Taurine in development

Life Sciences Vol . 21, pp . 1-22, 1977 . Printed In The U .S .A .

Pergamon Press

MINIREVIEW TAURINE IN DEVELOPMENT John A . Sturmau, David K . Rassin and Gerald E . Gaull Division of Human Development and Genetics Institute for Basic Research to Mental Retardation Staten Island, New York 10314 and Department of Pediatrics Mount Sinai School of Medicine of the City University of New York Nsw York, New York 10029

Taurine is one of the most ubiquitous and abundant ninhydrtn positive compounds in the body, but tt takes part in few known btoehaniul reactions (1) . It is conjugated with bile acids in the liver (2), and limited deamina tion to isethionic acid takes piece in a number of organs (3-8) . Taurine is conwr~sd to Inorganic sulfate by intestinal mtcroflora but not by mammalian tissue (9 .10) . In brain and rotina, taurine may function as a nsurotransmttter or neuromodulator, and tt has been implicated in the epilepstes, both in animal models and to man (see 11) . Taurine affects the structural intsgrtty of the retina, and a deficiency of taurins in the cat rosults in retinal degeneration and blindness (12-14) . Wb scantly roportsd migration of taurine, probably by axonal transport, In the goldfish visual system (15) . Taurine plays a role in the rogulation of membrane excitability in heart, and there is an tncroased ventricular concentration of taurins to congestive heart falluro (16-18) . Moroover, taurine may be involved to some endocrine and roproductiw functions (16) . It is puzzling that taurins is found to large concentrations in tissues when many of its proposed functions would roquiro only a small fraction of that actually prosent . Furthermoro, the concentration of taurine (n a given tissue varies widely f rom species to species . One might expect similar amounts to bs roquirod for similar functions own in different species . There aro also wide dtfferonees amongst apeefes in the capacity to synthesize taurina . For example, the activity of cysteinasulfinte acid deearboxylasa, the enzynb diroctly rosponsible for teurtne biosynthesis from cysteina, is far higher to liver and brain of the rat than it is Tn liver and brain of many other species, such as the cat and man (19) . The chick embryo and the chick can wmrert inorganic sulfate to taurine (20-23) " The adult rat is able to convert inorganic sulfate to taurine, although this ability is apparontly of minor gwntitatiw significance, whereas this oonwrston cannot ba demonstrated to occur in the ut (24-29) . Thus, the rat can synthesize taurine by these two dtffaront pathways and actively rosists any changes in taurine concentration to a wide variety of metabolically strossful situations (30- 33) " The eat, on the other hand, can synthesize only a limited amount of taurine from cystelns and none from inorganic sulfate (28,29) " Unless taurine is supplied to the diet, the cat becomes depleted of taurins and degeneration of the rotina ensues .

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During development there are largo changes to taurine concentration in many tissues . Those developmental changes in taurine concentration are widely ranging, encanpass both incroases and decreases, and may take place at differont rates in different tissues and in differont species . Ire have speculated that taurine may have a special, albeit undelineated, role in developing tissues in addition to the physiological roles which aro being delineated in maturo tissue (34) . The purpose of this roview is to summarize the available data relating to taurine In development in the hope that this may further our understanding of its role (s) in development . Taurine in Developing Brain By far the greatest amount of information on taurins Tn development is available for brain . The concentration of taurine in brain varies widely from species to species . In the brain of most species, taurine is the nlnhydrin positive compound present in the groatest concentration at birth . At maturity it is exceeded in concentration only by glutam(c acid, which increases during TABLE 1 TAURINE IN ADULT AND NEWBORN BRAIN Values aro Nmoles taurina/g wet weight of whole brain taken from the raferonce in parentheses .

Species

Adult

Mouse

8 .0 9.1 3 .2 4.7 5 .3 4.2 6* 6.5 0 .3 1 .6 1 .3 1 .0 1 .3 2.3 2 .3 1 .7 2 .4 1 .4

Rat

Gerbil Guinea pig Rabbit Dog Cat Chick Monkey* Human+*

Newborn

14 .1 16 .5 14 .0 18 .0 15 .7 18 .5 38~ 21 .2 0 .5 3 .4 4.3 5 .9 6.8 9.2 8.9 7 .0 6 .8 3 .3***

Referoncs

(35) (36) (37,38) (37) (40) (41) (42) (43) (37) (44) (45) (~) (40) (40) (47) (34) (48) (34,49)

*~unolas taurine/100 mg protein *occipital cortex *,~*groy matter only, mean of 5 chi ldron 1 to 5 years of age . development . The concentration of taurine in brain is groater at birth than it is in the mature animal (Table 1), whnroas the concentration of most amino acids in brain either incroases or changes very little during development (40) . The only exception to this generalization may be the frog, in which small amounts of taurine aro found in brain, whereas none is found in tadpole

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brain (50) . The concentration of taurine, however, is much smaller in frog brain than it is in mammalian brain (51) . In all of the species studied systematically throughout development, the dncroase in taurine concentration from the high values at birth to the lower values in the mature animal takes place gradually during postnatal development (34) . less information is available on the taurine content of fetal brain than that of newborn brain, and interspscles comparisons aro confounded by the relative differonus between the lengths of gestation and the degrees of brain maturation at birth . Tha taurine concentration of brain both in fetal mouse and in newborn mouse Is considerably groater than that of brain to adult mouse (52) . In the rat, the taurine concentration of brain increases during the last part of gestation (37) . In the guinea pig (37) and in the monkey, in several different regions of brain (34,53,54), them does not appear to be any significant change late in gestation . The taurine concentration of two brains from human fetuses of 5 and 8 months gestation aro groater than that of adult human brains (55) " Tie found that taurine concentration of fetal human brain during the 2nd-trimester of gestation is decroastng and that the decroase wrrelated significantly with incroasing crown-rump length of the fetus (30) . Another report indicated that the concentration of taurine in the brain from a fetus (22 weeks gestation) with Tay-Sacks disease was not different from the mean taurine concentration of brains from 4 normal fetuses (16-24 weeks gestation)(56) . This report differod from others, however, in that a lower mean taurine concentration for brain was obtained and that it was exceeded by the concentration of glutamate . The taurine concentration of fetal calf brain decroases steadily from the 4th month of gestation until birth at 9 months (57), and taurine concentration of chick embryo brain decroases during incubation (47) . The taurine concentration of brain varies considerably from area to area in all species investigated, but there is less information available on taurine concentrations of specific areas of brain during development . In differont aroas of rat brain (58-60), rabbit brain (61), cat brain (62), and monkey brain (48,63), there is a decrease during development, although the magnitude of the decrease varies from area to area . Taurine concentration is especially large in olfactory bulb, In which it also decroases with time after birth, at least in mouse and monkey (63,64) . The activity of cystetnesulfinic acid decarboxylase is low early in the development of rat brain, and it increases later . Therefore, biosynthesis of taurine seems unlikely to account for the large concentrations present in new born brain (39,65) . An efficient and highly selective transport system for attaining and maintaining high intracellular conuntrations of taurine in brain during development has been suggested, and such a mechanism might account for the large concentrations in newborn brain (39) . The existence of one unsaturable and two saturable transport systems for taurine has been demonstrated in slices of adult rat brain (66) ; experiments with slices of brain from 7-dayw ld rats suggest that a greater concentration gradient can be maintained between brain cells and extracellular fluid in immature brain than is possible in meturo brain (67) . Recent experiments, however, using adult rat cortex slius (68) and adult f rog spinal cord slices (69) suggest that there Is a low-affinity, non-specific uptake mechanism for taurine similar to that found for giyctne, glutamate and ~-amtnobutyrate, but that there is no specific, high-affinity uptake mechanism as found for )(-amtnobut rate, an inhibitory neurotransmitter . We have demonstrated rocently that 35 5] taurine infected Into a pregnant rat enters fetal brain as rapidly as it enters fetal liver, maximum values being reached after 12 hours (41) . In contrast, labelled taurine enters adult brain moro slowly than it enters adult liver, maximum values in brain being reached after 5-7 days (33 .41 .70,73) " Similar

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experiments using late-gestation prognant rhesus monkeys, however, indicated that labelled taurins continued to accunulate In 11 of the 13 differont areas of fetal brain studied (pons and medulla wero exceptional) for the 15 days duration of the experiments (63) . The same arose of maternal brain roached maximun values after 5 to 10 days and then decreased slowly, as found for adult rat brain . The rolatively greater maturity of monkey fetal brain near term, compared to rat fatal brain near term, msy account for these differences in acc~nulation of taurine by fetal brain . The taurine concentration of rat brain and the total taurins content of rat brain change in opposite dirocttons during postnatal development: taurine concentration decroasas, whereas total taurine content incroases (Fig . 1) . It

20

weih TAURINE/q eRAlll v ti

ts

lo

5

FErus ~

20

10 DAYS

FIG. 1

30

40

50

ADULT

AFTER BIRTH

Concentration of taurins and total taurins in developing rat brain .

seems unlikely that taurine functions in the rogulation of growth, cps se, since the brain of the rat is still growing rapidly at the time that the concentration of taurine is decreasing . Furthermoro, the hyperplasia and hypertrophy of various cellular elements in brain development occur at widely differont times relative to birth in differont species, whereas brain taurine concentration dscroasas after birth in all species . In the monkey, and probably in the human, the postnatal dacroase of brain taurine concentration is gradual wheroas the postnatal dscroase of Itver taurins concentration is rapid (Fig . 2) . In rat, rabbit and monkey, there appears to ba a rolationship between the time taken after birth for the taurine concentration of brain to roach that found to maturo brain and the weaning tams of the species (34) . rather than any rolationship with the formation of any particular structural elements of brain. The possible neurotransmitter function of taurine at central synapses was suggested originally because of the depressant action of this compound when it

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Taurine In Development

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w s. s.al'- o.ls

O

7"

O

t~

W Z C

".

F

0

b b 100 Ib NO 100

DAYS

GESTATION

weep

3.Sl = O.PO

O

b M 00

p 100

f00

Q

FZ W v Z O U

W

MONKEY

"

" .. .. a~

0

0 4-- I

ADULT

LIVER

Aleo~

Y. 79 t O. l6

4.

s-

r " -RO/ P>O.~I 0

Li

r " -O.Bl

r " O.l7

P
FIG . 2

a00

DAYS AFTER BIRTH

BIRTH

z 0

"00

"O b

100 I!O 1"O 100

DAYS

GESTATION

O

t:0

P>O.~ "O

b

00

100

DAYS

=00

300

s"O

AFTER BIRTH

ADULT

Concentration of taurine in monkey occipital lobe and monkey 1lwr as a function of age.

is applied in small concentrations via microlontophorosis to central nervous system neurons (74) . Subsequent studies of the biochemistry, alectrophysiology and subcallular distribution of taurins haw led to serious consideration of taurine as a neurotransmitter or nauromodulator (11,75-x5) . If taurine is a neurotransmitter in the fnaturo animal it must be available at the synapse . Thus, the pool of taurine used for this function must be establtshad or maintained despite the ow ra11 decroasa in taurins concentration which

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Taurine In Development

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takes place in brain during development . Studies in the rat at first found no taurine associated with synaptic vesicles (39) . Subsequent studies, however, found a small but consistent pool of taurine closely associated with synaptic vesicles (68,83,86) . Even the small pool of taurine that is associated with the synaptic vesicles of rat brain would be sufficient to fulfill the suggested neurotransmitter function (87) . During development whole rat brain homogenate and the soluble fraction derived from this homogenate undergo a 3-fold to 4-fold roduction in the concentration of taurine, +vheroas the crude mitochondrial plus synaptosomal frac tion undergoes a relatively slight decroase, approximately 25% (Fig . 3) (83) .

I° FRACTIONS FETUSES

TAURINE

80 F A 70

YOTHERS Ss(SUPER)

60 50 z 0 F 20

_

m_

K 10 r f!f

G ô 70 60

~_iI_,_____x____ "

0

Z

A

"

Ps(MICROIt

8

it

Ss(SUPER) ~"

A

~36 5]TAURINE P=1M1T0-SYNAPI

20 10 BIRTH FIG . 3

P~(MITO-SYNAP) l P,(NUCL)y

b

" DAYS

-x~~~

P, (NUCLI

8

Ps (YICRO)f

20 30 AFTER BIRTH

40

Distribution of taurine and C35S7 taurine in the primary subceilular fractions of developing rat brain .

This rolative maintenance of taurine in the crude synaptosomal fraction during development Is apparent also from data comparing 7-day-old rat brain to adult rat brain (39) . In the last study, the taurine concentration of whole brain homogenate and of supernatant decreases by approximately 6096, whereas that of nerve-ending particle fraction decreases by only about 30% . Increases In the relative amount of taurine associated with crude mitochondrtal fraction (prosumably containing aynaptosomes) has been noted also by others (42) ; however, the units in which the data of these workers is prosented do not allow diroct comparison with the other published data . Ths rolative enrichment of taurine in the crude mitochondrial plus synaptosanal fraction (with roapect to the other primary subcelluiar fractions) of rat brain during development Is found also in the subf ractlons of the crude fraction . The taurine content of the synaptic vesicles romains constant during development, and them is a rolative increase in the amount of taurine observed in the purified synaptosomal fraction during development (83) .

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It should be noted also that a population of synaptosomes from rat brain that accumulates [35S]taurine has been identified and shown to be different from the synaptosames that accumulate [3H] noropinephrine or [3H]iÎ-amino butyrate (88) . Synaptosomal uptake of teurtne in the rat is apparontly highly specific and may be attributed to high-affinity and low-affinity systems (89) . Synaptosomes isolated from various ragions of rat and monkey brains were found to have a groater taurine uptake in the newborn than they do to the adult animal (90) . The degroe of uptake apparontly correlates with the endogenous content of taurine in slices f ram various ragions of rat and rhesus monkey brain (90) . Thus, the greater brain taurine concentration of the newborn, as comparod to the adult, may be the result of groater taurine uptake by the brain of the newborn . Examination of subcellular fractions from mature guinea pig cerebral cortex failed to show a special rolationship between taurine and synaptic vesicles (91) . The guinea pig, as compared to the rat, however, has small con centrations of taurine in the brain both during development and at maturity (37,x+4,92) . Fractions propared from whole guinea pig brain should be examined, since it is possible that this special rolationship between synaptic vesicles and taurine found in fractions proparod from homogenates of whole rat brain is found moro in subcortical synapses than in cortical synapses . The subcallular distribution of the enzyme rosponsible for the synthesis of taurine, cystelnesulfinic acid decarboxylass, also has been studied . In the adult rat, 50-60~ of this enzyme has been found within the synaptosoma by throe different groups (93-95) " During the development of the rat them is an increase in the activity of this enzyme in brain (39,65,95) . Approximately 80X of this activity in brain of the 7-dayrold rat has been described as bound to an unidentified membrane fraction (39) . A pattern of development of this enzyme (95), lwwever, has been observed moro rooently to be similar to that found for taurine (83) : a decrosse in the relative amount of cystsinasulfinic acid decarboxylase in the soluble fraction is acoompanled by an increase in the rolative amount of the enzyme located in the crude mitochondrial plus synaptosomal fraction . A similar pattern of development of cysteinesulflnic acid decarboxylase has been observed in monkey brain (96) . Finally, tt should be mentioned that them is soma evidence that taurine administration during development can Influence, albeit weakly, adult inhibitory behaviors . Rats lnJected with taurine every 2 days between postnatal days 4 end 20 subsequently ran significantly less in the spinning wheel test and displayed lower rosponse/roinforcertiant ratios than saline-injected controls (97) " Taken together, these findings suggest that a taurinergic neurotransmitter system Is developing or was formed early In development and that this system is protected from the decrease to taurine concentration to the large soluble pool of brain which takes place during development . These date do not indicate a function for the maJor proportion of taurine in the soluble fraction of brain . Taurine in Developing Ratina Taurins has been known for many years to be prosent in the rotina in large concentrations (98) . Many studies provide evidence for the tnvolv~ement of taurine in the process of retinal transmisalon : it is taken up actively by the isolated rotina, it is roleased from rotina when the rotina is stimulated electrically or by light, and It deprossed the "b" wave of the electrorotlnogram (99-103) . Retina has been divided into nine separate layers, and the taurine concentration of each layer was determined (104) . In all of five

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Taurine In Development

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species examined, the outer nuclear layer contains the highest concentration of taurine. Since photoreceptors constitute the main call volume of this layer, it is likely that a substantial proportion of rotinal taurine is located within the photoreceptors (105-107) . In addition, loss of photoroeeptors is accompanied by loss of the major portion of rotinal taurine (12,105, 108) . Furthermoro, the layers which contain the greatest concentrations of taurine also wntain the greatest activity of cysteinasulfinie acid daearboxylase and thus have the greatest capacity for endogenous synthesis of taurine (109) . Absence of dietary taurine in the cat leads to a detreesa in taurine concentration of rotina, followed by defects in the aleetrorstinogram, degeneration of the photoroteptors and eventual blindness (12-14) . These changes aro reversible by taurine in the early stages . Of the amino acids studied, only taurine is axonally transported In the goldfish visual system suggesting that It may have spatial function in that system (15) . Furthermore, the amount of taurine prosent in rotina, as to brain, is far greater than would bs needed solely for a transmitter function, The concentration of taurine in the retina of the rat (42,110), the gerbil (43) and the cat (62) increases during development, in contrast to other neural tissue in which the concentration of taurine decroases during development . The activity of cystelnssulfinic acid dscarboxylase in rotina of the chick and of the rat incroases during development (111) in a manner similar to that found in rat brain . The taurine toncantration of monkey retina remains constant from late gestation to msturity (6 ;) . Thero is a five-fold dscroase in taurine concentration of monkey lens during development (63) ; however, the lens does not arise from neural ectoderm, as does the rotina . It is of interost that in the fetal cat the concentration of taurina in the lens is greater than that of rotina (62) . Unlike the rotina, however, taurina eoncsntration of lens changes little during development . It should be noted that the rat, gerbil and cat aro born with their eyes closed, whsroas the monkey is born with its eyes open . Taken together these findings suggest that taurine has a role in the structural integrity of the maturo rotina, in addition to its role as a neurotransmitter or neuromodulator . These findings suggest also that the retina would be particularly susceptible to a deficiency of taurine during development . Indeed, the pathological changes in kittens fad a diet devoid of taurine aro detected first in the retina . In fact, in the kitten fed a taurins-deficient diet, the dscroase in rotinal taurine concentration ras the smsllast percentage dscroase of any 24 different tissues studied (112) . Ons must conclude, thorofore, that tM rotina (at least of the cat) is particularly susceptible to atruetural damage during taurine deficiency and that the turnover of taurins in rotina has been dacroased . Apparontly rotina, the tissue which is most susceptible to taurine deficiency, is the one best able to sequester it . Another factor which may account for the sensitivity of cat rotina to taurine deficiency is the large concentration of taurins. It is moro than throe times that of monkey rotina and moro than twice that found in amr other of a wide variety of tissues of the cat which wsro examined (112) . In the monkey, in contrast, the taurins concentration of rotina is axuaded by that of several other organs (28,63) . The taurine eontsntratton of human rotina is unknown. Taurine_ in DeveloQin~ hiver Ths reports of changes in taurine concentration of developing rat liver appear to differ from oath other . Ons group roported a steady dscroase during postnatal development when taurins was maasurod rolative to protein wntent (perhaps because protein content incroases) (42) . Another group roported that

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Taurine Ia Development

9

taurine conmntration rolatiw to liver weight incroases rapidly during the last few days of gestation but changes little during postnatal development (37) " Using a very Iargs number of animals, ws found no change in taurine conmntratton of liver In the period from late gestation to maturity (41) ; however, there was a wide range of values at all times during development . In addition, we noted a tendency for pups from the same mother to haw similar conmntrations of taurine in liver at various times after birth, although there was .n o apparont corrolatlon with the concentration of taurina in the mother's 11ver . A single roport indicates that the taurine concentration of fetal, neonatal and maturo guinea pig liver is low and approximately constant (37) . The taurine eonmntratton of rabbit liver shows a ninety-fold decroase from birth to maturity according to one roport (45), with the greatest decrease taking place during the first few days after birth . In another roport thsro is a decroase of only five-fold (113) . 41b haw roportsd a rapid decroase In taurine conmntration of monkey liver Immediately after birth, although the magnitude of the decroase is only two-fold (34) . The same rapid postnatal decroase to taurine conmntration of 1 fiver also apparontly takes plain in human liver during development (34) . Ths taurina conmntrations of fetal monkey liver and of fetal human liver aro simtisr to those found at birth and them is no apparont change during the periods of gestation studied (34,53,114) . The only known function of taurina in liver is conjugation with bile acids to form predominantly taurocholic acid (2) . This is clearly an important function, for, in the taurine-deficient u t (a species which conJu gates bile acids with taurine only and not with glycine), them Is only a 10X decroase in taurlna-conjugated bile acids . In contrast, them is a groater than fifty-fold decroase in taurina conmntration of 11ver in the taurlnedefictent cat (28,112,115) " Furthermoro, the decroase to taurine-wnJugated bile acids is accompanied by the secretion of free cholic acid, which is ordinarily not secroted . Thero is no conversion to glycine-conjugation of bile acids under these circumstanms . Most species, including men, oonJugate bile acids both with taurins end with glyctns . Taurins-conJugated bile acids, which are nsussary for the absorption from the gut of lipids, and therefore secondarily of calcium, appear to haw priority in the cat when the m is an insufficiency of taurine (116) . The human neonate conJugates bile acids chiefly with taurine during the first week or two of life and gradually converts to predominantly glycinsconJugated bile acids, eventually roaching the normal adult proportions of 25% taurine-conJugated and 75X glycine-conJugated bile acids (117-120) . This conversion from predominantly taurins-conJugated bile acids to prodominantty glycine-conJugated bile acids may roduee the taurine requirement of the human neonate sufficiently to avoid the retinal problems found to the cat, even when Infants are fed a taurine-deficient diet such as commercial formulas currently represent . The pathogenesis of retinal degeneration (n the taurins-deficient kitten may be the rosult of a eonu tenation of factors which include : 1) the rapid ineroase in taurine concentration in cat retina after birth ; 2) the high taurins conuntretion ultimately attained by cat rotina ; 3) the inability of the cat to convert from the synthesis of taurine-conjugated bile acids ; 4) the rapidity with which the kitten can outgrow its endogenous supply of taurine, i .e . its rapid rate of postnatal growth ; 5) the low rate of synthesis of taurine by the cat (28) . Taurine In Developing Mu~~e Taurine appears to affect membrane permeability to cardiac muscle (16) .

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Taurine In Development

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It is thought to stabilize membrane calcium and potassium under conditions in which them is a depletion of electrolytes . It affects drug-induced cardiac arrhythmias by deprossing hyperirritability due to loss of cellular potassium . Taurine has been suggested for use as a therapeutic agent for vascular pain to patients with angina pectoris or intermittent elaudieatlon (121) . The taurine concentration of the left ventricle in patients who died of congestive heart falluro is twits normal (17,18) . Very little data is available on taurine to developing heart, and what data is available varies among species studied . In the rat, the taurine con-~ eentration of heart in the newborn is high and decreases suddenly during the first few days of life ; it than slowly increases during postnatal development to attain approximately the same value at maturity as that found in the newborn (42) . The taurine concentration of heart in the newborn gerbil is similar to that of the adult gerbil (43) . In the rabbit, the taurine concentration of heart In the newborn is high and decreases rapidly within a few days (45) : however, it then ineroases rapidly during postnatai development, roturns to the original high values at birth by ten days of age, decreases rapidly again over the next few days, and finally increases slowly to attain values at maturity which aro considerably higher than those found at birth . In the cat, our preliminary results suggest that the concentration of taurine in heart does not change during postnatal development (62) . In the developing monkey, there was no change in taurine concentration of heart during development, either in the atria or in the ventricles (63) . Limited data is available for developing skeletal muscle . The taurine concentration of gastrocnemtus muscle in the rabbit is high at birth, decreases rapidly over the next few days, and decreases slowly thereafter to reach the low values of maturity (45) . These changes in skeletal muscle are different from those in cardiac muscle in the same developing rabbits vide supra ) . Perhaps the most striking differonee Is the extremely high taurine concentration of heart in the mature rabbit compared to other tissues (including gastrocnemius muscle which has a concentration eight-fold lower than that of heart) . The concentrations of taurine in gastrocnemius, biceps, triceps and diaphragm in the monkey are similar to one another at the end of gestation, during neonatal life and at maturity (63) . It is striking that the taurine concentration of these muscles of the monkey is approximately two-fold higher during the neonatal period than it is during late gestation or at maturity . The monkey is different from the rabbit in that there is no apparont change in taurine concentration of heart during development . Also, in the mature monkey, the taurine concentration of heart is only two-fold higher than that in other muscle tissue . Both leg and breast muscle of chick embryos and newborn chicks have much higher taurine concentrations than those of mature chicks (122) . These data do not suggest a role of taurine (n muscle tissue generally, although they do indicate that cardiac muscle is different from other muscle tissue . Boys with Duchenne's muscular dystrophy, a defect in muscle cell mem branes Inherited In a sex-linked rocesaive manner, have an abnormally large urinary excretion of taurine which is unacaompaniad by generalized aminoaeiduria (123-125) . Such specific taurinuria, however, vss not observed in myotonic, limbgirdle or faetoseapulohumeral dystrophy . Taurine has been demonstrated to depress neuromuscular transmission in the cat, and It has been proposed that it is involved in the etiology of muscular dystrophy (126) . Experiments in the rat demonstrated only a small effect of taurine on neuromuscular transmission : taurine caused a hyperpolarizatton of the membrane and shortened the time of the action potential (127) . It was suggested that taurine stabilized the membrane potential and thereby reduced the effectiveness both of neuromuscular transmission and of excitation-contraction coupling

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Taurine In Development

11

(127) .

The suggestion that taurine causes hyperpolarization of the membrane by stabilization of the membrane potential is not compatible with the previous suggestion that taurine is involved in the pathogenesis of muscular dystrophy in which the membrane is depolarized . Some recent observations on the changes in concentration of taurine in the tall of the anuran tadpole during metamorphosis aro of interost (128) . The tail of this tadpole, which consists mainly of skeletal muscle, grows and then regresses during metamorphosis . The taurine concentration of the tail increases two-fold and then decreases three-fold during this sequence of changes ; however, it is still incroaslng at the time when tail rogression begins . No change in taurine concentration Is observed in trtiodothyrontnsinduced metamorphosis which produces the tail rogression . Thus, tt seams likely that the changes in taurine concentration which take place in natural metamorphosis may be a consequence of tail regression . The changes in taurine concentration aro not causally rotated to tall rogression, since the muscle changes can be induced without the accampanylng changes in taurine concentration. Taurine in Other Developing Organs The taurine concentration of kidney in the developing rat decreases slightly over the first few days of life and then remains approximately eonstant (42) . 4k have found no change in taurine concentration of developing kidney in the monkey (63) . In the rabbit, the taurine eoncentratton of the kidney decreases immediately after birth to attain the values found to mature kidney . This decrease is interrupted by en increase at ten days of age (45) . In the spleen of the rabbit, them is a decrease in taurine concentration following birth, and them is also an apparont peak at ten days of age (45) . In the rat, the taurine concentration of spleen increases slowly during devel opment (42) . Wè found no change in taurine wnoentration of developing spleen in the monkey (63) ; however, spleen had the highest concentration of the more than twenty maturo organs investigated . In the lung, a small, transient incroase in taurine concentration was observed during the neonatal period both in rat and monkey (42,63) . In small intestine of the rat, the taurine concentration increases slowly during de velopment (42) . In the pancroas of the monkey, the concentration of taurine decroases two-fold during development (63) " There is no change to the taurine concentration of adronal, pituitary or thyroid of the monkey during the periods of development studied (63) . Adronal has a high eoneentratlon (similar to that of spleen) throughout development . It has been suggested that taurine may stabilize the membranes of the adronal medullary granules, since oral administration of taurine prevented the strcss-induced decrease of epinephrine in rat adronal gland (129) . Taurine in Body F1utd~DurinJc Development The taurine concentration of human plasma is somewhat lower to the prognant female than it is in the non-pregnant female ; its concentration in the plasma of the fetus is higher than that of either the prognant or the nonprognant female (130-134) . The taurine concentration of plasma in the human fetus appears to decrease during gestation, sinoa that of plasma taken from the umbilical vein of infants at various times during gestation decreases with length of gestation (135) : it decroases rapidly after birth (136) . The large urinary excretion of taurine of the newborn infant decreases greatly during the first weeks after birth (136-140) . The urinary excrotion of taurins in women is large during early prognancy ; lactation does not affect taurine ax-

12

Taurine In Development

Vol . 21, No . 1, 1977

erotion . The taurine concentration of human amniotic fluid is similar to that of normal adult hwnan plasma ; during the 2nd trimester of pregnancy, the concentration in amniotic fluid decreases with increasing fetal crown-rump length (133,141) . The taurine concentration of fetal plasma in the rhesus monkey is greater than that of maternal plasma (142,143), as it Is in the human . In contrast to the human, the taurine concentration of plasma Is somewhat higher in the prognant than it Is in the non-prognant female rhesus monkey and the taurine concentration of amniotic fluid In the rhesus monkey incroases as prognaney progresses (144) . The taurinn concentration of plasma and urine in the protean human neonate is dependant upon diet (145,146) . Protean infants fed 3 cartrnerciat formulas derived f ram cow's milk, especially the casein-prodominant formulas, had a progrossive decrease in the taurine concentrations of plasma and urine (Fig . 4) . Protean infants fad pooled human milk, in contrast, did not have such decroases (146) . Pooled human milk, unlike cow's milk and artificial formulas derived from it, contains a considerable amount of free taurine (146) . The small taurine concentration of plasma in .prnterm Infants found by others, but not caimantad upon, also can bs explained by such dietary effects, because these infants were fed similar formulas (147) . A greater excretion of taurine in term Infants fed human milk than in those fed cow's milk also has been roported (137,148,149) . This diet-dependent decroase of taurins concentration in plasma makes it difficult to determine the time course of the decrease from plasma concentrations of between 20 and 34 tmolas X in the fetus to plasma concentrations of about 6 yunoles X in the adult (131-133) . The smaller taurine concentration of plasma and urine in the protean infant fed commerc)al fornwlas derived from cow's milk is unique : most of the other amino acids aro present in larger concentrations in plasma and urine of infants fed synthetic formulas than they aro in plasma and urine of infants fed pooled human milk (146,150,151) . Taurine is a meJor constituent of the free amino acid pool of milk in a number of species, second in concentration only to glutamate (152) . This is true for the milk of the human, baboon, Rhesus monkey, Java monkey, chimpanzee, sheep and rat (Table 2) . Gerbil milk is exceptional in that taurine concentration is much greater end that taurine comprises the bulk of the free amino acid pool . Other exceptions are milk of the rabbit and guinea pig in which the concentration of taurine is exceeded by that of several amino acids (152) . A further exception is cow's milk in which the concentration of taurine is smaller and is also exceeded by that of several amino acids (152,153) . Thus taurine represents a much smaller proportion of the total amino acid pool in milk of these species . In a number of species the taurine concentration of milk Is great during the first days of lactation and decreases to a fairly constant concentration after the first week . This has been noted in the chimpanzee, Rhesus monkey, sheep and rat (152) . Thus, for most species studied, taurine is a major constituent of milk and has a greater concentration early in lactation . The concentration of taurine in rat milk is large for the first few days after birth ; at this time it is the ninhydrin-positive compound present in the groatest concentration (8) . Taurine concentration decroases rapidly thero after and by a week after birth has reached an approximately constant value (Fig . 5) . The total amount of taurine transferred to the pup via the milk decreases initially, but increases again by the first week after birth (Fig . 6) . Wa have studied the transfer of [355] taurinn, Injected Into the mother 6-8 h after birth, via the milk to brain and liver of the pups . This study demonstrated that labelled taurine from thn mother Is secreted in the m(ik (Fig . 6) and accumulates in liver and brain of the pups (Fig . 7) . We calculated that approximately 4 Mnoles of taurine is supplied to each pup in

13

Taurine In Development

Vol . 21, No . 1, 1977

PLASMA TAURINE

W O

`

0~ `

e a .o"~

I

Y8

0 0

v

a

2

~

s

srEEKs

ô s

~

s

URINE TAURINE

20

0 ! 18 12

4

e

~' .

b

p

\~

3.0 "/.

o~ `./ /, o ""b. .ro,

~~_0 ~~ - -o

LIS%

IwEEK3 FIG . 4

Effect of dietary regimen on the moan plasma taurine concentration and mean urine taurine concentration of protsrm human Infants . BM ~ pooled, banked human milk ; 1 .596, 3X ~ 1 .5 g % protein, 3 .0 g % protein, 18 parts bovine whey proteins : 82 parts bovine caseins .

14

Taurine In Development

Vol . 21, No . 1, 1977

the first five days and that, of this, a minimum of 0 .5 fm~olea ended up in the brain at five days . TABLE 2 TAURINE

IN MILK

Values are yrtwles/100 ml, mean f S .E . of the number of samples in parentheses, taken from the reference indicated . Except where noted, all samples were collected no earlier then seven days after the start of lactation .

Species Muman Chimpanzee Baboon Rhesus monkey Java monkey Cow Sheep Rabbit Guinea pig Rat Gerbil

Taurine Concentration 33 .6 33 .7 26 .6 26 .4 38 .0 53 .2 13 .5 3 .7 12 .1 14 .1 13 .6 16 .6 15 .2 63 .3 678

t ± ± { ± ±

8 .5 2 .8 2,9 1 .2 4 .6 5 .6

± ± ± ± ± ± ± t

0 .7 8 .0 3 .1 3 .2 3 .0 1 .2 7 .8 240

(3) (28) (6)~ (3) (11) (4) (1) (4) (3) (3) (7) (3) (27)ßr (9)*k* (3)

Reference (153) (152) (150) (152) (152) (152) (152) (152) (153) (152) (152) (152) ($) (8) (152)

*separate pools of banked milk **samples taken more than five days after the start of lactation . ***samples taken during the first two days of lactation . Thus, even in the developing rat, which has a greater capacity for biosynthesis of taurine than most other species, dietary taurine is a algniftcant source of tissue taurine, eapectally that of brain . In the light of our finding that preterm human infants fed commercial formulas become taurinedeflclent, as far as can be Judged from plasma concentrations and urinary excretion, it seems likely that there is a dietary requirement for taurine, in the rapidly growing human infant (145,146) . In addition, both fetal and mature human liver have very tow activity of cystainesulfintc acid decarboxylase, the enzyme directly responsible for the formation of taurine from cysteine (19,146) . In adult humans only 1X of an oral load of L-cysteine was recovered as increased urinary excretion of taurine, suggesting that even the mature home has a relatively limited ability to synthesize taurine and also may be largely dependent on dietary taurine (154) . The limited ability of the adult human to convert dietary cysteine to taurine is to striking contrast to the considerable ability of the rat to convert dietary cysteine to taurine (155) . Although no overt adverse clinical signs have been observed to human infants fed commercial formulas, the potenl~tal long-term clinical effects of e deficiency of taurine, especially in the prate nn infant, warrant systematic

Vol . 1, No . 1, 1977

Taurine In Development

15

~ .0 É w "J _ G

E z 0

â

0.8

MILK

o.s

z W

z 0 U

0.4

W Z

0

FIG. 5

10 20 DAYS AFTER BIRTH

30

Taurine concentration in rat milk throughout the period of lactation .

investigation . In the Itght of the growing evidence of the physToiogical importance of taurine during development, the possibility that it might be involved in the etiology of same forms of the sudden infant death syndrome(:), perhaps by causing cardiac arrhythmia or failure of some autonomic transmitter function, should be kept to mind . Conclu sions and Speculations The foregoing collation of data on taurine in development suggests to us same reasonably firm conclusions and same tantalizing speculations . The evidence for a functional role of taurine is firmest In the central nervous system . This functional role is elucidated best in the retina and visual system In whleh eonsidereble evldenee suggests that taurine acts as a neurotransmitter or neuromodulator ; 1) The subcallular dtatributton of taurine and of eysteinesulfinic acid deearboxylase and their change during development suggest taurine and the enz,me which synthesizes It are enriched in nerve-ending particles and that taurine is bound to vesicular protein . 2) There are specific mechanisms in nerve-ending particles and retina for uptake of taurine and these aro particularly active early in development . 3) The presence of taurine and of cystelnesulfinic ac td decarboxylase in photoreceptor cells, the photoreceptor cell degeneration in the taurinedefictent kitten, the changes In the electroretinogram induced by taurine and taurine deficiency and the axonal transport of free taurine all suggest an important functional and possibly structural role for taurine to the visual system . The developmental finding for taurine which seems common to all species studied is that the taurine concentration of brain is greater in the newborn

16

Taurine In Development

DAYS

FIG. 6

Vol . 21, No . 1, 1977

AFTER BIRTH

Total taurine and total [35~] taurine transferred to each rat pup via the milk after injecting 250 NCi [35S] taurine into the mother 6-8 hours after birth .

animal than it is In the msture animal and that the high concentration decreases gradually during the neonatal period to attain, at the time of weaning, values similar to those in the mature animal . It Is likely that dietary taurine, obtained from the milk, Is an important source of brain taurine for many species . The taurine concentration of ratina incroases in animals born with their eyes closed, wheroas it remains constant after birth, presumably already having reached a maximum, In animals born with their eyes open . It is tempting to speculate that taurine is rotained by brain during synaptogenesis and that this relative enrichnent to synaptosomes is most prominent in the areas of brain which are involved in visual function . The taurine concentration of brain decreases as the wlume of brain Increases during rapid growth . The taurine content per brain increases, however, because tt is rotained for functional purposes by the visual system end other systems which roquiro it as a neuromodulator or neurotransmitter . The increase in taurine content per brain probably results from taurine rotentlon during synaptogenests . In animals in which the m is a dietary requirement for taurine and in which the liver conjugates bile acids with taurine only, the ratios and brain may not be able to compete effectively for available taurine . Such a short-circuiting of available taurine would result in functional and/or structural damage in ratios and brain . This hypothesis alone doss not explain the high concentrations of taurine In the soluble fraction of brain prior to birth . In general, large taurine concentrations are found In tissues which aro characterized by large amounts of contractile protein, especially microtubuiar protein, e .g, fetal brain, rotinal photoreceptor cells, platelets, muscle, adrenal medulla . The parallelism between taurine and mierotubules in these tissues deserves further investigation .

Vol . 21, No . 1, 1977

Taurine In Development

17

E .3

r Io~ar" I"sl TAUInREieRruR

2.0

Ls

LO

o .a,

0

i s

~

i

'

~ lo°a" fAsl

1

I

Y

3

4

5 DAYS

FIG,

7

6

7

B

9

10

II

12

TAURIRE/UVER

13

14

10

AFTER BIRTH

Total C35S7 taurine which ace mulates in brain and liver of each ret pup after injecting 250 YCI ~355~ taurine into the mother 6-8 hours after birth . References

11 .

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19

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Taurine In Development

20

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104 . 105 .

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Taurine In Development

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