant sex differences in the number and morphology of microglia in various areas of the brain (preoptic area, hippocampus, parietal cortex, and amygdala). For example, in the preoptic area the microglia in the male brain have larger cell body size and a decrease in process length and branching when compared to females (Lenz & McCarthy, 2015). The roles of microglia in the immature brain differ significantly from those attributed to microglia in the mature brain (injury or inflammation response), and these functional differences are thought to support the developing brain (Lenz et al., 2013). Research has shown that microglia regulate processes that are critical for development including synapse elimination, spinogenesis, and spine elimination (Tremblay et al., 2011). Lenz et al. (2013) found that treating 2-day-old female rats with estradiol (the precursor to testosterone) led to complete masculinization of microglial expression. This finding adds to previous findings showing that microglia are critical for sexspecific development.

14.4.4 Sex differences in behavior It is not far-fetched to believe that with all the sex differences reported in the brain and its development, sex differences exist in behavior. There is compelling evidence for sex differences in at least five cognitive domains; verbal abilities, spatial analysis, motor skills, mathematical aptitude, and perception. In regards to verbal fluency and

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memory, women are superior. It has long been known that girls begin talking before boys and this may contribute to the observed sex differences (Wallentin, 2009). However, when comparing spatial abilities men outperform women on mental rotation, spatial navigation, and geographical knowledge, while women are better at spatial memory (McBurney, Gaulin, Devineni, & Adams, 1997; Voyer & Voyer, 1995). There seems to be a mix of sex differences when it comes to motor skills; with men being better at throwing and catching and women being better at fine motor skills (Hall & Kimura, 1995; Nicholson & Kimura, 1996). The same is seen with mathematical abilities, where females are better at computation and males better at mathematical reasoning (Hyde, Fennema, & Lamon, 1990). Lastly, when it comes to perception, females seem to have an advantage over males to sensory stimuli (having a lower threshold), sensory speed (faster detection), noticing subtle body and facial cues, and better recognition memory (Kolb & Whishaw, 2015).

14.5 CONCLUSION The developing brain is remarkable and the processes behind its development are complex. Although the organizational/activational theory originally proposed by Phoenix and colleagues still holds true today, much has been added to expand and understand this phenomenon. As shown, the sex differences seen in humans are a complex interaction between, not only, the sex chromosomes but dimorphic gene expression, sex hormones, and the prenatal and perinatal environment. Environmental contaminants, drugs, and diet can interfere with typical development. In addition, sex differences that arise in response to trauma, addiction, and social influences are well described (see Chapter 16: Socioeconomic Status for more details).

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FURTHER READING Cota, D. (2008). The role of the endocannabiniod system in the regulation of hypothalamic pituitary adrenal axis activity. Journal of Neuroendocrinology, 20, 35 38. Available from http:// dx.doi.org/10.1111/j.1365-2826.2008.01673.x. Kirschbaum, C., Schommer, N., Federenko, I., Gaab, J., Neumann, O., Oellers, M., . . . Hellhammer, D. H. (1996). Short-term estradiol treatment enhances pituitary adrenal axis and sympathetic responses to psychosocial stress in healthy young men. The Journal of Clinical Endocrinology & Metabolism, 81, 3639 3643. Reynolds, R. M., Hii, H. L., Pennell, C. E., McKeague, I. W., Kloet, E. R., Lye, S., . . . Foster, J. K. (2013). Analysis of baseline hypothalamic pituitary adrenal activity in late adolescence reveals gender specific sensitivity of the stress axis. Psychoneuroendocrinology, 38, 1271 1280. Uban, K. A., Comeau, W. L., Ellis, L. A., Galea, L. A. M., & Weinberg, J. (2013). Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress. Psychoneuroendocrinology, 38(10), 1953 1966. Available from http://dx. doi.org/10.1016/j.psyneuen.2013.02.017.