Developmental Exposure to Poly chlorinated ...

AMER. ZOOL., 37:399-408 (1997)

Developmental Exposure to Poly chlorinated Biphenyls or Dioxin: Do Changes in Thyroid Function Mediate Effects on Spatial Learning?1 SUSAN

L.

SCHANTZ,*! BYUNG-WOUN

SEO,t

JAMAL MOSHTAGHIAN,* AND SHAHID AMIN*

* Department of Veterinary Biosciences and fNeuroscience Program, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Ave. Urbana, Illinois 61802

INTRODUCTION Polychlorinated biphenyls (PCBs) and polychlorinated dibenzodioxins (PCDDs or dioxins) are widely dispersed, environmentally persistent organic compounds. PCBs were manufactured commercially from the 1930s through the 1970s and were widely used as dielectric fluids in capacitors and transformers (Broadhurst, 1972). Dioxins are produced as unwanted byproducts during the manufacture of certain herbicides and wood products. They are also formed during combustion of chlorinated compounds and are found in fly ash from mu' From the Symposium Behavioral Toxicology: Mechanisms and Outcomes presented at the Annual Meeting of the Society for Integrate and Compara-

nicipal and hospital incinerators (Ahlborg et a/-, 1992). Both PCBs and dioxins are very widespread and are found in the tissues of wildlife, domestic animals and humans worldwide {e.g., Jensen, 1987). The primar y s o u r c e o f n u m a n exposure is through consumption of contaminated food products - including fish from polluted waters (Humphrey, 1988). Epidemiological studies suggest that children exposed to complex mixtures of P C B s a n d d i o x i n s durin S earl .y developm e n t ma y experience long-lasting deficits ' " cognitive functioning (e.g., Chen et ah, 1992; Jacobson and Jacobson, 1996). Longterm neurobehavioral changes have also been

P

r e p o r t e d i n monkeys and J- • J • r,/~,n t o P C B s Or d l o x i n S d u n n

, OSed

rodents exr «. w g fetal/neo-

tive Biology, 27-30 December 1995, Washington, natal development (e.g., Seegal and D.C. Schantz, 1994). Very little is known about 399

Downloaded from icb.oxfordjournals.org by guest on July 16, 2011

SYNOPSIS. Polychlorinated biphenyls (PCBs) and dioxins are widespread environmental contaminants that are suspected of causing cognitive deficits in children exposed in utero. Very little is known about which of the PCB and dioxin congeners present in the environment are responsible for the changes in cognitive function or about the mechanisms through which these chemicals affect the central nervous system (CNS). Because both PCBs and dioxins reduce circulating thyroid hormone levels, it has been proposed that these chemicals may affect CNS function indirectly by reducing the availability of thyroid hormone to the brain during development. Thyroid hormones play a critical role in brain development, and spatial learning and memory is one of the behavioral functions most severely affected by neonatal hypothyroidism. In the studies reviewed here, we investigated the effects of three ortAo-substituted PCBs, two coplanar PCBs and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on spatial learning and memory in the rat. Pups exposed to PCBs or TCDD in utero and during lactation were tested when they reached adulthood. All three ortAo-substituted PCBs caused deficits in spatial learning, but only two of the three reduced circulating thyroid hormone concentrations. Furthermore, the learning deficit was observed only in females, but thyroid hormones were equally depressed in males and females. Thus, the PCB-induced deficit in spatial learning did not appear to be mediated by the decreased thyroid hormone levels. TCDD and coplanar PCBs caused moderate reductions in thyroid hormone, but facilitated rather than impaired spatial learning, an effect that has been reported in neonatally /type/thyroid rats. The possibility that TCDD and coplanar PCBs may act as "mixed" thyroid agonists/antagonists causing hypothyroid-like effects in some tissues and hyperthyroid-like effects in other tissues is discussed.

400

S. L. SCHANTZ ET AL.

following neonatal PCB exposure. Furthermore, the reduction in ChAT was partially ameliorated by supplementation with T4. Goldey et al. (1995a, 1996) reported a similar finding with respect to hearing loss. Neonatally PCB- or dioxin-exposed rats showed a low frequency hearing loss similar to that observed with the classic thyroid impairing drug, propylthiouracil (Goldey et al, \995b). The PCB-induced hearing loss was partially ameliorated by supplementation with T4 (Goldey et al., 1995c). As noted above, deficits in spatial learning and memory are one of the key neurobehavioral sequelae following neonatal hypothyroidism (Akaike et al., 1991; Davenport, 1976; Stein et al., 1991). Neonatal PCB exposure has also been shown to cause spatial learning and memory deficits (Schantz et al., 1991). Therefore, our laboratory has investigated the potential role of decreases in circulating thyroid hormones in mediating the effects of PCBs and dioxins on spatial learning and memory. Because the commercial PCBs released into the environment were complex mixtures of chlorobiphenyl congeners with different chemical properties and toxicological effects, we investigated a number of different PCB congeners with a range of different chlorine substitution patterns. In general, PCB congeners can be divided into two broad classes based on their similarity to 2,3,7,8-tetrachlorodibenzo-pdioxin (dioxin or TCDD). PCBs with no ortho chlorines, two para chlorines and at least two meta chlorines can assume a planar configuration similar to that of TCDD (Fig. 1), bind to a cytosolic receptor protein known as the aryl hydrocarbon receptor (AhR) and elicit toxic effects similar to those of TCDD. In contrast, most PCB congeners with ortho chlorine substitutions cannot assume the planar configuration necessary for binding to the AhR and differ from TCDD in their pattern of toxic effects. In our studies we investigated three orf/io-substituted PCBs, two coplanar PCBs and TCDD. The three orffco-substituted PCBs were selected because of their prevalence in the environment and their presence in human tissue, including breast milk (Safe et al., 1985) and blood samples from


the mechanisms through which PCBs and dioxins affect central nervous system (CNS) functioning, but recently it has been proposed that these chemicals may affect the CNS indirectly by reducing circulating thyroid hormone levels (Porterfield, 1994). Thyroid hormones are known to play a critical role in brain development. Neonatal hypothyroidism results in delayed myelinogenesis, delayed or impaired neuronal differentiation and synaptogenesis, (Nunez, 1984; Timiras, 1988) and alterations in neurotransmitter function (Vacarri, 1988). These morphological and neurochemical changes are accompanied by impaired neurobehavioral function including delayed reflex development, changes in motor activity and emotionality, and deficits in learning and memory, particularly spatial learning and memory (Akaike et al., 1991; Davenport, 1976; Stein et al., 1991). Both PCBs and dioxins have been shown to reduce thyroid hormone levels in adult animals {e.g., Gray et al., 1993; Potter et al., 1985). Thyroxine (T4) is usually much more severely impacted than triiodothyronine (T3), the more biologically active form of the hormone. However, T3 does not cross the blood brain barrier readily (Calvo et al., 1990; Ruiz de Ona et al., 1988). Instead, T4 enters the brain and is converted to T3 in situ. Thus, it has been argued that compounds like the PCBs, which reduce serum T4 levels in the absence of significant changes in T3, could have a more negative impact on the brain than on other tissues (Porterfield, 1994). However, it is known that type II deiodinaze, which is responsible for the conversion of T4 to T3 in brain, is up regulated when T4 levels fall. The extent to which induction of type II deiodinaze can protect the brain in the face of decreased circulating T4 levels is not clear. Dramatic reductions in circulating T4 concentrations have been reported in rat pups following combined in utero and lactational exposure to commercial PCB mixtures {e.g., Goldey et al., 1995a; Ju&rez de Ku et al., 1994). Moreover, these reductions in T4 have been linked to CNS effects. Juarez de Ku and colleagues (1994) found that hippocampal choline acetyl transferase (ChAT) activity was reduced

401

PCBs, THYROID HORMONES AND SPATIAL LEARNING a

a

a

_ci

a

a PCB 118 2,3;4,4',S-P*nOchUlTxMphtnyl

\J~SJ a

PCB 77 3,3;4,4'-Titmchlorobil>htnyl

PCB 126 3,3;4,4',S-PntaehloroUfkmyl

FIG. 1. Chemical structures of the PCBs and TCDD. Congeners 77 and 126 are coplanar. Congeners 28, 118 and 153 have one or more ort/io-chlorine substitutions.

METHODS

The animals, PCB or TCDD exposure and neurobehavioral testing methods used in these studies have been described in detail in previous reports (Schantz et al., 1995; Schantz et al, 1996) and will, therefore, only be summarized here. For each experiment, time-mated Sprague-Dawley rat dams were obtained from Harlan SpragueDawley (Indianapolis, Indiana) on day one of gestation (day of sperm plug was considered day zero) and assigned to treatment groups. On gestation days 10—16, each dam was gavaged with corn oil vehicle or chemical dissolved in corn oil vehicle. The chemicals and doses used in each study are shown in Table 1. The PCBs were obtained

TABLE 1. Chemical names, chlorine substitution patterns, doses and number of litters tested per group in studies 1 and 2. Study

Chemica!"

1

Control PCB 28 PCB 118 PCB 153 Control PCB 77 PCB 126 TCDD

2

Chlorine substitution pattern

Corn oil vehicle (n = 6) 244'-trichlorobiphenyl 23'44'5-pentachlorobiphenyl 22 '44' 55 '-hexachlorobiphen y 1 Corn oil vehicle (n = 11) 3 3' 44' -tetrachlorobipheny I 33'44'5-pentachlorobiphenyl 2,3,7,8-tetrachlorodibenzo-p-dioxin

High doseb (nf

Low dose (n)

32 mg/kg (9) 16 mg/kg (6) 64 mg/kg (7)

8 mg/kg (8) 4 mg/kg (8) 16 mg/kg (8)

8 mg/kg (11) 1 M-g/kg (10) 0.1 u.g/kg (10)

' IUPAC numbers are used for individual PCB congeners. Doses are maternal doses on gestation days 10-16. c n = number of litters. One male and one female from each litter were tested. b

2 mg/kg (10) 0.25 u.g/kg (11) 0.025 (xg/kg (10)


children who were breast fed as infants (Jacobson et al., 1989). One congener, 2,3',4,4',5-pentachlorobiphenyl (PCB 118), dramatically reduced serum T4 levels, the second, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), had a moderate effect on serum T4, and the third, 2,4,4'-trichlorobiphenyl (PCB 28), had no effect on serum T4 levels (Ness et al., 1993). The concentrations of TCDD and coplanar PCBs in human tissue are much lower than those of orr&o-substituted PCBs, but these compounds are toxic at doses of only a few u.g/kg (Safe, 1994) and can produce moderate reductions in serum T4 levels (Seo et al., 1995). Therefore, TCDD and coplanar PCBs were also studied.

402


The animals retained for behavioral testing were tested for spatial learning and memory in a radial arm maze and a T-maze. The features and dimensions of both mazes are described in detail in previous reports (Schantz et al., 1995; Schantz et al., 1996). Maze testing was conducted five days per week during the dark phase of the lightdark cycle. Prior to the beginning of maze testing, animals were handled daily for a period of one week. This was followed by one week of shaping, the purpose of which was to adapt the animals to the maze and to the food reinforcements (Kellogg's Froot Loops) to be used during the maze training.

Eight-arm radial arm maze working memory task The radial-arm maze is one of the most commonly used methods for testing spatial learning and memory in rodents. When training takes place with all arms baited the maze provides a simple, straightforward test of working memory. When only a subset of the arms is baited, both working and reference memory can be assessed. Rats were tested in the radial arm maze beginning at 90 days of age. The rats in Study One (orf/io-substituted PCBs) were tested on a working memory/reference memory task in an eight-arm radial maze in which four of the eight arms were baited (Schantz et al, 1995). The rats in Study Two (coplanar PCBs and TCDD) were tested on a slightly different task in which all eight arms of the maze were baited and only working memory was assessed (Schantz et al., 1996). The maze was located in a dimly lit room that contained abundant extra-maze visual cues. For testing, approximately J4 of a single Kellogg's Froot Loop was placed in the food cups at the ends of four of the eight arms (Study One) or all eight arms (Study Two). At the beginning of each session, the rat was placed inside the opaque ring located on the center platform. After 10 sec, the ring was lifted and the rat was free to move about the maze. An arm entry was recorded each time the rat placed all four paws into one of the arms. The session was terminated when the rat had retrieved all the reinforcers, or after five min had elapsed, whichever came first. Animals were tested once per day (Monday—Friday) for seven consecutive weeks (35 test sessions) in Study One, or for four consecutive weeks (20 test sessions) in Study Two. The number of errors (reentries into arms from which the reinforcer had already been retrieved), and the latency to retrieve all reinforcers were recorded using a computerized scoring system developed in our lab (Mazemate by Chao Tang). T-maze delayed spatial alternation (DSA) task Later a T-maze was used to test the same animals on another spatial learning and


from AccuStandard (New Haven, CT) and were guaranteed >99% pure. The TCDD was obtained from Cambridge Isotope Laboratories (Woburn, MA) and was guaranteed >98% pure. Ortho-substituted PCBs were passed through an activated charcoal column to remove any trace levels of contamination with coplanar PCBs or dibenzofurans. Litters were culled to eight on day two. Beginning on day 11 all of the animals in each litter were observed daily and the number of pups with both eyes open was recorded. Pups were weaned on day 21, and one male and one female from each litter were retained until adulthood for behavioral testing. The animals were ear-punched for identification, housed two per cage in likesex, like-treatment pairs and maintained on a reverse light-dark cycle (lights off at 9:00 am). Another male and another female from each litter were sacrificed at weaning and blood was collected for thyroid hormone analysis according to published methodology (Ness et al., 1993; Seo et al., 1995). Total T3 (triiodothyronine) and T4 concentrations were determined using commercially available radioimmunoassay (RIA) kits (Diagnostic Products Corporation, Los Angeles, CA). Thyroid stimulating hormone (TSH) concentrations were determined by RIA using the materials and protocols of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Hormone and Pituitary Program.

403

PCBs, THYROID HORMONES AND SPATIAL LEARNING

Statistical analysis The data were analyzed via repeated measures analysis of variance (ANOVA). The litter was used as the unit of variance in all analyses and sex was treated as a within litter variable. Significance was set at P < 0.05. Radial arm maze errors were averaged into weekly blocks of five sessions each for analysis. The analysis had one between litter variable (PCB exposure) and two nested within litter variables (sex and session blocks). Number correct on the T-maze was averaged into three blocks of five sessions each. The analysis had one be-

Control Low

High

PCB 28

Low High PCB 118

Low High PCB 153

FIG. 2. Serum total T4 concentrations at weaning (day 21) in PCB 28, PCB 118 and PCB 153-exposed pups. Values are means ± standard errors, n = 6—9/ dose group (see Table 1). The dams were dosed with 8 or 32 mg/kg/day PCB 28, 4 or 16 mg/kg/day PCB 118, 16 or 64 mg/kg/day PCB 153 or corn oil vehicle on days 10—16 of gestation. Statistical significance was set at P < 0.05. (***/> < 0.001).

tween litter variable (treatment) and three nested within litter variables (sex, session blocks, and delays). Significant interactions were analyzed further via tests of simple main effects followed by planned comparisons of the treatment groups to the control group (Keppel, 1982). RESULTS AND DISCUSSION

As illustrated in Figure 2, the three orf/zo-substituted PCBs had very different effects on circulating T4 concentrations (Ness et al., 1993). PCB 118 markedly reduced serum T4 concentrations, with the highest dose producing a 90% reduction in T4. Despite the marked depression in T4, serum T3 concentrations were unchanged (data not shown). The reduction in T4 was accompanied by histological changes to the thyroid which were suggestive of sustained TSH stimulation (Ness et al., 1993). However, serum TSH levels were not measured in these animals. PCB 153 had a more moderate effect, reducing serum T4 by about 50% at the highest dose, and PCB 28 had no effect on serum T4 concentrations at either dose. Although the three congeners had distinctly different effects on thyroid hormones, they had very similar effects on spatial learning. None of the congeners pro-


memory task known as delayed spatial alternation or DSA. This task was very similar to a DSA task used previously to test PCB-exposed monkeys (Levin et al., 1988; Schantz et al., 1991). The rats were tested on DSA beginning at about 165 days of age. One test session consisting of 13 trials was given daily Monday-Friday for three consecutive weeks (15 test sessions). On the first trial of each session, both arms of the T were baited with a food reinforcer. The rat was placed in the start box at the base of the T, the start box door was opened and the rat was allowed to choose one arm. For the next 12 trials, the reinforcer was placed in the arm opposite that chosen by the rat on the previous trial. Delays of 15, 25, or 40 sec were interposed between trials in a counterbalanced order with each appearing four times within each test session. Animals were given a maximum of 30 sec to make a response on each trial. If an animal did not make a choice within 30 sec a balk was scored, the trial was terminated, and the animal was returned to the start box for the next trial. If an animal balked either three consecutive times or a total of five times during a test session, the session was terminated and the data were not used. Animals that balked were tested until they had 15 complete test sessions. Number correct and latency to respond were recorded. A correct response was recorded if the animal placed all four paws in the correct choice arm. Latency to respond was defined as the time from opening of the start box door until the animal had placed all four paws in one of the choice arms.

404


lbei

rre

11 13 10 9Oo 8 7t 6z

**

1

9 Control - • - PCB 28 Low - A - PCB 28 High

2

3

Blocks of Five Sessions 11 fc 9 o O 8 -

!

Control PCB 118 Low PCB 118 High

6-

2

3

11 -

9 8 7 -

Control PCB 153 Low PCB 153 High

1

2

3

Blocks of Five Sessions

FIG. 3. Number correct on the T-maze averaged across all trials for female rats whose dams were exposed to 8 or 32 mg/kg/day PCB 28, 4 or 16 mg/kg/ day PCB 118, 16 or 64 mg/kg/day PCB 153 or corn oil vehicle on days 10-16 of gestation, n = 6-9/dose group (see Table 1). Values are means ± standard errors. Statistical significance was set at P < 0.05 (*P < 0.05; f < 0.10). Reprinted with permission from Schantz et at., 1995.

duced any changes in acquisition or performance on the radial arm maze, but all three congeners resulted in slower acquisition of the T-maze DSA task in female rats (Schantz et al., 1995; Fig. 3). PCB-exposed female rats made more errors than controls during the first and/or second blocks of sessions, but by the third block of sessions had improved to within measurement error of


1

Blocks of Five Sessions

controls. Interestingly, this slower acquisition of the DSA task was seen only in female rats. PCB-exposed male rats showed no evidence of a similar delay in learning. In contrast, serum T4 concentrations were equally depressed in male and female PCBexposed rats. Thus it seems unlikely that the PCB-related deficit in spatial learning was mediated by changes in circulating thyroid hormones. The fact that PCB 28 did not reduce thyroid hormone concentrations, but did cause a learning deficit similar to that observed in PCB 118 and PCB 153exposed rats, provides further evidence against reduced thyroid hormone levels as a mediating factor. Because we sampled only at weaning, we cannot rule out the possibility that serum T4 levels in the PCB 28-exposed rats were depressed earlier in development. However, T4 is critical to overall growth and development, and the PCB 28-exposed pups did not show a decrease in birth weight or early postnatal growth (Ness et al., 1993). Thus, it seems unlikely that there was a large decrease in T4 earlier in development. It should be noted that there were no significant differences between male and female control rats in serum T4 concentrations, nor were there any significant differences in the spatial learning of male and female controls. The coplanar PCB congeners and TCDD caused mild reductions in serum T4 concentrations (Fig. 4), but did not alter serum T3 or TSH levels (Seo et al., 1995). Although the effects on thyroid hormones were in the same direction as those observed with the orf/io-substituted PCBs, the neurobehavioral effects of the coplanar PCBs and TCDD were very different from those of the orf/xo-substituted PCBs. The TCDD and coplanar PCB-exposed rats did not show any evidence of a deficit similar to that observed in the or//io-PCB-exposed rats on the DSA task. In contrast, the TCDD and coplanar PCB-exposed rats did differ from controls on the radial arm maze task. However, they made fewer, not more, errors than controls (Figs. 5 and 6). This apparent facilitation of learning was most pronounced in the TCDD-exposed rats (Fig. 5), but significant decreases in errors were also observed in the PCB 77 and PCB 126-

PCBs,

Control Low

405

THYROID HORMONES AND SPATIAL LEARNING

High Low High Low High

PCB 77

PCB 126

TCDD

Control Low High

Low High

PCB 77

PCB 126

Low High TCDD

FIG. 4. Serum total T4 concentrations at weaning (day 21) in PCB 77, PCB 126 and TCDD-exposed pups. Values are means ± standard errors, n = 10-11/dose group (see Table 1). The dams were dosed with 2 or 8 mg/kg/day PCB 77, 0.25 or 1.0 (jig/kg/day PCB 126 or 0.025 or 0.10 p.g/kg/day TCDD on days 10-16 of gestation. Statistical significance was set at P < 0.05. *Significantly different from controls. Reprinted with permission from Seo et al., 1995.

impaired in their learning of the radial arm maze (Akaiki et al, 1991; Seo, Meisami and Schantz, unpublished data). Interestingly, neonatal hyperthyxoidism has been shown to improve radial arm maze performance in adulthood (Crusio and Schwegler, 1991). Some of the other effects observed in the TCDD and coplanar PCB-exposed rats also resemble effects observed in neonatally hyperthyroid rats. For example, exposure to either TCDD or coplanar PCBs resulted in early eye-opening (Fig. 7). In contrast, the low frequency hearing loss ob-

Control 0.025 ng/kg/day 0.1 ug/kg/day

2

1

2

3

4

Blocks of Five Sessions FIG. 5. Radial arm maze errors on each of four blocks of five sessions in rats born to darns dosed with TCDD (0.025 or 0.10 (ig/kg/day) or corn oil vehicle on gestation days 10-16. Values are means ± standard errors, n = 10-1 I/exposure group (see Table 1). Insert shows mean number of errors averaged across all 20 sessions of testing. Significant differences from control are indicated on the inserts (***/> < 0.001, **P < 0.01, *p < 0.05). Reprinted with permission from Schantz et al., 1996.


exposed rats (Fig. 6). Both male and female rats made fewer errors, but the effect was most pronounced in male rats. Not only do these findings differ from the effects observed after perinatal exposure to the three o/t/io-substituted PCBs, they also differ markedly from the pattern of effects that has been observed in rats rendered hypothyroid via treatment with PTU during the neonatal period. In contrast to the facilitated learning observed in the TCDD and coplanar PCB-exposed rats, rats exposed to PTU neonatally are profoundly

406


12 2 ui

22

1

1 • Control 0.25 ng/kg/day • 1.0ng/kg/day

1 2 3 4 Blocks of Five Sessions

E • Control • 2 mg/kg/day • 8 mg/kg/day

1 2 3 4 Blocks of Five Sessions

FIG. 6. Radial arm maze errors on each of four blocks of five sessions in rats born to dams dosed with PCB 77 (2.0 or 8.0 mg/kg/day), PCB 126 (0.25 or 1.0 u-g/kg/day), or corn oil vehicle on gestation days 10-16. Values are means ± standard errors, n = 10-11/exposure group (see Table 1). Insert shows mean number of errors averaged across all 20 sessions of testing. Significant differences from control are indicated on the inserts (***/» < 0.001, **P < 0.01, *P < 0.05). Reprinted with permission from Schantz et al., 1996.

mone receptors. However, the "mixed bag" of effects observed following perinatal TCDD exposure does seem to fit the combined agonist/antagonist model. SUMMARY AND CONCLUSIONS

In summary, exposure to any one of the three orf/io-substituted PCB congeners evaluated in these studies resulted in a sexspecific learning deficit on a T-maze DSA task. The ortho PCB-exposed females learned the task more slowly than control females. In contrast, only two of the three ortfco-substituted PCB congeners reduced serum T4 concentrations, and T4 was equally depressed in males and females. Thus it seems unlikely that the learning impairment was mediated by the changes in serum T4. Exposure to TCDD or coplanar PCBs caused moderate reductions in serum T4, but resulted in a pattern of behavioral effects that was not consistent with the effects observed with the three orr/io-substituted PCBs nor with effects observed following neonatal hypothyroidism. There were no differences between exposed and control rats on the T-maze DSA task, but exposed rats showed an apparent facilitation of radial arm maze learning. A similar improvement has been reported in neonatally hyperthyroid mice. Other effects reminiscent of those seen with neonatal hyper-


served in neonatally TCDD-treated rats by Goldey and colleagues (1995c) is characteristic of neonatal /rypothyroidism. Given these findings, it is interesting to speculate that TCDD may actually act as a thyroid hormone agonist in some tissues while simultaneously acting as an antagonist in other tissues. A number of years ago, McKinney and colleagues (1985) proposed just such a model. Based on molecular modeling studies, they suggested that TCDD could act as an agonist at thyroid hormone nuclear receptors. If so, this would lead to effects similar to those seen in /ryperthyroidism. At the same time, interactions of TCDD with serum binding proteins for T4, such as transthyretin, and/or T4 metabolizing enzymes such as UDP-glucuronyl transferase (UDPGT) could result in lowered serum T4 levels and create effects resembling those seen in /rypothyroidism. They concluded that the "mixed" agonist and antagonist properties of TCDD would be likely to result in a complex array of toxic effects characteristic of both hyper- and hypothyroidism. It has now been demonstrated that PCBs and dioxins do bind to transthyretin (Brouwer et al, 1990) and induce UDPGTs (Barter and Klaassen, 1994). We are aware of no experimental studies demonstrating that TCDD binds to nuclear thyroid hor-

PCBs,

THYROID HORMONES AND SPATIAL LEARNING

407

REFERENCES

100.0 -

PCB 77

)

1

"till


Ahlborg, U., A. Brouwer, M. Fingerhut, J. Jacobson, S. Jacobson, S. Kennedy, A. Kettrup, J. Koeman, / 60.0H. Poiger, C. Rappe, S. Safe, R. Seegal, J. Tuom-•- com II) isto, and M. van den Berg. 1992. Impact of po/yj 40.0 - -m- Low -*- High if lychlorinated dibenzo-p-dioxins, dibenzofurans, 20.0 and biphenyls on human and environmental health, with special emphasis on application of the 0.0 - » t rr—i—.-I toxic equivalency factor concept. Eur. J. Pharma11 12 13 14 15 16 col. 228:179-199. Postnatal Day Akaike, M., H. Kato, H. Ohno, and T. Kobayashi. 1991. Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism. Neurotoxicol. Teratol. 13:317-322. Barter, R. A. and C. D. Klaassen. 1994. Reduction of thyroid hormone levels and alteration of thyroid function by four representative UDP-glucuronosyltransferase inducers in rats. Toxicol. Appl. Pharmacol. 128:9-17. Broadhurst, M. 1972. Use and replaceability of po11 12 13 14 15 16 lychlorinated biphenyls. Environ. Health Perspect. Postnatal Day 2:81-102. Brouwer, A., E. Klasson-Wehler, M. Bokdam, D. C. Morse, and W. A. Traag. 1990. Competitive in100.0 hibition of thyroxin binding to transthyretin by TCDD /y 80.0 c monohydroxy metabolites on 3,4,3',4'-tetrachloT/7 / robiphenyl. Chemosphere. 20:1257-1262. 60.0 —#— Cont / / W Calvo, R., M. J. Obregon, C. Ruiz de Ona, F. Escobar s 40.0 - —•— Low / / / J del Rey, and G. Morreale de Escobar. 1990. Cona—A— High / J/ genital hypothyroidism, as studied in rats. J. Clin. 20.0 Invest. 86:889-899. l JL 0.0 Chen, Y.-C, Y.-L. Guo, C.-C. Hsu, and W. Rogan. 11 12 13 14 15 16 1992. Cognitive development of Yu-Cheng ("Oil Postnatal Day Disease") children prenatally exposed to heat-degraded PCBs. J. Am. Med. Assoc. 268:3213FIG. 7. Percent of pups with both eyes open on post3218. natal days 11—16. Values are means ± standard errors