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Journal of Wildlife Diseases, 36(4), 2000, pp. 615–635q Wildlife Disease Association 2000

A REVIEW OF CHEMICALLY-INDUCED ALTERATIONS IN THYROIDAND VITAMIN A STATUS FROM FIELD STUDIES OF WILDLIFEAND FISH

Rosalind M. Rolland1

1 Center for Conservation Medicine, Tufts University School of Veterinary Medicine, 200 Westboro Rd., North Grafton,Massachusetts 01536, USA (e-mail: [email protected])

ABSTRACT: This paper reviews 22 published field studies that have found an association betweenexposure to environmental contaminants and alterations in thyroid gland structure, circulatingthyroid hormones and vitamin A (retinoid) status in free-ranging populations of wildlife and fish.Vitamin A and thyroid hormones play critical roles during development, growth and functionthroughout life. Studies of captive wildlife and laboratory studies support a relationship betweenalterations in thyroid hormones and vitamin A status and exposure to dioxins, furans, and planarpolychlorinated biphenyls, which bind to the aryl hydrocarbon receptor. Some studies have foundadverse health effects in wildlife associated with exposure to polyhalogenated aromatic hydrocar-bons and altered thyroid and retinoid status including: decreased reproductive success, immunesystem changes, dermatologic abnormalities and developmental deformities. A direct causal re-lationship between these effects and thyroid and retinoid changes has not been demonstrated.Field researchers studying the responses to these synthetic chemicals in wildlife and fish shouldinclude measurement of thyroid hormones and retinoids and histological examination of the thy-roid gland in their study design as biomarkers of exposure to these chemicals in the environment.

Key words: Dioxin, fish, organochlorines, polychlorinated biphenyls, retinoids, thyroid, vita-min A, wildlife.

INTRODUCTION

It is now widely accepted that free-rang-ing populations of wildlife and fish havebeen impacted by exposure to man-madechemicals in the environment that can in-terfere with the development and functionof the reproductive, endocrine, immuneand nervous systems (Colborn et al., 1993;Rolland et al., 1995, 1997). These chemi-cals are referred to as ‘‘endocrine disrup-tors’’ and act by interfering with hormonaland other cell messaging systems (Colbornand Clement, 1992). Exposure to thesechemicals during development and differ-entiation of major organ systems may re-sult in irreversible physiological, morpho-logical, and behavioral changes by alteringthe hormones that control the course ofdevelopment. Referred to as organization-al changes (Guillette et al., 1995), thesealterations are of particular concern be-cause developing organisms are more like-ly to exhibit effects at chronic environ-mentally-relevant exposure levels than

adult organisms, which may not be im-pacted at all (Bern, 1992).

Important clues to the actions of endo-crine disrupting chemicals have comefrom field studies of wildlife and fish.Many of these observations involve disrup-tion that has occurred during embryonicdevelopment and sensitive early life stagesresulting in impaired reproduction and de-velopmental abnormalities in the offspringof exposed parents (Guillette, 1995). Someof the anomalies reported to date include:developmental deformities and wasting infish-eating birds in the Great Lakes (Hoff-man et al., 1987; Fox et al., 1991; Gilbert-son et al., 1991; Giesy et al., 1994); repro-ductive impairment in bald eagles (Hal-iaeetus leucocephalus) (Bowerman et al.,1995) and wood ducks (Aix sponsa) (Whiteand Hoffman, 1995); abnormalities of sex-ual development and reproductive hor-mone levels in alligators (Guillette et al.,1994); histological abnormalities of thethyroid gland in Great Lakes herring gulls(Larus argentatus) (Moccia et al., 1986)

616 JOURNAL OF WILDLIFE DISEASES, VOL. 36, NO. 4, OCTOBER 2000

and salmonids (Moccia et al., 1981); al-tered reproductive hormone levels andchanges in secondary sex characteristics infish (Munkittrick et al., 1991); altered im-mune system characteristics in marinemammals (De Swart et al., 1994; Lahvis etal., 1995); and altered neurological devel-opment in great blue herons (Ardea her-odias) (Henschel et al., 1995).

Although well over 50 synthetic chemi-cals have been identified as endocrine dis-ruptors, much of the field ecotoxicologicalresearch has focused on the persistent, li-pophilic polyhalogenated aromatic hydro-carbons (PHAHs), which are ubiquitousenvironmental contaminants. Some of themost studied of these compounds are thetoxic congeners of the polychlorinated di-benzo-p-dioxins (PCDDs), dibenzofurans(PCDFs) and the planar polychlorinatedbiphenyls (PCBs) that share the ability tobind to the Ah receptor (aryl hydrocar-bon), which results in induction of the cy-tochrome P450 and other enzyme systems.The polynuclear aromatic hydrocarbons(PAHs) are another class of omnipresentenvironmental contaminants that can bindto the Ah receptor.

Experimental studies have demonstrat-ed that contaminants such as PHAHs andPAHs have the ability to alter thyroid hor-mone levels, thyroid gland structure, andvitamin A levels through a variety of mech-anisms (reviewed in Zile, 1992; Brouweret al., 1998). It has been well establishedthat PHAHs can disrupt vitamin A metab-olism, depleting body stores (Zile, 1992;Spear et al., 1986). In mammals and birds,both thyroxine (T4) and retinol (the maincirculating form of vitamin A) are trans-ported in the blood on the same carrierprotein complex, transthyretin (Goodman,1980). Hydroxylated metabolites of somePCB congeners can interfere with trans-thyretin, resulting in decreased circulatinglevels of thyroxine and retinol (Brouwer etal., 1986; Brouwer and van den Berg,1986; Brouwer et al., 1988; Brouwer et al.,1990). PHAHs are also known to interfere

with the enzymes controlling thyroid hor-mone metabolism (Brouwer et al., 1998).

Because of the documented effects ofPHAHs on both retinoids and thyroid hor-mones, these physiological parameters havebeen suggested as sensitive biomarkers ofexposure to these chemicals in the environ-ment (Peakall, 1992; Fox, 1993). Levels ofthyroid hormones and retinoids can be in-fluenced by many other factors includingage, gender, diet, nutritional status, seasonand physiological condition. Therefore,studies should be designed to control forthese variables and results should be inter-preted accordingly.

Vitamin A (retinoids) and thyroid hor-mones play critical roles during develop-ment, growth and function throughout life.Retinoic acid (RA) is believed to have en-docrine-like properties based upon therecognition that its nuclear receptors arestructurally homologous to those of steroidand thyroid hormones (Giguere et al.,1987; Petkovich et al., 1987). Vitamin A isessential to normal differentiation of epi-thelial structures, reproduction, vision andimmune system function (Zile, 1983). Agradient of RA in limb buds controls nor-mal limb development in avian and mam-malian embryos (Thaller and Eichele,1987), and excessive or insufficient amountscan result in malformations. Thyroid hor-mones are involved in vertebrate devel-opment, metamorphosis in amphibiansand some fish (e.g., flounder, eels) as wellas growth and regulation of metabolic pro-cesses (McNabb and King, 1993). Alter-ations in thyroid function are known to af-fect mammalian reproduction (Leathem,1972).

In this paper I review 22 field studies ofwildlife and fish that report thyroid and/orvitamin A alterations associated with ex-posure to persistent synthetic chemicals inthe environment. I also discuss relevantexperimental studies that support the fieldobservations, and shed light on the mech-anisms of action involved. Adverse healtheffects reported in wildlife and fish in thefield studies are discussed, but because ex-

ROLLAND—CHEMICALLY-INDUCED ALTERATIONS IN THYROID AND VITAMIN A IN WILDLIFE 617

perimental studies proving the mechanis-tic links are lacking, associations betweenthese effects and retinoid and thyroid al-terations are speculative. The goal of thisreview is to summarize the changes in thy-roid gland structure, function and vitaminA status possibly associated with exposureto PHAHs and PAHs in several species ofwildlife and fish. I examine the use ofthese parameters as biomarkers of expo-sure to these environmental chemicals,and suggest that some adverse health ef-fects in wildlife and fish may be associatedwith alterations in thyroid and vitamin Astatus. Information about marine mam-mals will be described first, followed byavian species and fish.

MARINE MAMMALS

Field studies that have reported alter-ations in thyroid gland morphology, thy-roid hormones, and retinoid levels in ma-rine mammals associated with exposure toPHAH’s are summarized in Table 1.

Thyroid gland histological changes

Morphological changes in the thyroidgland associated with an elevated tissueburden of persistent organochlorine chem-icals (OCs) have been reported in harborseals (Phoca vitulina) and in beluga whales(Delphinapterus leucas). Histological ex-amination of the thyroid glands from 40harbor seals that died in the North Seaduring the 1988–89 epizootic of phocinedistemper virus revealed colloid depletionand interfollicular fibrosis in most of theseals (Schumacher et al., 1993). Seals thatdied during this epizootic had higher tis-sue levels of OCs compared to survivors(Hall et al., 1992), especially the PCBs(Luckas et al., 1990). No thyroid gland col-loid depletion or fibrosis was seen in healthycontrol seals from Iceland that had muchlower levels of OCs and were negative forantibodies to canine distemper virus andphocine distemper virus. Similar but lesssevere changes were seen in the thyroidglands of seven harbor porpoises (Pho-coena phocoena) from the North Sea. The

porpoises inhabit the same region as theseals but were unaffected by the viral epi-zootic. The fibrosis seen in both types ofmarine mammals from the North Sea wascharacterized by the presence of maturecollagen fibrils and the absence of vascu-larization, suggesting that these changeswere due to a chronic process, and prob-ably not associated with an acute eventsuch as the viral epizootic.

Morphological changes in the thyroidgland have also been reported in belugawhales inhabiting the St. Lawrence estuary(De Guise et al., 1995). This is an endan-gered population that has very elevatedlevels of organochlorine pollutants and ex-periences a high incidence of neoplasticlesions, secondary bacterial infections andother pathologic lesions, along with a re-duced rate of reproduction (Beland et al.,1993). Morphological changes observedduring postmortem examination have in-cluded thyroid abscesses and one case ofa thyroid adenoma.

Thyroid hormone and retinoid alterations

Investigators have hypothesized thatPCB exposure accompanied by depressedlevels of thyroid hormones and retinol mayplay a role in the pathogenesis of a skindisease affecting stranded immature north-ern elephant seals (Mirounga angustiros-tris). This condition, named northern ele-phant seal skin disease, is a generalized ul-cerative dermatitis characterized histologi-cally by hyperkeratosis of surface andfollicular epithelium, acanthosis, and squa-mous metaplasia and atrophy of sebaceousglands. Affected seals have depressed levelsof total triidothyronine (TT3), total thyrox-ine (TT4) and retinol, and elevated serumlevels of total PCB’s and dichloro-diphenyl-dichloroethylene (p, p9-DDE) compared tounaffected controls (Beckman et al., 1997).

Exposure to PHAH’s (PCBs and poly-brominated biphenyls) has been linkedwith hyperkeratosis accompanied by squa-mous metaplasia of sebaceous glands inhumans, cattle, rodents, rabbits and non-human primates (Zinkl, 1977; Klein-Szan-


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to et al., 1991; Jubb et al., 1993). Squa-mous metaplasia of sebaceous glands is pa-thognomonic of PHAH exposure in hu-mans (Crow, 1991). However, squamousmetaplasia of meibomian glands is a fea-ture of PCB toxicosis that was not seen inthe elephant seals (Beckman et al., 1997).An ulcerative dermatitis was also describedin grey seals in the Baltic Sea and the in-vestigators hypothesized that it may be as-sociated with the elevated levels of PCBsin that ecosystem (Bergman and Olsson,1985).

Thyroid hormones are important tomaintaining skin integrity, but the skin le-sions in the northern elephant seals werenot typical of those seen in hypothyroiddermatopathies in other species (Scott,1982). Skin lesions similar to those seenwith vitamin A deficiency have been de-scribed with PHAH toxicity (Zile, 1992).Hyperkeratotic skin lesions are a feature ofvitamin A deficiency in mammals, butsquamous metaplasia of sebaceous glandshas not been described with his condition(Pitt, 1985; Jubb et al., 1993). Therefore,PCB exposure could potentially underliethe thyroid and retinol alterations and theoccurrence of this skin disease in thenorthern elephant seals. However, wheth-er the depressed retinol and thyroid levelscontributed directly to the etiology of thisdisease is unclear.

Two experimental studies using captiveharbor seals have found a relationship be-tween consumption of contaminated fishand reductions in plasma thyroid hor-mones and retinol, accompanied by al-tered reproductive function or immunesystem changes. In one 2-yr study, a groupof 12 female seals was fed a diet of fish(mostly plaice, flounder and dab) from thepolluted western Wadden Sea while thereference group was fed fish (mainlymackerel) from the relatively uncontami-nated northeast Atlantic Ocean (Reijnders,1986). The fish from the Wadden Sea weresignificantly more contaminated with PCBsand p, p9-DDE compared to the controldiet. Three males fed the reference group

diet were rotated between the two femalegroups allowing mating to occur through-out the study. There was a significant de-crease in pregnancy in the females fed themore contaminated diet over the 2-yr pe-riod (Reijnders, 1986). This appeared tobe caused by disruption of implantationcaused by a smaller rise in levels of estra-diol in the group fed contaminated fish,although this association could not be sta-tistically tested because there were onlytwo non-pregnant animals in the controlgroup. The decreased reproductive suc-cess in seals fed the contaminated fish isparticularly noteworthy because of thedrastic reduction in the seal population inthe 1960s and 1970s in the western partof the Wadden Sea apparently resultingfrom decreased pup production (Re-ijnders, 1978).

Both pregnant and non-pregnant sealson the more contaminated diet had signif-icantly lower plasma levels of retinol (30–55%) at two sampling intervals during thestudy. Reductions in TT3, TT4 and freethyroxine (FT4) occurred at one samplinginterval, but were less dramatically de-creased compared to retinol levels (Brou-wer et al., 1989). The reductions in plasmaretinol normalized 6 mo after the sealswere switched to the control group diet.Based upon supporting evidence from ex-perimental studies, the authors concludedthat the decreased plasma retinol and thy-roid hormones were most likely the resultof PCB exposure. Whether the reproduc-tive effects were directly related to thethyroid or retinoid alterations, or indepen-dent consequences of contaminant expo-sure is unclear from this study.

A second study examined immune sys-tem changes in juvenile captive harborseals fed contaminated fish from the BalticSea (De Swart et al., 1994). Age and gen-der matched seals were fed either contam-inated herring from the Baltic Sea or her-ring from Atlantic Ocean for 93 wk, andblood samples were obtained every 6 to 9wk. Concentrations of OCs in the extract-able fat of the fish were measured, includ-


ing congener specific analysis of PCDDs,PCDFs and coplanar PCBs. The averagedaily intake of the Ah-receptor-binding OCsin toxic equivalents (TEQs) relative to 2,3, 7, 8-tetrachlorodibenzo-p-dioxin (2, 3, 7,8-TCDD or dioxin) was 288 ng TEQ/dayin seals fed Baltic fish compared to 29 ngTEQ/day in the reference group. PCBs ac-counted for 93% of the TEQs. Blubber bi-opsies taken at wk 104 found 208.7 6 11.6ng TEQ/kg lipid in the seals fed Baltic fishcompared to 61.8 6 4.13 ng TEQ/kg lipidin the reference group. Several parametersof basal immune function were signifi-cantly suppressed including natural killercell activity and specific T-cell responses.Circulating vitamin A levels were de-pressed throughout the study in seals fedthe Baltic fish, similar to the findings inthe study of seals fed Wadden Sea fish de-scribed previously.

Additionally, in a short-term study, bothexperimental groups underwent a 15-dayfast in order to study mobilization of OCsfrom blubber. While the reference groupshowed an increase in circulating TT3 andTT4 during the fast, the group fed Balticfish had significantly lower plasma TT3 andTT4 over the course of the fast (De Swartet al., 1995). When laboratory rats wereput on the same fish diets, the group fedBaltic fish had significantly depressed plas-ma TT4 levels (Ross, 1995). Increased lev-els of thyroid hormones may be part of thephysiologic response to a fasting state inseals, a time during which lipids fromblubber are utilized as the primary energysource. These results suggest that the Bal-tic fish-fed seals may be less able to adaptduring fasting.

Studies of free-ranging seals have beenmore equivocal. A study of wild Norwe-gian grey seal pups (Halichoerus grypus)found that the ratio of TT4:FT4 was neg-atively correlated to serum concentrationsof PCBs (Jenssen et al., 1995). However,this study did not control for the effects ofage on circulating T4 levels. Another studylooking at the relationship between thyroidhormones and PCB exposure in young

grey seals in the United Kingdom founddeclining T4 levels with age but no rela-tionship between blubber concentrationsof PCBs and the ratio of TT4:FT4 (Hall etal., 1998). However, this study did find asignificant relationship between the con-centration of PCB 169 (3, 39, 4, 49, 5, 59-hexachlorobiphenyl) and the ratio of TT3:TT4 when stage of lactation was used as acovariate (no relationship was seen foradult seals). As this study demonstrates, in-terpretation of thyroid hormone alter-ations must include a consideration of ageand other variables such as nutritional sta-tus and physiological state that are knownto be associated with natural hormonalvariations.

AVIAN SPECIES

Field studies reporting alterations inthyroid gland morphology, thyroid hor-mones and retinoid levels in avian speciesassociated with exposure to PHAH’s aresummarized in Table 2.


Histological abnormalities of the thyroidgland have been reported in herring gulls(Larus argentatus) nesting around theLaurentian Great Lakes. Thyroid glandhistology and morphology were examinedin 213 herring gulls collected from ninecolonies during the period 1974–83 (Moc-cia et al., 1986). Reference thyroid glandswere collected from a colony of herringgulls in the Bay of Fundy (1977–82), aniodine rich marine environment with low-er concentrations of PHAHs. Compared tothe reference population, the majority ofGreat Lakes gulls had an increased thyroidmass and diffuse microfollicular hyperpla-sia of the thyroid gland. The severity of thelesions varied both between and withinlakes, and the spatial and temporal distri-bution of the severity of the thyroid ab-normalities supported the hypothesis thatthe changes may be related to PHAH ex-posure.

A more recent study analyzed the he-patic OC residues (PCBs, DDE, dieldrin


and Mirex) and several biomarkers includ-ing thyroid mass in eight Great Lakes her-ring gull colonies and an Atlantic coast ref-erence colony from 1974–93 (Fox et al.,1998). The OC concentrations decreasedat most sites over the study period, withthe greatest declines occurring prior to1985. A concomitant decrease in thyroidgland enlargement (from moderate toslight) was consistent with the decline inOC levels.

Although the Great Lakes basin is anendemic region of iodine deficiency goiterin humans, the observations from thesestudies and others are not consistent withan iodine deficiency etiology as the solecause of the lesions observed in the her-ring gulls. The temporal and spatial occur-rence of thyroid pathology seen in the her-ring gulls does not correlate with inter-lakedifferences in iodine content (Moccia etal., 1986). Rather, the evidence suggeststhat a thyrotoxic factor exists in the GreatLakes food web and lipophilic OCs havebeen studied as possible causative agents.Laboratory studies showing thyroid dys-function in rats fed Great Lakes cohosalmon (Oncorhynchus kisutch) supportthe concept that Great Lakes fish carry agoitrogenic factor (Sonstegard and Leath-erland, 1979; Villeneuve et al., 1981),which is the most likely exposure route forfish-eating Great Lakes gulls.

Experimental studies with several avianspecies support the hypothesis that expo-sure to PCBs and other persistent OCs caninduce histological changes in the avianthyroid gland. Pigeons (Columba livia)dosed with p, p9-dichloro-diphenyl-trichlo-roethane (p, p9-DDT), p, p9-DDE anddieldrin had histological changes in thethyroid gland consisting of hypertrophy,hyperplasia and colloid depletion (Jefferiesand French, 1969, 1972). Lesser black-backed gulls (Larus fuscus) dosed with Ar-ochlor 1254 (a commercial PCB mixture)had increased thyroid weight and size,with histological changes resembling thy-roid goiter (Jefferies and Parslow, 1972).No increase in thyroid weight was seen

with increased dosage rates in this study,and the biggest thyroids were seen withthe two lowest dosages (50 and 100 mg/kg/day). Guillemots (Uria aalge) dosedwith Arochlor 1254 showed an increase inthyroid size, colloid area, and follicle sizeat lower doses (12 and 25 mg/kg/day) andprogressive dose-related decreases in theseparameters at higher doses (up to 400 mg/kg/day) (Jefferies and Parslow, 1976). Theweight of the anterior lobe of the pituitarygland also decreased in a dose-relatedmanner, suggesting that higher levels ofPCBs had a direct effect on the pituitarycausing a dose-related decrease in thyro-tropin leading to secondary thyroid glandatrophy. The concentration of PCBs in theliver of the experimental guillemots waswithin the range of levels measured in wildguillemots from the North Atlantic.

Thyroid hormone and retinoid alterations

Liver levels of retinyl palmitate (the es-terified storage form of vitamin A) weremeasured in 130 Great Lakes herring gullsand in gulls from two Atlantic coastal col-onies during 1980–85 (Government ofCanada, 1991). Generally marine gullshave a high dietary availability of retinoidsand vitamin A precursor carotenoids mak-ing them a good reference population.Overall, hepatic retinyl palmitate levelsfrom the Atlantic coastal gulls were signif-icantly higher than those from Great Lakesgulls. While some Great Lakes colonieshad retinoid levels similar to the referencepopulation (possibly due to compensationby adequate dietary vitamin A sources),other colonies showed severe depletion ofliver retinyl palmitate. It is noteworthy thatgulls from western Lake Erie had the mostsevere depletion of retinoids, and gullsfrom the same area had the most severehistological changes in the thyroid gland(Moccia et al., 1986).

A similar study also found that concen-trations of hepatic retinol and retinyl pal-mitate were significantly lower in GreatLakes gulls as compared to New Bruns-wick (Canada) gulls, and there were sig-


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←a Polyhalogenated aromatic hydrocarbons.b 2,3,7,8-tetrachlorodibenzo-p-dioxin.c Sum of the concentrations of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans.d Dioxin toxic equivalents.e Sum of the concentrations of polychlorinated biphenyls 105 and 118.f Sum of polychlorinated biphenyls 105 and 108 toxic equivalents.g Present in the highest concentrations—believed responsible for the effects seen.h Free thyroxine.i Ethoxyresorufin-O-deethylase.j In egg yolk.k In prefledgling chicks.l In egg yolk.m Total triiodothyronine.n Total thyroxine.o Dichloro-diphenyl-dichloroethylene.p 16-day-old hatchlings.q Aryl hydrocarbon receptor-binding chemicals. Decreases in retinol were correlated with EROD induction.

nificant differences among the GreatLakes colonies (Spear et al., 1986). Reti-noid levels in both the coastal and GreatLakes colonies were inversely proportionalto dioxin levels reported at these sites.Among the Great Lakes colonies, LakeOntario gulls had the lowest retinoid levelsand the highest dioxin contaminationwhile Lake Superior gulls had the highestretinoids and lowest dioxin levels. Experi-mental studies using a single intraperito-neal injection of the dioxin-like PCB 77 (3,39, 4, 49-tetrachlorobiphenyl) in ring doves(Streptopelia risoria) found that retinollevels significantly decreased as aryl hydro-carbon hydroxylase activity increased(Spear et al., 1986), supporting the rela-tionship seen in the wild gulls between di-oxin and retinoid status.

Fox et al. (1998) compared levels of he-patic retinyl palmitate and hepatic OC res-idues (PCB, DDE, dieldrin and mirex) inherring gulls from eight Great Lakes col-onies and a coastal reference colony from1974–93. The concentrations of most con-taminants decreased over time, particular-ly prior to 1985. Retinyl palmitate levelsincreased significantly at two colonies overthe same period, but despite the lower lev-els of OCs, moderate to severe depletionof vitamin A stores persisted at some sites.This could be related to changes in thedietary availability of vitamin A and/or

continuing effects of contaminants on theability to store vitamin A.

Grasman et al. (1996) found diminishedT-cell immune system responses and lowerplasma retinol levels associated with high-er exposure to OCs (primarily PCBs) inprefledgling herring gulls and Caspianterns (Sterna caspia) exposed to a gradientof pollution in the Great Lakes. In bothspecies, there was a negative relationshipbetween total PCBs in eggs from the col-ony (reflecting perinatal exposure) andplasma retinol in chicks. No significant as-sociation between thyroxine levels and OCexposure was seen, and there was no ap-parent relationship between the lower lev-els of plasma retinol and the altered im-mune system parameters. This study didnot control for variability in dietary avail-ability of vitamin A precursors betweencolonies, so it is not possible to determinewhether the decreased plasma retinol wasdirectly related to PCB exposure, the re-sult of variations in dietary availability ofvitamin A precursors, or a combination offactors.

Egg yolk is a reservoir of retinoids avail-able to avian embryos during develop-ment. Retinoids from the maternal circu-lation and body stores are incorporatedinto the lipid-rich egg yolk, primarily asretinol and retinyl palmitate. Measure-ment of retinoid concentrations in egg yolk


and the molar ratio of retinol to retinylpalmitate in egg yolk have been used tocharacterize the vitamin A status of devel-oping avian embryos exposed to variouslevels of contaminants in the environment(Spear et al., 1990). Embryos utilize reti-noids in the later stages of incubation,therefore the timing of sampling becomesimportant. In herring gulls the concentra-tion of retinol and the molar ratio of reti-nol to retinyl palmitate are stable duringdays two to twelve of incubation, but de-cline thereafter because of utilization ofretinol by the developing embryo (Spearet al., 1990). Therefore, it is optimal to col-lect the eggs during these early stages ofincubation when the retinol levels are nor-mally more stable.

Polychlorinated dibenzofurans, PCDDsand retinoids were measured in herringgull eggs collected during early incubationin 1986–87 from seven colonies in LakesHuron, Ontario and Erie (Spear et al.,1990). The molar ratio of retinol to retinylpalmitate was positively correlated withthe sum of the concentrations of thePCDDs and PCDFs measured at the var-ious sites, with the concentration of 2, 3,7, 8-TCDD (the major contaminant atmost sites) and with the sum of the PCDDand PCDF toxic equivalents. No correla-tion was found between contaminant con-centrations and the individual levels of ei-ther retinol or retinyl palmitate.

Retinoid and b-carotene (retinoid pre-cursor) levels in eggs from seven greatblue heron (Area herodias) colonies alongthe St. Lawrence River and at two refer-ence sites were compared along with theconcentration of 17 organochlorine chem-icals and 42 polychlorinated biphenyl con-geners in eggs from the same clutch (Boilyet al., 1994). While retinol and b-carotenelevels did not vary significantly betweensites, the molar ratio of retinol to retinylpalmitate and the concentration of retinylpalmitate in eggs did vary significantly be-tween colonies. Significant negative cor-relations were found between retinyl pal-mitate in eggs and the sum of PCBs 105

(2, 3, 39, 4, 49-pentachlorobiphenyl) and118 (2, 39, 4, 49, 5-pentachlorobiphenyl)and TCDD-EQs based on PCBs 105 and118 (mono-ortho coplanar congeners).Negative correlations were also observedwith three mono-ortho-tetrachlorobiphen-yls that are usually not considered envi-ronmentally relevant. The lack of variationbetween colonies in the levels of b-caro-tene and retinol implies that a dietary de-ficiency probably did not contribute to thelower retinyl palmitate levels in eggs fromthe more contaminated colonies.

A study of tree swallows (Tachycinetabicolor) at seven sites around the GreatLakes and the St. Lawrence River foundno association between PCBs and retinoidlevels in nestling liver or eggs (Bishop etal., 1999). However, liver EROD (ethoxy-resorufin-O-deethylase) induction wasnegatively correlated with nestling liverretinol levels. EROD activity is a specificand sensitive biomarker of exposure toTCDD and related chemicals actingthrough the Ah receptor in avian species(Kubiak et al., 1989). Diet samples wereanalyzed for retinol and a- and b-caroteneand there was no indication of limited vi-tamin A availability. Because induction ofEROD is generally associated with expo-sure to coplanar PCBs, other dioxin-likecontaminants or PAHs, these results implythat the decreased hepatic retinol was as-sociated with exposure to Ah-inducingchemicals. The authors found no signifi-cant decreases in hatching or fledging suc-cess at any of these sites indicating thatalthough hepatic retinol levels were de-pressed in nestlings, sufficient retinoidswere available from dietary sources orthrough compensatory mechanisms to al-low for apparently normal reproductivesuccess.

The relationship between exposure toPCDDs and PCDFs, and alterations inretinoids, plasma thyroid hormone levels,and breeding parameters was examined ina study of eight common tern colonies(Sterna hirundo) in Belgium and theNetherlands exposed to a gradient of pol-


lution levels (Murk et al., 1996). Data onthe colonies was grouped based upon yolksac PCDD/PCDF, and associations withtime of egg laying, incubation time andsize of eggs and chicks were examined.Unfavorable breeding parameters (lateregg laying, prolonged incubation andsmaller eggs and chicks) were correlatedwith higher yolk sac PHAH concentra-tions, hepatic cytochrome P4501A1 induc-tion, decreased yolk sac retinoids and plas-ma thyroid hormone levels in hatchlings,and an increase in the ratio of plasma ret-inol in hatchlings to yolk sac retinyl pal-mitate. Again, dietary vitamin A availabilitywas not controlled in this study, making itdifficult to interpret the retinoid alter-ations.

Further evidence for contaminant-relat-ed impacts on reproductive success and al-terations in retinoid and thyroid hormonelevels of hatchlings was found in anotherstudy in the Netherlands. This study ex-amined cormorant (Phalacrocorax carbo)hatchlings from two colonies with differentlevels of exposure to PCBs, PCDDs andPCDFs (van den Berg et al., 1994). A 50%difference in reproductive success was ob-served between the two colonies in thefield, and the more contaminated colonyhad two to five times the level of PCBsand 25% more PCDD and PCDFs in yolksacs. Hatchlings from the more contami-nated colony had increased EROD activi-ty, a 50% decrease in plasma free T4, andan increased in ovo respiration rate. On anindividual basis, significant concentration-response relationships were seen betweenEROD induction, plasma free T4 reduc-tions, yolk sac weight, liver weight, cranialsize and concentrations of mono-orthoPCBs and/or PCDDs and PCDFs in theyolk sac. The weight at birth of hatchlingsfrom the more contaminated colony wasreduced, and the authors hypothesizedthat the weight reduction coupled with theincreased in ovo respiration rate might in-dicate PCB-induced wasting disease whichhas been reported in other avian species(Kubiak et al., 1989).

Experimentally, the relationship betweenthyroid hormone alterations and exposureto Ah receptor-inducing contaminants hasbeen inconsistent with the findings in fieldstudies. Single dose exposure of adult greatblue herons to 2, 3, 7, 8-TCDD resulted ina six-fold induction of EROD, significantelevation of plasma T4 levels and no effecton plasma total T3 or the plasma T3:T4 ratio(Janz and Bellward, 1997). In ovo exposureto low levels of 2, 3, 7, 8-TCDD failed toproduce abnormalities in thyroid hormonesin hatchlings of three species: the domesticchicken (Gallus gallus), domestic pigeon(Gallus livia), and the great blue heron(Janz and Bellward, 1996). Induction of he-patic microsomal EROD activity and de-creased growth was observed in the pigeonand heron. In these studies, thyroid hor-mone responses to TCDD seem equivocal,although dosage, species sensitivity andvarying experimental protocols all may in-fluence the results. Thus, it is unclearwhether the association between thyroidhormone alterations seen in some fieldstudies are directly related to exposure toAh-inducing chemicals, to other unmea-sured contaminants, or to other biologicalfactors.

Alterations in yolk retinoids have beendemonstrated experimentally after PCBexposure. In a study designed to mimic en-vironmental exposures, white leghorn hens(Gallus domesticus) were fed PCB’s (0.5–6.6 mg/kg diet) derived from carp (Cypri-nus carpio) from Saginaw Bay in the GreatLakes for a period of 7 wk (Zile et al.,1997). Retinoid levels were analyzed in 11-day-old embryos and eggs. Retinoid con-centrations in the embryos were unaffect-ed, however, the high PCB group showeda 50% reduction in the molar ratio of ret-inol to retinyl palmitate in eggs. In con-trast, Spear et al. (1990) found a positivecorrelation between several indices ofPCDD and PCDF concentrations and themolar ratio of retinol to retinyl palmitatein wild herring gull eggs. Many factors, in-cluding dietary availability of vitamin A,may be responsible for these different re-


sponses, but the experimental feedingstudy shows that prenatal exposure toPCBs can significantly affect the retinoidprofile in eggs.

FISH

Field studies reporting alterations inthyroid gland morphology and retinoidlevels in fish associated with exposure toPHAHs and PAHs are summarized in Ta-ble 3.


While thyroid enlargement (goiter) israre in fish in the wild, the Pacific salmonintroduced into the Great Lakes decadesago have experienced an epizootic of en-larged thyroid glands (Sonstegard andLeatherland, 1976). Every adult salmonexamined from the mid-1970’s to the early1990’s had evidence of thyroid gland hy-pertrophy and hyperplasia regardless ofthe lake of origin or the species when com-pared to comparable species and agesfrom the Pacific Northwest (reviewed inLeatherland, 1992, 1993). The lesionswere similar histologically to those previ-ously described in Great Lakes herringgulls (Moccia et al., 1986). Although thereare inter-lake differences in levels of cir-culating thyroid hormones in affectedsalmon during gonadogenesis (Leather-land and Sonstegard 1981) and in eggsfrom maternal deposition (Leatherland etal., 1989), growth and development appearto proceed normally. Therefore, it appearsthat thyroid hormone levels in these salm-on are still within the compensatory rangeof normal homeostasis.

As with the gulls, the available evidenceargues against iodine deficiency as thecause of the thyroid enlargement in salm-on (Leatherland and Sonstegard, 1984). Incoho salmon there was no apparent cor-relation between lake or tissue iodide lev-els and the prevalence or size of goitersfrom different lakes, and experimentally ithas not been possible to induce thyroidenlargement using iodide-free diets(Leatherland, 1993). Furthermore, levels

of plasma thyroid hormones in coho salm-on collected in the spring and summermonths were high, which would not bepossible with iodide deficiency (Leather-land, 1993).

As top predators in the Great Lakesfood web, salmonids bioaccumulate signif-icant levels of halogenated aromatic hydro-carbons, especially PCB’s, and a role forsome of these contaminants in the etiologyof the thyroid enlargement has been in-vestigated with equivocal results. No cor-relation between the severity of thyroid le-sions in Great Lakes salmon and tissue lev-els of PCBs or mirex has been observed(Leatherland, 1992; Leatherland and Son-stegard, 1982). Experimentally, coho salm-on and rainbow trout (Oncorhynchus my-kiss) fed diets containing PCBs and mirex(chemicals found in Great Lakes salmon)failed to develop any thyroid enlargement(Leatherland and Sonstegard, 1978, 1979).Immature coho salmon fed diets com-posed of 100% Great Lakes salmon like-wise failed to develop thyroid enlargement(Leatherland and Sonstegard, 1982). How-ever, when laboratory rodents were fed di-ets containing 100% Great Lakes salmon,hypothyroidism, thyroid hyperplasia andgoiters were seen in the rodents along withincreased activity of cytochrome P450 en-zymes and hepatomegaly (Sonstegard andLeatherland, 1979). The observed thyroidpathology correlated with the organochlo-rine content of the diet, and coupled withthe changes in cytochrome P450 activity,these results suggest that these thyroidchanges are associated with OCs found inGreat Lakes salmon. The potential role ofother environmental contaminants in theetiology of thyroid enlargement in GreatLakes salmon has not been investigated.These studies imply that Great Lakessalmon contain some substance that is goi-trogenic for rodents, but it may not be thesource of the goitrogenic factor affectingthe salmon.

Although the direct cause of the thyroidenlargement in the Great Lakes salmon isnot known, an environmentally-induced


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etiology appears likely. As mentioned ear-lier, thyroid gland enlargement has alsobeen reported in herring gulls that feed onGreat Lakes fish, supporting the hypoth-esis of a common environmental etiology(Moccia et al., 1981; Moccia et al., 1986).A re-evaluation of the status of thyroid en-largement in Great Lakes salmon and gullsalong with current exposure levels toPCBs, mirex and other persistent contam-inants of concern could shed light on therole that OCs have played in the etiologyof this condition.

Experimentally, in an in vitro bioassayusing slices of pig thyroid gland, waterfrom Lake Erie inhibited synthesis of io-dinated tyrosine and thyronine compoundsindicating the presence of a goitrogenicsubstance in the water (Leatherland,1993). It has been hypothesized that thegoitrogenic factor may be a waterborne by-product of bacterial metabolism, as suchcompounds have been shown to inducegoiters in humans (Gaitan et al., 1980).Clearly, further research is needed to iden-tify the goitrogenic substance(s) present inthe Great Lakes food web.

Retinoid alterations

The scientific literature contains severalfield studies looking at the relationship be-tween retinoid status and contaminant ex-posure in fish. An investigation into reti-noid levels in larval white sucker (Catos-tomus commersoni) living in the contami-nated Ottawa River near Montreal(Canada) was prompted by the observationof increased deformities in the adult pop-ulation (Branchaud et al., 1995). De-creased liver retinoid stores had been pre-viously documented in adult white suckerand in lake sturgeon (Acipenser fulvescens)captured near Montreal (Spear et al.,1992; Branchaud et al., 1995). Lower lev-els of intestinal retinoids (retinyl palmitateand dehydroretinyl palmitate) were alsofound in lake sturgeon captured nearMontreal (Ndayibagira et al., 1994). Whencompared to a reference population at arelatively uncontaminated site on the same

river, laboratory-raised larvae from fishcollected at the Montreal site had very lowhepatic stores of retinol and retinyl pal-mitate. Larvae from the contaminated sitehad an elevated incidence of deformities,and hepatic EROD activity in females waspositively correlated with the occurrenceof deformities in their progeny. These re-sults suggest that compounds actingthrough the Ah receptor may be associatedwith the deformities. The principal Ah-ac-tive compounds present at this site werePCBs; the sum of coplanar PCBs in eggsfrom the affected fish was 36 times the lev-el in fish from the reference site.

Doyon et al. (1998) documented up toa 40-fold lower level of hepatic retinoidsin sturgeon from a site in the St. LawrenceRiver compared to a geographically sepa-rate reference population. Possible expla-nations included differences in food web-related dietary availability of vitamin A andexposure to PCBs in the St. Lawrencepopulation.

Further studies of these sturgeon pop-ulations have examined the relationshipbetween deformities, exposure to coplanarPCBs and RA metabolism (Doyon et al.,1999). Adult lake sturgeon from the St.Lawrence River had an estimated defor-mity rate of 2.9%, while larvae raised inartificial streams had a 6.3% rate of fin de-formities, significantly higher than larvaefrom a reference site. To examine a pos-sible relationship between the deformitiesand imbalances of RA, the cytochromeP450 dependant hydroxylation of RA to 4-hydroxy retinoic acid (4-OH-RA) and he-patic concentrations of retinoids and co-planar PCBs were measured. The rate of4-OH-RA formation was over three-foldhigher in the St. Lawrence sturgeon andthe hepatic concentration of PCBs (ex-pressed as toxic equivalents) was 20-foldhigher compared to sturgeon from the ref-erence site. Liver retinoid levels were neg-atively correlated with the RA hydroxyl-ation rate. These results support an asso-ciation between exposure to PCBs, in-creased metabolism of RA by cytochrome


P450 enzymes, lower hepatic retinoidstores, and an increase in developmentaldeformities in lake sturgeon.

Laboratory studies support the hypoth-esis that Ah receptor-active coplanar PCBsmay be responsible for the altered retinoidstatus reported in fish. Exposure of adultbrook trout (Salvelinus fontinalis) to a sin-gle intraperitoneal injection of PCB 77 de-creased plasma retinol and intestinal reti-noids in males (Ndayibagira et al., 1994).Oral exposure to the coplanar PCB 126 (3,39,4,49,5-pentachlorobiphenyl) resulted indecreased liver retinoids in lake trout (Sal-velinus namaycush) (Palace and Brown,1994). In rainbow trout (Onorhynchusmykiss) exposure to PCB 77 increased RAhydroxylation through induction of cyto-chrome P4501A isoenzymes (Gilbert et al.,1995). Together these results suggest thatincreased retinoid metabolism induced byPCBs could cause the vitamin A depletionreported in the field studies.

Alterations in retinoids have also beenassociated with exposure to PAHs. In astudy of brown bullheads (Ameiurus ne-bulosus) sampled from three PAH-con-taminated sites in the lower Great Lakes,a significant correlation was found be-tween induction of EROD activity and de-pleted hepatic retinoid stores (Arcand-Hoyand Metcalfe, 1999). Fish from the con-taminated sites also had an increased he-patosomatic index and an elevated inci-dence of hepatic neoplasms compared toreference sites.

A relationship between PHAH and PAHexposure and alterations in plasma and he-patic retinols was also observed in an ex-perimental mesocosm study in whichflounder (Platichthys flesus) were exposedto polluted sludge from Rotterdam Harbor(The Netherlands) or sludge wash-off for3 yr (Besselink et al., 1998). A significantdecline was seen in plasma and hepaticretinols and hepatic retinyl palmitatestores in fish exposed to the sludge wash-off (but not to sludge alone). In this study,no relationship was found between induc-tion of EROD activity and plasma or he-

patic retinoid levels. Clearly more researchis required to understand the role that Ahinduction by planar PHAHs and PAHsplays in altering retinoid homeostasis infish.

DISCUSSION

The studies reviewed in this paper havefound associations between exposure toPHAHs or PAHs and histological changesof the thyroid gland, alterations in circu-lating thyroid hormone levels, and alter-ations in vitamin A homeostasis in a varietyof wildlife and fish species (Tables 1, 2, 3).As this review demonstrates, similar ob-servations have been made across bothvertebrate classes and species. In somecases the observed changes in thyroid and/or vitamin A status were associated withadverse health effects, including decreasedreproductive success and altered immunesystem function in harbor seals; skin dis-ease in northern elephant seals; unfavor-able breeding parameters and decreasedreproductive success in common terns andcormorants, respectively; and develop-mental deformities in white suckers andlake sturgeon.

Experimental studies support the hy-pothesis that these observations in wildlifemay be causally linked to exposure to someenvironmental contaminants. The PHAHsand PAHs are known to cause severe dis-turbances in vitamin A metabolism andhomeostasis in laboratory species (re-viewed in Zile, 1992). The known mecha-nisms of action include accelerated metab-olism and breakdown of vitamin A and de-pletion from circulation and hepatic tissuestores. Certain coplanar PCBs have beenshown to lower retinoid stores in labora-tory rats (Spear et al., 1988), mice (Brou-wer et al., 1985) and ring doves (Spear etal., 1986, 1989). Dioxin and related con-taminants acting through the Ah receptormay interfere with vitamin A metabolismand storage through enzyme inductionmechanisms because cytochrome P450 hy-droxylation is a step in the retinoid meta-bolic pathway (Spear et al., 1992).


Numerous experimental studies havealso documented disruption of circulatingthyroid hormones and thyroid gland struc-ture and function after exposure to dioxin,dioxin-like furans and PCBs, and hydrox-ylated metabolites of certain PCB conge-ners (reviewed in Brouwer et al., 1998). Inaddition to causing histological changes inthe thyroid gland itself, PHAHs interferewith enzymes that regulate thyroid hor-mone metabolism and homeostasis includ-ing the UDP-glucuronyl-transferases thatregulate T4 glucuronidation and excretion;the iodothyronine deiodinases that activateand deactivate thyroid hormones; and thesulfotransferases that regulate free thyroidhormone concentrations in the blood(Brouwer et al., 1998). In addition, the hy-droxylated metabolites of certain PCBcongeners interfere with the plasma pro-tein complex that transports both thyrox-ine and retinol in the blood resulting indecreased circulating levels of both sub-stances (Brouwer and van den Berg, 1986;Brouwer et al., 1986, 1988, 1990).

Further research is required to deter-mine if disruption of thyroid or vitamin Ahomeostasis is causally related to the ad-verse health effects reported in wildlifeand fish exposed to PHAHs or PAHs. Thehealth effects observed in the field studiesreviewed in this paper could be the directresult of chemical toxicity. However, thy-roid hormones and retinoids are essentialto normal development, growth, epithelialintegrity, immune function, reproductionand metabolism (Leathem, 1972; Zile,1983; McNabb and King, 1993). There-fore, if thyroid or retinoid levels are al-tered beyond the limits of homeostaticcompensation, adverse health effects mayresult. The consistency of responses seenamong different vertebrate classes lendscredence to an association that deservesfurther research. It has also been notedthat some of the pathological effects ofTCDD and TCDD-like chemicals in labanimals are quite similar to those causedby vitamin A deficiency (Thunberg, 1984).However, without knowledge of the un-

derlying mechanisms involved to delineatea cause-effect relationship, any associationbetween thyroid and retinoid alterationsand the adverse health effects reported inthese field studies is only circumstantial.

Alterations in thyroid hormones and vi-tamin A levels could prove to be useful infield studies as another biochemical bio-marker of exposure to PHAHs and PAHs.Because of normal variations in thyroidhormones and retinoids associated withage, gender, diet, nutritional status, seasonand physiological condition, results mustbe interpreted with caution and studiesshould be designed to control for thesevariables. Researchers undertaking ecotox-icological investigations should considerincluding measurements of thyroid hor-mones and vitamin A levels and histologi-cal examination of thyroid gland structurewhen designing field research projects tostudy the responses to these chemicals inwildlife and fish populations.

ACKNOWLEDGMENTS

Funding for this project was provided by grantsto the Wildlife and Contaminants Program ofthe World Wildlife Fund-US from the JeniferAltman Foundation, the Dodge Foundationand the Joyce Foundation. Many thanks to T.Colborn for reviewing this manuscript, to P.Short for her assistance with literature search-es, and to J. Patrick for her excellent editorialassistance.

LITERATURE CITED

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BECKMEN, K. B., L. J. LOWENSTINE, J. NEWMAN, J.HILL, K. HANNI, AND J. GERBER. 1997. Clinicaland pathological characterization of northern el-ephant seal skin disease. Journal of Wildlife Dis-eases 33: 438–449.

BELAND, P., S. DE GUISE, C. GIRARD, A. LAGACE,D. MARTINEAU, R. MICHAUD, D. C. G. MUIR,R. J. NORSTROM, E. PELLETIER, S. RAY, AND L.R. SHUGART. 1993. Toxic compounds and repro-ductive effects in St. Lawrence beluga whales.Journal of Great Lakes Research 19: 766–775.

BERGMAN, A., AND M. OLSSON. 1985. Pathology ofBaltic grey seal and ringed seal females with spe-


cial reference to adrenocortical hyperplasia: Isenvironmental pollution the cause of a widelydistributed disease syndrome? Finnish GameResearch 44: 47–62.

BERN, H. A. 1992. The fragile fetus. In Chemically-induced alterations in sexual and functional de-velopment: The wildlife/human connection, T.Colborn, and C. Clement (eds.). Princeton Sci-entific Publishing, Princeton, New Jersey, pp. 9–15.

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