Considering the importance of thyroid hormone (TH) in brain development, it is of potential concern that a wide variety of environmental chemicals can interfere with thyroid function or, perhaps of greater concern, with TH action at its receptor (TR). Recently bisphenol-A (BPA, 4,4' isopropylidenediphenol) was reported to bind to the rat TR and act as an antagonist in vitro. BPA is a high production volume chemical, with more than 800 million kg of BPA produced annually in the United States alone. It is detectable in serum of pregnant women and cord serum taken at birth; is 5-fold higher in amniotic fluid at 15-18 wk gestation, compared with maternal serum; and was found in concentrations of up to 100 ng/g in placenta. Thus, the human population is widely exposed to BPA and it appears to accumulate in the fetus. We now report that dietary exposure to BPA of Sprague Dawley rats during pregnancy and lactation causes an increase in serum total T4 in pups on postnatal d 15, but serum TSH was not different from controls. The expression of the TH-responsive gene RC3/neurogranin, measured by in situ hybridization, was significantly up-regulated by BPA in the dentate gyrus. These findings suggest that BPA acts as a TH antagonist on the beta-TR, which mediates the negative feedback effect of TH on the pituitary gland, but that BPA is less effective at antagonizing TH on the alpha-TR, leaving TRalpha-mediated events to respond to elevated T4.

Thyroid hormone is essential for normal brain development. Therefore, it is a genuine concern that thyroid function can be altered by a very large number of chemicals routinely found in the environment and in samples of human and wildlife tissues. These chemicals range from natural to manufactured compounds. They can produce thyroid dysfunction when they are absent from the diet, as in the case of iodine, or when they are present in the diet, as in the case of thionamides. Recent clinical evidence strongly suggests that brain development is much more sensitive to thyroid hormone excess or deficit than previously believed. In addition, recent experimental research provides new insight into the developmental processes affected by thyroid hormone. Based on the authors' research focusing on the ability of polychlorinated biphenyls to alter the expression of thyroid hormone-responsive genes in the developing brain, this review provides background information supporting a new way of approaching risk analysis of thyroid disruptors. endemias occurring in different parts of the world have led to the proposal that the various symptoms of the two forms of cretinism arise from thyroid hormone deficits occurring at different developmental windows of vulnerability (15,17,49). Therefore, thyroid hormone appears to play an important role in fetal brain development, perhaps before the onset of fetal thyroid function.The second type of pathological situation is that of subtle, undiagnosed maternal hypothyroxinemia. The concept and definition of maternal hypothyroxinemia were developed in a series of papers by . Low thyroid hormone was initially defined empirically-those pregnant women with the lowest butanol-extractable iodine among all pregnant women (55,57). This work was among the first to document an association between subclinical hypothyroidism in pregnant women and neurological function of the offspring. After the development of radioimmunoassay for thyroid hormone, Pop et al. (58) found that the presence of antibodies to thyroid peroxidase in pregnant women, independent of thyroid hormone levels per se, is associated with significantly lower IQ in the offspring. Subsequent studies have shown that children born to women with thyroxine (T 4 ) levels in the lowest 10 th percentile of the normal range had a higher risk of low IQ and attention deficit (25). Excellent recent reviews discuss these studies in detail (24,57,59). Taken together, these studies present strong evidence that maternal thyroid hormone plays a role in fetal brain development before the onset of fetal thyroid function, and that thyroid hormone deficits in pregnant women can produce irreversible neurological effects in their offspring (18,19,22,37,(60)(61)(62). Thyroid Hormone and Brain Development in Experimental AnimalsConsiderable research using experimental animals has provided important insight into the mechanisms and consequences of thyroid hormone action in brain development. The body of this work is far too extensive to review here but has been rev...

Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 μM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [ 3 H]ryanodine to RyR1enriched microsomes, the mixture and the individual congeners (50 nM to 50 μM) increased RyR activity by 2.4−19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial PCB mixture, Aroclor 1254 (A1254), exerts effects in the fetal brain by one or both of these mechanisms. Dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine (T 3 ) and thyroxine (T 4 ) in pregnant rats but increased the expression of several THresponsive genes in the fetal cortex, including neuroendocrine-specific protein A (NSP-A), RC3/neurogranin, and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, we did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. These findings indicate that PCBs can interfere with TH signaling in the fetal brain by direct actions on the fetus rather than by producing maternal hypothyroidism. producing a variety of functional TR isoforms (TRβ1, TRβ2, TRβ3, TRα1) (Flamant and Samarut 2003). TRα1 and TRβ1 are the predominant isoforms that are expressed throughout brain development (Bradley et al. 1989(Bradley et al. , 1992(Bradley et al. , 1994 and in other tissues such as liver, intestine, and heart (Brent 2000). However, only one report has addressed this proposal directly (Cheek et al. 1999), finding that two hydroxylated PCB congeners (4´-OH-PCB-14 and 4´-OH-PCB-106) exhibit a relatively low affinity for human TRβ1 (K i = 32 µM).Considering these findings, the present studies were initiated for two reasons. First, we tested the hypothesis that maternal PCB exposure could affect the fetal cerebral cortex by reducing the availability of TH to the fetus. We previously showed that low maternal TH, produced experimentally by goitrogen treatment, can alter gene expression in the fetal cortex before the onset of fetal thyroid function (Dowling et al. , 2001. Therefore, if PCBs reduce circulating levels of maternal TH, then gene expression in the fetal cortex should respond in a manner consistent with hypothyroidism. Second, we tested the hypothesis that individual PCBs or their metabolites could bind to the TR. To test this, we used rat hepatic nuclei as a source of both TRα1 and TRβ1. Materials and MethodsChemicals. Aroclor 1254 (A1254; lot no. A8110048) and individual PCB congeners (PCBs 77, 105, 118, 126, 138, and 153) were purchased from AccuStandard, Inc. (New Haven, CT). Methylsulfonyl-PCBs (MeSO 2 -PCBs) were synthesized according to Haraguchi et al. (1987). The purity of these compounds was > 99% as determined by gas chromatography. The hydroxylated PCBs were synthesized using the ...

This work tests the mode-of-action (MOA) hypothesis that maternal and developmental triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via up-regulation of hepatic catabolism and elimination of T4. Time-pregnant Long-Evans rats received TCS po (0–300 mg/kg/day) from gestational day (GD) 6 through postnatal day (PND) 21. Serum and liver were collected from dams (GD20, PND22) and offspring (GD20, PND4, PND14, PND21). Serum T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) concentrations were measured by radioimmunoassay. Ethoxy-O-deethylase (EROD), pentoxyresorufin-O-depentylase (PROD) and uridine diphosphate glucuronyltransferase (UGT) enzyme activities were measured in liver microsomes. Custom Taqman® qPCR arrays were employed to measure hepatic mRNA expression of select cytochrome P450s, UGTs, sulfotransferases, transporters, and thyroid-hormone responsive genes. TCS was quantified by LC/MS/MS in serum and liver. Serum T4 decreased approximately 30% in GD20 dams and fetuses, PND4 pups and PND22 dams (300 mg/kg/day). Hepatic PROD activity increased 2- to 3-fold in PND4 pups and PND22 dams, and UGT activity was 1.5-fold higher in PND22 dams only (300 mg/kg/day). Minor up-regulation of Cyp2b and Cyp3a expression in dams was consistent with hypothesized activation of the constitutive androstane and/or pregnane X receptor. T4 reductions of 30% for dams and GD20 and PND4 offspring with concomitant increases in PROD (PND4 neonates and PND22 dams) and UGT activity (PND22 dams) suggest that up-regulated hepatic catabolism may contribute to TCS–induced hypothyroxinemia during development. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4 changes in PND14 and PND21 offspring. These data support the MOA hypothesis that TCS exposure leads to hypothyroxinemia via increased hepatic catabolism; however, the minor effects on thyroid hormone metabolism may reflect the low efficacy of TCS as thyroid hormone disruptor or highlight the possibility that other MOAs may also contribute to the observed maternal and early neonatal hypothyroxinemia.