Cognitive Effects of Endocrine-Disrupting Chemicals in Animals

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Environmental Health Perspectives VOLUME 109 | NUMBER 12 | December 2001 1197

Cognitive Effects of Endocrine-Disrupting Chemicals in Animals

Susan L. Schantz and John J. Widholm

Department of Veterinary Biosciences and Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA

There is increasing concern about chemicalpollutants that have the ability to act as hor-mone mimics. Because of a structural similar-ity with an endogenous hormone, an abilityto interact with hormone transport proteins,or an ability to disrupt hormone metabolism,these chemicals have the potential to mimic,or in some cases block, the effects of theendogenous hormone. In either case, thesechemicals serve to disrupt the normal actionsof endogenous hormones and thus have

become known as endocrine disruptors. Alarge number of environmental pollutantsincluding phthalates, alkylphenolic com-pounds, polychlorinated biphenyls (PCBs),polychlorinated dibenzodioxins, organochlo-rine pesticides, bisphenol A, and heavy met-als including lead, mercury, and cadmiumhave been shown to disrupt endocrine func-tion in animals. Because hormonally medi-ated events play a central role in centralnervous system (CNS) development andfunction, there is speculation that some ofthe cognitive deficits that arise from develop-mental exposure to environmental chemicalsmay be the result of endocrine disruption.

For example, thyroid hormone is essen-tial for proper neuronal proliferation, cellmigration, and differentiation in the devel-oping mammalian brain (1). Disruption ofthe thyroid system during development hasbeen shown to result in permanent changesin neurochemical (2), morphologic (3,4),and neurobehavioral end points (57).There are a number of environmental conta-minants that have been shown to affect thy-roid system function (8). One example isPCBs. PCBs alter thyroid function through

multiple mechanisms including direct toxiceffects to the thyroid gland, induction ofthyroid hormone metabolism via UDP-glu-curonyl transferase, and interaction withthyroid hormone carrier proteins (9).Further complicating matters is the fact thatPCBs have multiple endocrine effects,impacting not only thyroid hormones butthe gonadal (1012) and adrenal steroid sys-tems (13) as well. PCBs are just one exampleof the many environmental contaminants

capable of disrupting one or more endocrinesystems. When one considers that humanpopulations have body burdens of multiplecontaminants capable of affecting multipleendocrine systems, the potential humanhealth risk could be significant. Therefore,an understanding of the endocrine-disrupt-ing potential of these chemicals and subse-quent neurobehavioral changes that result isan important task facing environmental toxi-cologists, endocrinologists, and behaviorists.

The goals of the current review are todiscuss the evidence for cognitive changesresulting from exposure of laboratory ani-mals to chemicals classified as endocrine dis-

ruptors and to examine the extent to whichthese cognitive changes appear to be medi-ated by changes in hormonal function. Thediscussion is focused on the three hormonalsystemsthe gonadal steroids, the thyroidhormones and the glucocorticoids, for whichthe richest data set on endocrine disruptionexists. Although other hormones, growthhormone in particular, play important rolesin brain development and behavior, rela-tively little is known about the effects ofchemical pollutants on other hormonal

systems. We begin by reviewing the roles of

the gonadal steroids, thyroid hormones, andglucocorticoids in brain development andfunction. We then review the endocrinechanges and cognitive effects that have beenreported for several major chemical pollu-tants including PCBs, dioxins, and lead, dis-cuss the evidence for causal relationshipsbetween the endocrine disruption and cogni-tive effects, and conclude by highlightingimportant directions for further research.

Role of Hormones in BrainDevelopment and CognitionEstrogens and androgens. The role of gonadalsteroids in the development of brain areas

involved in reproduction has been recognizedfor many years (14). The brain is particularlysensitive to the differentiating effects ofgonadal hormones during a critical periodearly in development. The absence of testicu-lar hormones during this period allows thedevelopment of a female pattern of behaviorand neuroendocrine function. Conversely,the presence of testicular hormones allowsthe development of a male pattern. In the rat,the critical period for sexual differentiation ofthe brain starts a few days before birth andends approximately 10 days after birth. Thebrain is exquisitely sensitive to estrogens and

androgens during this time. Female ratstreated with testosterone during the criticalperiod permanently lose the capacity tosecrete leutinizing hormone in a cyclical fash-ion in response to estrogen stimulation anddo not show typical female reproductivebehaviors, such as lordosis. Conversely, theyhave the capacity to exhibit masculine sexualbehaviors in response to administration oftestosterone. Male rats castrated during thecritical period are unable to display typicalmale sexual behaviors after administration oftestosterone in adulthood, but will show lor-dosis in response to estrogen treatment.

In the rat, sexual differentiation primarily

occurs through the aromatization of testos-terone to estrogen locally within the brain(14). Estrogen then acts to organize neural

Address correspondence to S.L. Schantz, Departmentof Veterinary Biosciences, College of VeterinaryMedicine, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL61802 USA. Telephone: (217) 333-6230. Fax: (217)244-1652. E-mail: [email protected] thank Geoff B. Clarkson for his help with the

review and revision of this manuscript.Received 20 July 1999; accepted 4 May 2001.

A large number of chemical pollutants including phthalates, alkylphenolic compounds, polychlo-rinated biphenyls and polychlorinated dibenzodioxins, organochlorine pesticides, bisphenol A,

and metals including lead, mercury, and cadmium have the ability to disrupt endocrine functionin animals. Some of these same chemicals have been shown to alter cognitive function in animals

and humans. Because hormonally mediated events play a central role in central nervous systemdevelopment and function, a number of researchers have speculated that the changes in cognitivefunction are mediated by the endocrine-like actions of these chemicals. In this paper we review

the evidence that cognitive effects of chemicals classified as environmental endocrine disruptorsare mediated by changes in hormonal function. We begin by briefly reviewing the role of gonadalsteroids, thyroid hormones, and glucocorticoids in brain development and brain function. We

then review the endocrine changes and cognitive effects that have been reported for selectedendocrine-disrupting chemicals, discuss the evidence for causal relationships between endocrine

disruption and cognitive effects, and suggest directions for future research. Key words: cognitivefunction, endocrine disruptors, learning, memory. Environ Health Perspect109:11971206(2001). [Online 14 November 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p1197-1206schantz/abstract.html

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components in the hypothalamus and preop-tic area in a male-specific pattern. In theabsence of testosterone, the hypothalamusdevelops in a female-specific pattern. Themost striking sex difference in brainanatomy is present in an area within themedial preoptic area (MPOA) known as thesexually dimorphic nucleus of the preoptic

area (SDN-POA). This nucleus is 5- to7-fold larger in male rats than in females(15). The nucleus is dimorphic not only interms of its volume, but also in terms of theneurotransmitters in the cell bodies of theneurons comprising the nucleus and in thefibers innervating it (16). Another region,the ventral medial nucleus of the hypothala-mus (VMN), is also sexually dimorphic (17).The roles of these hypothalamic nuclei inreproductive behavior are not completelyunderstood, but the VMN appears to beinvolved in the lordosis response in femalerats (17), and the SDN-POA has beenimplicated in the execution of coital behav-

ior in male rats (16). Some aspects of sexualdifferentiation of the brain, including thedevelopment of sexually dimorphic patternsof social play, appear to be regulated by thedirect actions of androgens in the brain,rather than by the aromatization of andro-gens to estrogen (18). A similar process ofsexual differentiation appears to occur in thebrains of all mammalian species includinghumans. However, in other species, particu-larly nonhuman primates and humans, themechanisms are not as well understood.

Recently it has become clear that earlyexposure to estrogens and androgens has

important actions in areas of the brain thatare not involved in reproduction. One ofthese is the hippocampus, which plays animportant role in learning and memory, par-ticularly spatial learning and memory (19).Sex differences in spatial learning have beenreported by many investigators and appearto be present in humans as well as in animals(20). In general, men outperform women ontasks that require spatial skills. Male rodentsalso make fewer errors than females on spa-tial learning tasks. The work of Williams etal. (21) suggests that these differences couldbe due to differences in the way males andfemales process spatial information. Male

rats appear to attend primarily to geometriccues (the shape of the environment), whereasfemales use a combination of landmarks andgeometry to locate a target.

As reviewed by McEwen et al. (19), sexdifferences in hippocampal morphology alsoexist. These include differences in the num-ber of spines on the apical dendritic shafts ofCA3 pyramidal cells (22), as well as differ-ences in the number of mossy fiber synapsesto these cells (23). Male rats have morespines on the apical dendrites and more

mossy fiber synapses. They also have a largerand more asymmetric dentate gyrus (24).Neonatal testosterone treatment causes thefemale dentate gyrus to appear masculine andalso improves the spatial learning ability offemale rats (24). In contrast, neonatal castra-tion of male rats results in a female pattern ofspatial learning (20).

The rat hippocampus shows a transientincrease in estrogen receptors for a shortperiod during perinatal development (25).This coincides with transient expression ofthe aromatase that converts testosterone toestrogen (26). Thus, hippocampal estrogenreceptors of male rats are exposed to locallygenerated estrogen during a brief periodearly in development. Just as in the hypo-thalamus, this appears to lead to sexual dif-ferentiation of hippocampal structure andfunction. Exposure to chemicals that perturbthe delicate balance of gonadal hormonesduring early development could result inchanges in hippocampal morphology and

alter the normal pattern of male/female dif-ferences in spatial learning.

Estrogen receptors are sparsely distrib-uted in the adult hippocampus, but recentresearch indicates that estrogen continues toplay an important role in the hippocampusduring adulthood. Morphologic studies haveshown that estrogen induces cyclical changesin dendritic spine density on pyramidal cellsin the CA1 region of the hippocampus infemale rats (27). More recent in vitrostudieshave demonstrated that the estradiol-induced increase in spine density increasesthe sensitivity of the cells to N-methyl-D-

aspartate receptor-mediated synaptic input(28). There are a number of studies suggest-ing that learning ability varies over thecourse of the estrous cycle in female rats(2933), although several other studies havenot found any changes (34,35). In addition,estrogen replacement therapy appears to pre-serve memory function in post-menopausalwomen (36,37), as well as in ovariectomizedfemale rats (38). Thus, exposure to environ-mental chemicals that have estrogenic orantiestrogenic actions could also impact cog-nitive function during adulthood and aging.

There are two estrogen receptor subtypes(ER and ER) that are differentially distrib-

uted throughout the CNS. Some regionsincluding the neurons of the olfactory bulb;supraoptic, paraventricular, suprachiasmatic,and tuberal hypothalamic nuclei; zonaincerta; ventral tegmental area; and cerebellarPurkinje cellscontain only ER (39). Incontrast, only ER is found in the ventrome-dial hypothalamic nucleus and the subfornicalorgan. Neurons in many other brain regionscontain both ER and ER. However, therelative amounts of the two receptor subtypesvary by region. For example, Shughrue et al.

(39) found that the cerebral cortex and hip-pocampus contain both ER and ER, butthe relative amount of ER is much greaterthan ER in these brain regions. Region-spe-cific expression of ER and ER may beimportant in determining the physiologicresponses of neurons to estrogen action.Thus, if different environmental estrogens

have different affinities for the two ER sub-types, they could potentially affect braindevelopment and behavior in very differentways.

Thyroid hormones. The actions of thy-roid hormones are vital for normal braindevelopment (1). Thyroid hormones areinvolved in regulating many aspects of ner-vous system development including neuronalproliferation, cell migration, and differentia-tion. Neonatal hypothyroidism results indelayed myelinogenesis, alterations in cellmigration, delayed or impaired neuronal dif-ferentiation and synaptogenesis, and alter-ations in neurotransmitter function (24).

These morphologic and neurochemicalchanges are associated with permanentimpairments in neurobehavioral function,including delayed reflex development,changes in motor activity and emotionality,and deficits in learning and memory(5,6,40). Although thyroid hormone imbal-ances during adulthood can also lead to cog-nitive and behavioral disturbances, these areusually completely reversible with appropri-ate hormone therapy.

Many of the biochemical and morpho-logic changes observed in the brains ofneonatally hypothyroid rats appear to

recover with time, but several brain regions,including the hippocampus, show persistentmorphologic changes in response to earlythyroid hormone manipulations (41). Earlyhypothyroidism results in hippocampal CA3pyramidal cells with markedly stunted den-dritic trees (42). The CA3 cells originateduring the early embryonic period (43), butundergo extensive dendritic remodeling dur-ing the second and third postnatal weeks(42). The timing of these changes coincideswith peak levels of thyroid hormones (44)and thyroid hormone receptor (45), whichmay explain the unusual sensitivity of theCA3 pyramidal cells to neonatal thyroid hor-

mone imbalances. In contrast, hippocampalCA1 pyramidal cells do not undergo exten-sive dendritic restructuring during the post-natal thyroid hormone surge and appear tobe less affected by neonatal thyroid hormonemanipulations (42). Neonatal hypothy-roidism also reduces the number of dentategyrus granule cells (46) and impairs theirdendritic arborization (42,47).

The cognitive effects of neonatal hypothy-roidism reflect the fact that the hippocampusis one of the most severely damaged brain

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regions. Spatial learning and memory isseverely impaired on the radial arm maze (5)and Morris water maze (6), as well as onother complex mazes (40). Congenitallyhypothyroid children have cognitive deficitsnot unlike those observed in neonatallyhypothyroid rats. These include impairedmemory and spatial perception, as well as

attentional problems (1

). Subtle problemswith hearing, speech, and word comprehen-sion are also common. A large number ofenvironmental chemicals are known or sus-pected of altering thyroid hormone function(8). Exposure to these chemicals during earlydevelopment could potentially interfere withbrain development and cause permanentdeficits in cognitive function.

Glucocorticoids. Glucocorticoids also havea profound affect on brain development. Inthe rat, the first 2 weeks of life are character-ized by low basal levels of corticosterone andhyporesponsiveness of the hypothalamic-pitu-itary-adrenal (HPA) axis to stressful stimuli

(48). During this period, the brain is verysensitive to environmental or chemical manip-ulations. Various environmental stimuliincluding electric shock, heat stress, exposureto novelty, and handling of the neonate havebeen shown to produce long-lasting or perma-nent changes in brain glucocorticoid receptorexpression and behavior. The best studiedamong these is the effect of early handling(49). Rats handled during infancy have a per-manent increase in glucocorticoid receptors inthe hippocampus, which results in greater hip-pocampal sensitivity to glucocorticoids andbetter regulatory control of the stress response.

Less corticosterone is secreted in response tostress, and levels return to baseline morerapidly. Over the life span, this translates intolower cumulative exposure to glucocorticoids,which results in less hippocampal cell loss andless decline in memory function during aging(50). Interestingly, mothers of handled pupsspend more time licking and manipulatingtheir pups, and it is these alterations in mater-nal behavior that seem to mediate the han-dling effect on glucocorticoid function (49).

Unlike the positive effects of neonatalhandling, exposure to elevated levels of glu-cocorticoids during the period when theHPA axis is normally quiescent can have

detrimental effects on brain development(48). Cell proliferation ceases early, andaxonal outgrowth, myelination, formation ofdendritic spines, and synaptogenesis areretarded. Some of these effects may bereversible if the exposure to exogenous glu-cocorticoids ends early enough, but recoveryis seldom complete. As with thyroid hor-mone imbalances, these changes in brainmorphology are accompanied by deficits inbehavioral function, including deficits inlearning and altered motor activity (48).

Many studies have shown that hip-pocampal development and function areexquisitely sensitive to the circulating levelsof glucocorticoids. Formation of the granulecells of the dentate gyrus, in particular, isclosely linked to adrenal steroids (51 ).Immediately before birth the levels of gluco-corticoids are high and the number of den-

tate gyrus granule cells that incorporate3H-thymidine is low. As discussed above,after birth, the levels of adrenal steroids dropand remain low for roughly 2 weeks. Duringthis period, the number of dentate gyrusgranule cells that incorporate 3H-thymidineincreases dramatically. As glucocorticoid lev-els rise again at the end of the hyporespon-sive period, granule cell proliferationdiminishes once again. In adulthood, thelevels of adrenal steroids are relatively highand the rate of granule cell proliferationremains low. Injecting either developingpups or adult rats with corticosteronereduces the rate of granule cell proliferation,

wher ea s re mova l of th e ad re na l gl andincreases proliferation. Paradoxically, adrenalsteroids also suppress granule cell death.Throughout the life of the rat, the level ofadrenal steroids correlates negatively withthe number of degenerating dentate gyrusgranule cells. In the adult animal, adrenalec-tomy results in massive granule cell death.

Normal levels of circulating adrenalsteroids appear to be necessary for accurateperformance on spatial tasks, which is notsurprising given the role of the hippocampusin spatial learning and memory. Eitherincreases or decreases in corticosterone impair

spatial learning in the rat. Adrenalectomy hasbeen shown to impair performance on theradial arm maze (52) and the Morris watermaze (53). Conversely, restraint stress, whichelevates corticosterone levels, also impairsradial arm maze performance (54). Chemicalsthat alter the levels of adrenal steroids ormimic or block their actions, would have thepotential to alter dentate gyrus morphologyand disturb spatial learning and memory.Although exposure during development ismore likely to lead to permanent functionalchanges, cognitive deficits are possible regard-less of whether exposure occurs during devel-opment or in adulthood.

Interactions between hormone systems. Itis important to note that individual hormonalsystems interact with each other in complexways. Thus, the possibility exists for alter-ations in one specific hormonal pathway tocascade through multiple systems, producingnervous system effects that are complex anddifficult to interpret (55). For example, thy-roid hormones appear to be involved in medi-ating the effects of handling on glucocorticoidreceptor expression (49). Handling activatesthe hypothalamic-pituitary-thyroid axis,

increasing the levels of thyroid hormones.This results in increased 5-hydroxytryptamineturnover in the hippocampus, which in turnacts to permanently increase hippocampalglucocorticoid receptor expression. Directneonatal treatment with thyroid hormone hasthe same effect, whereas treatment with thegoitrogen propylthiouracil blocks the increase

in hippocampal glucocorticoid receptor bind-ing usually observed after handling (49).Alterations in thyroid hormones during

the critical period can also affect androgen-dependent sexual differentiation of the brain.Hyperthyroidism shortens the critical periodfor androgen exposure, whereas hypothy-roidism prolongs it. In addition to these indi-rect effects, there is recent evidence thatthyroid hormone may also inhibit estrogensactions directly at the genomic level (56).Thus, agents that increase thyroid hormonebioavailability or mimic the actions of thyroidhormone might be expected to attenuateestrogen-mediated responses such as sexual

differentiation of the brain, whereas agentsthat reduce or block thyroid hormone actionwould be expected to have the opposite effect.

Effects of Endocrine-DisruptingChemicals on CognitionA large number of synthetic chemicals havebeen identified as known or suspectedendocrine disruptors (57). For the most part,these are compounds that have estrogenic orantiestrogenic actions (58) and/or disruptthyroid function (8). A much smaller num-ber of chemicals have been evaluated foreffects on other endocrine systems such as

androgens and adrenal steroids. Keith (59

)has compiled a comparative list of environ-mental endocrine disruptors based on listsobtained from scientists at the U.S.Environmental Protection Agency (U.S.EPA), the Centers for Disease Control andPrevention (CDC), and the World WildlifeFund (WWF). Although many chemicalsappear on all three lists, there are also signifi-cant differences among the three lists. A totalof 103 different chemicals are representedwith 60, 48, and 68 chemicals appearing onthe U.S. EPA, CDC, and WWF lists, respec-tively. The discrepancies between the threelists highlight the fact that we do not have

adequate scientific data on many potentialendocrine disruptors. Because of the limitedscope of this review, we will limit our discus-sion primarily to those chemicals that allthree sources identified as environmentalendocrine disruptors. These fall into severalbroad chemical classes including phthalates,alkylphenolic compounds, organochlorinepesticides, PCBs, dioxins and furans, bisphe-nol A, and heavy metals (Table 1).

The lack of good scientific data onendocrine disruptors becomes even more

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obvious when one attempts to investigatethe effects of these chemicals on cognitivefunction. Despite the fact that hormonesplay a central role in CNS development andfunction, few endocrine disruptors have beenevaluated for cognitive effects in animal mod-els, and few, if any, mechanistic studiesdirectly relating changes in cognitive function

to altered endocrine status have been con-ducted. Table 1 lists individual endocrinedisruptors by chemical class, identifies someof the hormonal systems they act on, andindicates whether cognitive function has beenassessed. Because few or no data exist formost of the chemicals on the list, it will benecessary to focus this discussion on a fewexamples for which cognitive effects havebeen documented.

PCBs and dioxins. PCBs and dioxins arewidely dispersed, environmentally persistentorganic compounds. PCBs were manufac-tured commercially in the United Statesfrom the 1930s through the 1970s and were

widely used as dielectric fluids in capacitorsand transformers (60). Dioxins are struc-turally similar compounds that are formedas unwanted by-products during the manu-facture of certain herbicides and wood prod-ucts. Dioxins are also formed duringcombustion of chlorinated compounds andare found in fly ash from municipal andhospital incinerators (61).

The endocrine-disrupting properties andcognitive effects of PCBs and dioxins havebeen extensively studied in animal models.Both have complex effects on multipleendocrine systems (10,62). PCBs and dioxins

have been shown to alter thyroid function inrodents by multiple mechanisms, includingdirect toxic effects on the thyroid gland,induction of thyroid hormone metabolismvia the UDP-glucuronyl transferases, andinteractions with thyroid hormone plasmatransport proteins, particularly transthyretin(9). A number of investigators have evaluatedthe effects of maternal PCB exposure on thy-roid function of rat pups (6365). Pup serumthyroxine (T4) levels are markedly reduced byPCB or dioxin exposure, but the levels of theactive form of the hormone, triiodothyronine(T 3), are generally unchanged, or onlyslightly reduced. A relationship between

exposure to dioxins and PCBs and alterationsin thyroid hormones has also been reportedin human infants (66). Infants exposed tohigher levels of PCBs and dioxins had lowerfree T4 levels and higher thyroid-stimulatinghormone levels. Thyroid hormone is trans-ported to the brain as T4 and then convertedlocally to T3 (67). Based on this knowledge,it has been argued that the dramatic reduc-tions in serum T4 reported in rats after peri-natal PCB exposure could place the brain atspecial risk for hypothyroid-related effects

(68). However, recently Morse et al. (64)found that, although both serum and brainT4 levels were reduced after fetal PCB expo-sure, brain T3 levels remained normal or nearnormal. To complicate the situation evenfurther, a recent report suggests that PCBsmay actually act as thyroid hormone mimicsin the brain (69). Exposure to the PCB mix-

ture Aroclor 1254 caused marked reductionsin circulating T4 concentrations, yet elevationsin the expression of two key thyroid-hormoneresponsive genes, RC3/neurogranin andmyelin basic protein, were observed in thedeveloping brain. Chemical goitrogens such aspropylthiouracil and methimazole reduce theexpression of these same genes (70,71).

Commercial PCB mixtures have longbeen known to be estrogenic (11,12), butmore recent studies focusing on individualPCB congeners have revealed a complexarray of estrogenic and antiestrogenic effects(10). Certain congeners appear to act asestrogens in some assays and antiestrogens inothers. Until recently, coplanar PCBs and

dioxins were considered to be strictly anti-estrogenic, but it now appears that coplanarPCBs can act as estrogens in some assays(72,73). PCBs and dioxins can also disruptandrogen production (74). The ability ofdioxins to act as antiestrogens and antian-drogens has spawned a number of studiesassessing the effects ofin uteroexposure on



Table 1. Effects of synthetic chemicals on endocrine and cognitive function.

AltersEstrogen/ cognitive

Compound androgen Thyroid Glucocorticoids function? References

Industrial chemicalsBisphenol A A; E+ ? ? ?

PCBs, dioxins, and furansDioxins A; E Mixed (T4; Mixed Yes (85,86,94,95)

unchanged or (C; C;T3; unchanged unchanged oror TSH) ACTH)

PCBs E+/; A Mixed (T4; C Yes (8284,87,88)unchanged orT3; unchangedor TSH)

PCDFs E T4; TSH ? ?Pentachlorophenol E+; A G; T4 ? ?

PhthalatesButylbenzylphthalate A; E+ ? ? ?Diethylhexylphthalate ? T4 ? ?Di-n-Butylphthalate E+ ? ? ?

Alkylphenolsp-Nonylphenol A+; E+ ? ? ?

Organochlorine pesticidesAlachlor E+ T4; T3; ? ?

TSH; GChlordane A G C (females) Yes (142)

C (males)Chlordecone (Kepone) E+ ? Mixed (C or Yes (128,132134)

no change)DDT A;E+ T3; PBI; C; response Yes (128,135137)

G to ACTHDDE A;E+ G; I uptake C; response ?

to ACTHDieldrin A;E+ G; PBI ? Yes (123126)Endosulfan E+ T4; T3; G ? Yes (129131)Heptachlor A ? C ?Lindane E+/ T4; T3; ? Yes (127,128,143)

TSH; PBI; GOxychlordane ? G ? ?Other pesticides/herbicides

2,4-D A PBI; ? Yes (144)I uptake

Atrazine A;E Mixed (T3; ? Yes (145)T4; T3)

Heavy metalsCadmium E T4; T3; G Mixed ( C; Yes (146,147)

C; or no change)Mercury A; E T3; I uptake Mixed ( response Yes (148,149)

to ACTH; or no change)Lead A;E Mixed C Yes (110121)

Abbreviations: A+, androgenic; A, antiandrogenic; ACTH, adrenocorticotropic hormone; C, corticosterone; 2,4-D, 2,4-dichlorophenoxyacetic acid; E+, estrogenic; E, antiestrogenic; G, goiter; I, iodine; PBI, protein-bound iodine; PCDF, poly-chlorinated dibenzofurans; TSH, thyroid-stimulating hormone; ?, unknown.


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neuroendocrine function, reproductivebehavior, and CNS morphology of male rats(7577). Demasculinization and feminiza-tion of reproductive behavior, as well as fem-inization of neuroendocrine function, havebeen reported, but the only study thatassessed CNS morphology did not find anyevidence of altered sexual differentiation in

the brain (76

), so the mechanism for theseeffects remains uncertain. In contrast to thewealth of data available for dioxin, there arefew studies that assess reproductive behaviorand neuroendocrine function after in uteroPCB exposure.

Early PCB exposure can alter function ofthe HPA axis (13), suppressing basal andstimulated corticosterone levels, but effects onthis system have been less extensively studiedthan the estrogenic and thyrotoxic effects.High doses of dioxin alter adrenal steroidfunction in adult animals (78,79), but theeffects ofin uteroexposure on functioning ofthe HPA axis have not been assessed.

Glucocorticoid receptor binding was down-regulated in both the palate and thymus afterearly dioxin exposure (80,81). This suggeststhat there may be alterations in glucocorticoidreceptor expression in other tissues, includingthe brain, after early dioxin exposure.

In summary, PCBs and dioxins have anumber of documented endocrine-disruptingeffects, which could act individually or inconcert to alter CNS development and cog-nitive function. Neonatal hypothyroidismhas profound effects on brain developmentand cognitive function. Many investigatorshave hypothesized that PCBs and dioxins

alter behavioral function through theiractions on thyroid hormones (1,9). Othershave suggested that it is more likely that theactions of PCBs and dioxins on multiple hor-mone systems interact in complex ways toproduce CNS effects (55).

Is there evidence to support the con-tention that PCBs and dioxins impair cogni-tive function through their endocrine-disrupting actions? It is clear from laboratoryanimal studies that developmental exposure toPCB mixtures or ortho-substituted PCB con-geners results in long-lasting deficits in learn-ing and memory. The evidence for learningdeficits after exposure to dioxin or coplanar

PCB congeners is not as clear. In fact, undersome circumstances exposure to dioxin mayfacilitate learning. Early studies in monkeysexposed to complex mixtures of PCBs viamaternal transfer during gestation and lacta-tion found long-term deficits in spatial learn-ing and memory (82). The monkeys wereimpaired on two types of spatial learning tasks:spatial discrimination-reversal learning anddelayed spatial alternation. The deficit on thespatial alternation task was particularly strik-ing. The PCB-exposed monkeys were never

able to achieve control levels of performance,even after an extended period of testing. Thispronounced deficit in spatial learning wasobserved when the monkeys were 46 yearsold, even though they had not been exposedto PCBs since they were weaned at 4 monthsof age. The monkeys were equally impaired atshort and long delays, suggesting a deficit in

learning or attentional processes rather thanmemory.More recently, Rice and Hayward (83)

exposed monkey infants to a mixture of PCBcongeners formulated to represent the PCBstypically found in human breast milk, frombirth to 20 weeks of age. Beginning at 3 yearsof age, the monkeys were tested on a series oflearning tasks. As in the earlier study, thePCB-exposed monkeys showed a clearimpairment in their ability to learn a delayedspatial alternation task. Again, the impair-ment in spatial alternation was interpreted asa learning decrement rather than a deficit inmemory. Later, the monkeys in the Rice

study were tested in several operant sched-ules, including a multiple fixed interval-fixedratio schedule (84). The PCB-exposed mon-keys showed retarded acquisition of the fixedinterval schedule. The results of this study areparticularly noteworthy because the tissuelevels of PCBs after exposure were similar tothe tissue levels typically observed in thehuman population.

In contrast to PCB-exposed monkeys,monkeys exposed to dioxin during develop-ment did not show any impairments in spa-tial learning (85). In fact, they did slightlybetter than control monkeys on both spatial

discrimination-reversal learning and delayedspatial alternation (86). The dioxin-exposedmonkeys were, however, impaired in theirability to learn nonspatial discrimination-reversal problems using color or shape as therelevant cues (85,86). Based on these dis-crepant findings in PCB- and dioxin-exposed monkeys, it has been suggested thatthe impaired spatial learning in the PCB-exposed monkeys could be related to thenondioxin-like, ortho-substituted PCBspresent in the mixtures (86).

Later rodent studies using individualortho-substituted and coplanar PCB con-geners support this hypothesis. Rats

exposed to any of three different ortho-sub-stituted PCB congeners (2,4,4-trichloro-biphenyl; 2,3,4,4,5-pentachlorobiphenyl,or 2,2,4,4,5,5-hexachlorobiphenyl)showed impaired learning on a delayed spa-tial alternation task (87). However, a fourthortho-substituted congener (2,2,3,5,6-pentachlorobiphenyl) did not cause spatiallearning deficits, demonstrating that not allortho-substituted PCB congeners have thesame effects (88). As in both monkey stud-ies, the rats with spatial alternation deficits

were equally impair ed at short and longdelays, suggesting a decrement in learning orattentional processes. The same rats showedno impairments in learning a working mem-ory task on the eight-arm radial maze. Thespatial alternation deficit was present only infemale rats. Small group sizes had precludedanalyzing for sex differences in the monkey

studies, so this finding came as a surprise.More recently, rats exposed to the PCBmixture Aroclor 1254 were tested on a work-ing-reference memory task on a 12-armradial maze and a spatial reversal learningtask using operant procedures (89,90). Sex-specific deficits in spatial learning were againobserved. However, in these studies using acomplex PCB mixture rather than individualcongeners, deficits were observed primarilyin male rats. The PCB-exposed male ratsshowed impairments in both working andreference memory on the radial arm maze,whereas the females were not impaired oneither (89). The PCB-exposed males also

showed a deficit on the first reversal of thespatial reversal learning task (90). PCB-exposed female rats were not impaired onthe radial arm maze task but showed a learn-ing deficit that emerged on the later reversalsof the spatial reversal learning taska pat-tern very different from that seen in themales. Analyses of response patterns on thereversal learning task revealed underlyingfunctional differences that explained the dif-ferent effects in male and female rats. Thefirst reversal deficit in the male rats wasattributable to a tendency to perseverate tothe previously correct response site. The

female rats did not show an increased ten-dency to perseverate to the previously correctlever. Instead, they spent a longer periodresponding randomly to the two leversbefore finally beginning to associate thereward with the new response site. Whereasthe males show a deficit early in the task andwere able to overcome the deficit on laterreversals, the female deficit only emerged onlater reversals when the control animals werebecoming proficient at performing the task.

The reason for the heightened sensitivityof female rats on some tasks and males onothers is unknown. However, the discrepan-cies between studies could be partially

explained by the fact that the animals in theearlier study were exposed to individualortho-substituted PCB congeners, whereasthose in the later studies were exposed to acomplex PCB mixture. Certain effects ofPCB mixtures could be either masked orunmasked when specific congeners from themixture are given individually. Nevertheless,the sex differences in responses suggest thathormonal influences may be involved. Aspatial learning deficit such as that seen inthe female rats exposed to ortho-substituted




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PCB congeners would be consistent with areduction in thyroid hormone. However,circulating thyroid hormones levels wereassessed in litter mates of the tested animals(65), and it seems unlikely that alterations inthyroid hormones were directly mediatingthe learning deficit. The three PCB con-geners had roughly equal effects on spatial

learning but markedly different effects onthyroid hormone levels. One congener hadno effect on serum T4, one moderatelyreduced T4 levels, and one dramaticallyreduced serum T4 levels. Furthermore, malesand females showed equal reductions inserum T4, but only females were impaired onthe learning task. The learning deficits in thelatter studies would also be consistent with areduction in thyroid hormone, but againonly one sex was affected (this time males),whereas Aroclor 1254 is known to dramati-cally reduce circulating T4 levels in bothmales and females (63). This evidence is indi-rect, but it argues against direct mediation of

the learning deficit by reduced thyroid hor-mone. Koopman-Esseboom and colleagues(9193) also failed to find a relationshipbetween alterations in nervous system func-tion and thyroid hormone levels in PCB-exposed human infants. As discussed above,Morse et al. (64) found that pups exposed toPCBs during fetal development had reducedserum and brain T4 levels, but induction oftype II 5-deiodinase within the brainresulted in the maintenance of normal ornear normal brain T3 levels. Because T3 is theactive form of the hormone, these results alsoargue against a reduction in thyroid hormone

as the mediating factor in PCB-inducedlearning deficits.The extent to which changes in other

hormonal systems, or interactions of alteredthyroid function with other hormonal sys-tems, may play a role in mediating PCB-induced learning deficits has not beenaddressed. As discussed above, thyroid hor-mones are involved in mediating glucocorti-coid receptor expression in the brain and canalso influence the actions of estrogen in thebrain (49,56), both directly and indirectly.As both the glucocorticoid-mediated stressresponse and estrogens role in the brain aremarkedly sexually dimorphic, an interaction

of altered thyroid hormone levels (or alteredthyroid hormone action) with one or both ofthese systems could potentially explain thesex-specific effects that have been observed.In fact, given the complex and sexuallydimorphic pattern of PCB effects on cogni-tive function, this seems like a reasonablescenario. If this were the case, a clear rela-tionship between thyroid hormone concen-trations and cognitive deficits would notnecessarily be present. Thus, a reasonablefirst step to pursuing this line of research

would be to determine if cotreatment ofPCB-exposed animals with thyroid hormoneameliorates any of the PCB-induced cogni-tive deficits. If so, follow-up studies could bedesigned to determine if interactions ofreduced thyroid hormone with the estrogenor glucocorticoid systems are involved inmediating those specific cognitive deficits. If

not, follow-up studies could focus instead ondetermining whether particular cognitivedeficits are mediated directly by changes inone of these other hormone systems. Thevarious cognitive effects that have beenreported in males and females after PCBexposure could be mediated by several differ-ent hormonal mechanisms, and sorting outthe mechanisms for each behavioral effectwill require a focused, stepwise approach.

In contrast to the findings for ortho-sub-stituted PCBs, coplanar PCBs and dioxindid not impair spatial learning in rats (94).Dioxin-exposed rats did not differ from con-trols on delayed spatial alternation and actu-

ally made fewer errors than control rats onthe radial arm maze. Although both sexesshowed a trend toward better performance,the effect was more pronounced in dioxin-exposed male rats. Rats exposed to coplanarPCBs showed a similar but less strikingimprovement in learning. In a later studydioxin-exposed rats were tested on additionalspatial and nonspatial learning tasks to deter-mine whether the apparent facilitation inspatial learning was specific to the radial armmaze or would generalize to other tasks (95).The improved learning on the radial armmaze was replicated, but was found to be

specific to the radial arm maze. It did notgeneralize to other spatial learning tasks,including the Morris water maze, which likethe radial arm maze is primarily hippocam-pally-mediated. In addition, the dioxin-exposed rats showed a deficit in nonspatial,cue-based discrimination-reversal learning.This is similar to what was observed previ-ously in dioxin-exposed monkeys (86).Another study compared the performance ofdioxin-exposed litter mates on two differentradial arm maze tasks. The first was the orig-inal 8-arm radial maze task in which all 8arms were baited, and the second was a 12-arm radial maze task in which only 8 of the

12 arms were baited (96). Dioxin exposureimproved performance on the 8-arm mazetask in which all arms were baited, but noton the 12-arm maze task in which only asubset of the arms were baited, further high-lighting the specificity of this effect.

Recently Rice and Hayward (97,98)tested rats developmentally exposed to acoplanar PCB congener on a series of learningtasks. The coplanar PCB-exposed rats did notdiffer from controls on delayed spatial alterna-tion (97), visual-spatial or sustained attention

(98) or fixed interval, fixed ratio, progressiveratio, and differential reinforcement of lowrate operant tasks (99,100). These findingsreinforce the fact that the cognitive effects ofdioxin and coplanar PCBs are limited inscope, with the primary effect being animprovement in working memory, which isseen only in specific radial arm maze tasks.

It is not clear whether the cognitivechanges observed after perinatal dioxin expo-sure are hormone mediated. However,dioxin has been shown to alter functioningof the HPA axis in adult animals (78,79)and to down-regulate glucocorticoid recep-tor expression in several tissues during devel-opment (80,81). Previous studies haveshown that manipulations of circulating cor-ticosteroid levels (101) or hippocampal glu-cocorticoid receptor expression (102) canresult in improved spatial learning. Thus, itis conceivable that early dioxin exposurefacilitates spatial learning on the radial armmaze by permanently altering hippocampal

glucocorticoid receptor expression. Thishypothesis could be tested by measuring glu-cocorticoid receptor expression in the hip-pocampus after developmental exposure todioxin, and correlating receptor expressionwith spatial learning on the radial arm maze.

In summary, despite speculation bymany investigators (1,9,56), there is cur-rently no direct evidence mechanisticallylinking either PCB- or dioxin-inducedchanges in cognitive function to alteredendocrine function. It is important thatfuture studies directly assess whether thereare mechanistic relationships between altered

endocrine function and altered cognitivefunction after early exposure to these ubiqui-tous and persistent chemicals.

Lead. Lead exposure early in developmenthas been shown to disrupt multiple endocrinesystems, including the gonadal steroids (103),adrenal steroids (104,105), and thyroid hor-mones (105). The effects of developmentallead exposure on gonadal function are com-plex and appear to involve multiple sites ofaction. In uteroexposure has been reported toreduce circulating estradiol and luteinizinghormone levels, delay the onset of pubertyand produce irregular estrous cycling infemale rats, and reduce testosterone levels,

sperm counts, and masculine sexual behaviorin male rats (103,106). The volume of theSDN-POA was also reduced in male rats(106). The effects of developmental leadexposure on the sexually dimorphic patternof testosterone metabolism are variable. Apartially demasculinizing (2040%) decreasein adult CYP2C11-dependent 2- and 16-hydroxylation and CYP2C11 apoproteinexpression have been observed, along with adelay in the development of the sexuallydimorphic pattern of hepatic P450 and




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sulfotransferase enzymes at puberty (107).The findings in both male and female rats areconsistent with dual sites of action at the levelof the hypothalamus-pituitary and directly ongonadal steroidogenesis (103).

The effects of lead exposure on adrenalsteroids and thyroid hormones have been lessextensively studied, but both adult (105) and

developmental (104

) exposure has beenshown to elevate plasma corticosterone levels.The evidence for altered thyroid function ismixed. Some investigators report changes incirculating thyroid hormones after lead expo-sure, whereas others do not (8). Althoughgrowth hormone is not a focus of this report,it is important to note that early lead exposurealso disrupts growth hormone (107), and it ispossible that some of the cognitive effects ofearly lead exposure could be related to disrup-tion of the growth hormone system (108).

Few, if any, developmental neurotoxi-cants have been more extensively evaluatedfor cognitive effects than lead. A large num-

ber of independent investigators havereported cognitive impairments in develop-mentally lead-exposed rodents and primates,and a wealth of epidemiologic data points tocognitive deficits in lead-exposed children aswell (109). The effects in primates androdents include deficits in reversal learning(110112), delayed spatial alternation(113115), and schedule controlled behav-ior, particularly fixed interval and delayedreinforcement of low rates (116119). Aleading hypothesis to explain the deficitsexhibited by lead-exposed animals on manyof these tasks is that the animals continue to

respond to a previously correct response sitewhen the reward contingencies change (per-severation), and/or to respond excessivelyand inappropriately.

Developmentally lead-exposed mon-keys were impaired on both spatial andnonspatial discrimination-reversal learning(110,120,121). In general, they could learnthe initial discrimination problem butmade more errors when the reward contin-gencies changed on the reversals. Deficitswere especial ly pronounced on the fi rs treversal (110). Lead-exposed rats showed asimilar pattern. They could learn an initialolfactory discrimination but were impaired

on the subsequent reversals (112). The dis-crimination-reversal deficit in the rats wasnot due to perseveration. Analyses of the ani-mals response patterns indicated that thelead-exposed animals spent longer respond-ing randomly to the two levers before finallybeginning to associate the reward with thenew cue. They did not perseverate to thepreviously correct cue. On spatial alternationtasks, both lead-exposed monkeys and ratsshowed deficits in percent correct responsesthat were constant across a series of delays

(113,115). As discussed above, this patternsuggests a deficit in learning or attentionalprocesses rather than in memory. On fixedinterval operant schedules, which require theanimal to wait a fixed period of time forreinforcement, lead-exposed monkeys andrats showed higher response rates and shorterinter-response times (116,118). Similarly, on

a delayed reinforcement of low rate schedule,lead-exposed monkeys were slower to learnto withhold their responding to the low ratenecessary for reinforcement (119). In sum-mary, the nature of the cognitive deficits ona number of different tasks suggests that cog-nitive processes controlled by the prefrontalcortex including selective attention and theability to inhibit inappropriate respondingappear to be particularly sensitive to leadexposure. However, the deficit on discrimi-nation-reversal learning appears to be theresult of a decreased ability to learn new con-tingencies (i.e., an associative deficit), ratherthan a deficit in inhibitory control (112).

Although lead has been shown to disruptmultiple endocrine systems, little attentionhas been paid to the role changes in endocrinefunction might play in mediating the cogni-tive effects of developmental lead exposure.Interestingly, lead has recently been found toimpair choroid plexus transthyretin produc-tion (122). Because transthyretin is responsi-ble for transport of thyroid hormones into thebrain, it has been suggested that lead couldimpair brain development by depriving theCNS of thyroid hormones. However, theredo not appear to be any studies measuringthyroid hormone levels in brain after lead

exposure or relating such changes to cognitivedeficits. This could prove to be an importantarea for future research. Developmental leadexposure also increases circulating corticos-terone levels, which could potentially alterglucocorticoid receptor expression in thebrain. Finally, as discussed earlier, develop-mental lead exposure decreases circulatingtestosterone levels and demasculinizes the pre-optic area in male rats. Thus, lead couldpotentially alter hippocampal morphologyand spatial learning in male rats. However,the later mechanism is perhaps not as likelysince the cognitive effects of early lead expo-sure do not appear to be sexually dimorphic.

Organochlorine pesticides.As indicated inTable 1, many of the persistent organochlo-rine pesticides including DDT (and its break-down product DDE), Alachlor, chlordane,chlordecone, dieldrin, endosulfan, heptachlor,and lindane have been identified as endocrinedisruptors (8,59). Most are weakly estrogenicand some also alter thyroid or adrenal func-tion. Some organochlorine pesticides havebeen evaluated for cognitive effects, but themajority of the studies involve adult expo-sures. The question as to whether there are

cognitive effects in developing organisms islargely unanswered.

Dieldrin is a persistent chlorinatedhydrocarbon pesticide that was used as abroad range insecticide until the U.S. EPArestricted its use in 1974. Although no longerin use, dieldrin can remain undegraded insoil for many years. It is lipophilic and readily

bioaccumulates in animals and humans.Dieldrin exposure during adulthood resultedin deficits in visual discrimination-reversallearning in both sheep (123) and squirrelmonkeys (124) and caused rats to make moreerrors on a zig-zag maze (125). In contrast,one study of perinatal exposure to dieldrinreported facilitated retention of learning on asymmetrical maze (126).

Studies of other organochlorine insecti-cides have been limited almost exclusively toacute exposures followed by testing in simpleactive or passive avoidance paradigms andhave yielded mixed results. Lindane is achlorinated hydrocarbon insecticide as well

as a human and veterinary ectoparasiticide,which continues to be prescr ibed for thetreatment of body lice in humans. It is apowerful neurostimulant capable of causingconvulsions and electroencephalogram dis-turbances. Acute exposure to lindane in theearly postnatal period resulted in an appar-ent facilitation of acquisition on a passiveavoidance task (127). However, the lindane-exposed animals also showed significantreductions in spontaneous motor activity, sothese data must be interpreted with caution.Changes in locomotor activity can influenceavoidance behavior, with hypoactivity favor-

ing correct responding in passive avoidanceparadigms and hyperactivity favoring correctresponding in active avoidance paradigms.Acute exposure to lindane during adulthooddid not alter acquisition of a passive avoid-ance task, but did cause significant deficits inretention when animals were retested 7 daysafter the original training (128). In contrastto the passive avoidance task, lindane-exposed rats did show deficits in acquisitionof an active avoidance task. Respondingbetween trials was not significantly differentbetween groups, suggesting that the effect oflindane on active avoidance learning was notdue to a reduction in locomotor activity.

Endosulfan is an insecticide in currentuse. Chronic exposure of either immature oradult rats to endosulfan resulted in learningand memory deficits in an active avoidancetask where the rats were required to jump toa pole suspended from the ceiling of thechamber in order to avoid shock (129131).Chlordecone, or kepone, is a polycyclic chlo-rinated hydrocarbon that was used primarilyas an insecticide. Studies assessing the cogni-tive effects of chlordecone have yieldedmixed results. Tilson et al. (132) reported



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that acute exposure to chlordecone in theearly postnatal period did not result in anydeficits in learning of a two-choice visual dis-crimination-reversal task. Larger doses ofchlordecone given to adult rats also did notresult in any deficits in acquisition or reten-tion of a step-through passive avoidance task(128). Acute exposure of preweanling rats to

chlordecone did not lead to deficits in acqui-sition of passive avoidance, but when the ratswere retested 6 days after the original train-ing, a memory deficit was observed (133). Incontrast, pups were impaired on both learn-ing and retention of active avoidance tasks(134). DDT, once widely used in theUnited States as an insecticide, has beenbanned from use since 1973. However, itcontinues to be used in other parts of theworld and continues to present a health haz-ard. Tilson et al. (128) found few effects ofDDT on the ability of rats to learn activeand passive avoidance tasks. However, otherresearchers have reported impaired acquisi-

tion on active avoidance tasks (135,136), aswell as impaired retention on passive avoid-ance tasks (135137).

In summary, the data on cognitive effectsof organochlorine pesticides are sparse, and inmost cases, the tests that have been used tomeasure cognition are simplistic. The resultsdo suggest that many of the organochlorinepesticides have the ability to interfere with theacquisition and use of new information.However, the literature on both the endocrineand cognitive effects of organochlorine pesti-cides remains too sketchy to form usefulhypotheses about the possible endocrine

mediation of cognitive deficits.Other chemicals. A number of otherchemicals including compounds such asphthalates and bisphenol A, which are usedin the manufacture of plastics, and alkylphe-nols, which are breakdown products ofchemicals used in detergents, have been iden-tified as endocrine disruptors. Most of thesewere fir st identi fied as having est rogenicactivity (59), but some were later found todisrupt thyroid function as well (8). At thistime, the data on cognitive effects from anyof these compounds is sparse (138).

Concluding Remarks

Although it is reasonable to hypothesize thatcentral nervous system effects of endocrine-disrupting chemicals are mediated by inter-ference with hormone action, mechanisticstudies establishing causal relationshipsbetween the hormonal actions of environ-mental chemicals and their cognitive effectshave not been conducted. At present, theonly study we are aware of that establishes adirect link between hormone disruption byan environmental chemical and nervous sys-tem dysfunction is a study by Goldey and

Crofton (139), which showed that PCB-induced hearing loss closely resembles thehearing loss seen after propylthiouracil treat-ment and can be prevented by cotreatment ofPCB-exposed pups with thyroid hormone.Our own research has demonstrated that if arelationship between alterations in thyroidhormones and PCB-induced cognitive dys-

function exists, it is likely to be considerablymore complex. The complexity of this issueand the science needed to address it shouldnot keep us from moving forward.

Mechanistic studies directly addressingthe relationship between endocrine disrup-tion and the documented cognitive deficitscaused by chemical pollutants such as PCBsand lead are desperately needed. For exam-ple, thyroid hormone replacement studiessimilar to those used to investigate the rela-tionship between PCB-induced reductionsin circulating thyroid hormone concentra-tions and hearing loss would be a first steptoward determining the role, if any, of

reductions in thyroid hormones in mediat-ing specific PCB-related cognitive deficits.However, as we embark on such studies it isimportant to keep in mind that it is unlikelythat all of the cognitive effects of a particularcompound such as PCBs will be mediatedby a single mechanism. It is more likely thatthe multiple endocrine effects caused byPCBs interact in complex ways to producethe various cognitive effects that have beenreported. Sorting out these interactions willrequire a focused, stepwise approach. It isalso important to keep in mind that typicalanimal models in which high concentrations

of the chemical are given during a narrowwindow of development may not be relevantto the human condition in which exposuresare much lower and occur over an extendedperiod of time. In future studies it will beimportant to use animal models that aremore relevant to the human situation.

An important caveat is that endocrinedisruptors such as PCBs and lead can alsohave direct effects on the nervous system,and these direct actions undoubtedly con-tribute to the cognitive deficits induced bythese compounds. For example, PCBs havebeen shown to interact directly with ryan-odine-sensitive calcium release channels,

altering calcium signaling in neurons (140),and lead has been shown to act as an antago-nist at the N-methyl-D-aspartate receptor(141 ). The relative importance of directmechanisms versus indirect endocrine-related mechanisms in mediating the cogni-tive deficits induced by these compoundsremains to be determined.

Finally, more extensive studies of the cog-nitive effects of other endocrine-disruptingchemicals such as organochlorine pesticidesthat are still in active use, components of

plastics and cosmetics such as phthalates andbisphenol A, and alkylphenol breakdownproducts from detergents are desperatelyneeded. These studies should be designedwith the goal of determining mechanisms,not just screening for cognitive effects. It isonly through the active and continued pur-suit of this challenging research area that we

will gain the knowledge we need to protectthe health of future generations.

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