Search

Thyroid hormones (predominantly thyroxine, T4, and triiodothyronine, T3) are essential for normal development and for adult physiology. There are several challenges, however, that make identifying chemicals that produce adverse effects by interfering with the thyroid system difficult. First, individual variability in serum concentrations of thyroid hormones represent only about 10% of the population reference range that is considered to be "normal." This means that populations studies evaluating the relationship between chemical exposure and serum thyroid hormones must be large enough to overcome this internal variance. In addition, we know that there are chemicals that do not produce changes in thyroid hormone levels, but nevertheless impact thyroid signaling in target tissues. A good example is that of polychlorinated biphenyls (PCBs). PCB exposure during development are clearly associated with cognitive deficits in humans. But PCB exposure isn't uniformly associated with a reduction in serum thyroid hormone in human populations despite mechanistic studies showing that PCBs reduce serum T4 in animals. In contrast, perchlorate is a chemical that inhibits iodide uptake, thereby reducing thyroid hormone synthesis and serum hormone levels. Human studies have been variable in identifying a relationship between thyroid hormone and perchlorate exposure, but studies also show that dietary iodine, cigarette smoking and other factors can modify this relationship. The conclusion is that identifying chemicals that interfere with thyroid hormone could depend on in vitro analysis of chemicals that interact with different proteins important for thyroid hormone to function properly., Competing Interests: Conflict of interest The author has not received funding from any source for this chapter. The views expressed here are the professional opinions of the author and do not necessarily reflect those of his employers or any agencies that have funded his work. There are no contractual relations or proprietary considerations that restrict the authors' publication or dissemination of the findings described in the manuscript. Dr. Zoeller has served on various advisory boards and panels of the US EPA, the National Institutes of Health and Pew Charitable Trusts in relation to issues of EDCs. He is currently a member of the Endocrine Society's EDC Advisory Group and is co-chair of one of its Task Force groups. His travel has been sponsored by various government, academic, and industry groups to present findings of his research. Dr. Zoeller's research has been funded by government agencies in the United States and the European Union., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 RyR1-enriched 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.

Prenatal exposures to polybrominated diphenyl ethers (PBDEs) can harm neurodevelopment in humans and animals. In 2003-2004, PentaBDE and OctaBDE were banned in California and phased-out of US production; resulting impacts on human exposures are unknown. We previously reported that median serum concentrations of PBDEs and their metabolites (OH-PBDEs) among second trimester pregnant women recruited from San Francisco General Hospital (2008-2009; n = 25) were the highest among pregnant women worldwide. We recruited another cohort from the same clinic in 2011-2012 (n = 36) and now compare serum concentrations of PBDEs, OH-PBDEs, polychlorinated biphenyl ethers (PCBs) (structurally similar compounds banned in 1979), and OH-PCBs between two demographically similar cohorts. Between 2008-2009 and 2011-2012, adjusted least-squares geometric mean (LSGM) concentrations of ∑PBDEs decreased 65% (95% CI: 18, 130) from 90.0 ng/g lipid (95% CI: 64.7, 125.2) to 54.6 ng/g lipid (95% CI: 39.2, 76.2) (p = 0.004); ∑OH-PBDEs decreased 6-fold (p < 0.0001); and BDE-47, -99, and -100 declined more than BDE-153. There was a modest, nonsignificant (p = 0.13) decline in LSGM concentrations of ∑PCBs and minimal differences in ∑OH-PCBs between 2008-2009 and 2011-2012. PBDE exposures are likely declining due to regulatory action, but the relative stability in PCB exposures suggests PBDE exposures may eventually plateau and persist for decades.

Background: Increasing data on early biological changes from chemical exposures requires new interpretation tools to support decision-making., Objectives: To test the possibility of applying a quantitative approach using human data linking chemical exposures and upstream biological perturbations to overt downstream outcomes., Methods: Using polychlorinated biphenyl (PCB) exposures and maternal thyroid hormone (TH) perturbations as a case study, we model three relationships: (1) prenatal PCB exposures and TH changes, using free T(4) (FT(4)); (2) prenatal TH and childhood neurodevelopmental outcomes; and (3) prenatal PCB exposures and childhood neurodevelopmental outcomes (IQ). We surveyed the epidemiological literature; extracted relevant quantitative data; and developed models for each relationship, applying meta-analysis where appropriate., Results: For relationship 1, a meta-analysis of 3 studies gives a coefficient of -0.27 pg/mL FT(4) per ln(sum of PCBs) (95% confidence interval [CI] -0.82 to 0.27). For relationship 2, regression coefficients from three studies of maternal FT(4) levels and cognitive scores ranged between 0.99 IQ points/(pg/mL FT(4)) (95% CI -0.31 to 2.2) and 7.6 points/(pg/mL FT(4)) (95% CI 1.2 to 16.3). For relationship 3, a meta-analysis of five studies produces a coefficient of -1.98 IQ points (95% CI -4.46 to 0.50) per unit increase in ln(sum of PCBs). Combining relationships 1 and 2 yields an estimate of -2.0 to -0.27 points of IQ per unit increase in ln(sum of PCBs)., Conclusions: Combining analysis of chemical exposures and early biological perturbations (PCBs and FT(4)) with analysis of early biological perturbations and downstream overt effects (FT(4) and IQ) yields estimates within the range of studies of exposures and overt effects (PCBs and IQ). This is an example approach using upstream biological perturbations for effect prediction., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Polychlorinated biphenyls (PCB) are industrial chemicals linked to developmental deficits that may be caused in part by disrupting thyroid hormone (TH) action by either reducing serum TH or interacting directly with the TH receptor (TR). Individual PCB congeners can activate the TR in vitro when the metabolic enzyme cytochrome P4501A1 (CYP1A1) is induced, suggesting that specific PCB metabolites act as TR agonists. To test this hypothesis in vivo, we compared two combinations of PCB congeners that either activate the TR (PCB 105 and 118) or not (PCB 138 and 153) in the presence or absence of a PCB congener (PCB 126) that induces CYP1A1 in vitro. Aroclor 1254 was used as a positive control, and a group treated with propylthiouracil was included to characterize the effects of low serum TH. We monitored the effects on TH signaling in several peripheral tissues by measuring the mRNA expression of well-known TH-response genes in these tissues. Aroclor 1254 and its component PCB 105/118/126 reduced total T(4) to the same extent as that of propylthiouracil but increased the expression of some TH target genes in liver. This effect was strongly correlated with CYP1A1 expression supporting the hypothesis that metabolism is necessary. Effects were gene and tissue specific, indicating that tissue-specific metabolism is an important component of PCB disruption of TH action and that PCB metabolites interact in complex ways with the TR. These are essential mechanisms to consider when evaluating the health risks of contaminant exposures, for both PCB and other polycyclic compounds known to interact with nuclear hormone receptors.

Background: Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) signaling by reducing TH levels in blood, by exerting direct effects on TH receptors (TRs), or both., Objective: Our objective was to identify individual PCBs that directly affect TH signaling by acting on the TR., Methods: We administered a mixture of six PCB congeners based on their ortho substitution pattern, including PCBs 77 and 126 (non-ortho), PCBs 105 and 118 (mono-ortho), and PCBs 138 and 153 (di-ortho), to pregnant Sprague-Dawley rats from gestational days (G) 6 to 16. This mixture, or various combinations of the components, was also evaluated in a transient transfection system using GH3 cells., Results: The mixture reduced serum TH levels in pregnant rats on G16 but simultaneously up-regulated the expression of malic enzyme in liver. It also functioned as a TR agonist in vitro; however, none of the individual PCB congeners comprising this mixture were active in this system. Using the aryl hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone, and the cytochrome P450 (CYP)1A1 antagonist ellipticine, we show that the effect of the mixture on the thyroid hormone response element required AhR and CYP1A1., Conclusions: We propose that PCB 126 induces CYP1A1 through the AhR in GH3 cells, and that CYP1A1 activates PCB 105 and/or 118 to a form a compound that acts as a TR agonist. These data suggest that some tissues may be especially vulnerable to PCBs interfering directly with TH signaling due to their capacity to express CYP1A1 in response to coplanar PCBs (or other dioxin-like molecules) if sufficient mono-ortho PCBs are present.

Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) action by interacting directly with the TH receptor (TR). We found that the hydroxylated PCB metabolite, 4-OH-CB106, bound to the human TRbeta1 and significantly elevated endogenous growth hormone (GH) expression in GH3 cells in a manner similar to that of T(3) itself. This effect was also observed using a consensus TH response element (TRE) in a luciferase expression system, and was blocked by a single base-pair substitution in this TRE. In addition, we found that 4-OH-CB106 did not alter the ability of TRbeta1 to physically interact with the TRE in the GH promoter, or with SRC1 or NCoR. These effects were directly parallel to effects of T(3), indicating that 4-OH-CB106 exerts a direct agonistic effect on the TRbeta1.

Developmental exposure to polychlorinated biphenyls (PCBs) is associated with a variety of cognitive deficits in humans, and recent evidence implicates white matter development as a potential target of PCBs. Because PCBs are suspected of interfering with thyroid hormone (TH) signaling in the developing brain, and because TH is important in oligodendrocyte development, we tested the hypothesis that PCB exposure affects the development of white matter tracts by disrupting TH signaling. Pregnant Sprague Dawley rats were exposed to the PCB mixture Aroclor 1254 (5 mg/kg), with or without cotreatment of goitrogens from gestational d 7 until postnatal d 15. Treatment effects on white matter development were determined by separately measuring the cellular density and proportion of myelin-associated glycoprotein (MAG)-positive, O4-positive, and glial fibrillary acidic protein (GFAP)-positive cells in the genu of the corpus callosum (CC) and in the anterior commissure (AC). Hypothyroidism decreased the total cell density of the CC and AC as measured by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) staining and produced a disproportionate decrease in MAG-positive oligodendrocyte density with a simultaneous increase in GFAP-positive astrocyte density. These data indicate that hypothyroidism reduces cellular density of CC and AC and fosters astrocyte development at the expense of oligodendrocyte density. In contrast, PCB exposure significantly reduced total cell density but did not disproportionately alter MAG-positive oligodendrocyte density or change the ratio of MAG-positive oligodendrocytes to GFAP-positive astrocytes. Thus, PCB exposure mimicked some, but not all, of the effects of hypothyroidism on white matter composition.

Thyroid hormone is known to be essential for normal brain development both before and after birth, but much less is known about the role of thyroid hormone development before birth. In rodents, thyroid hormone of maternal origin can selectively regulate gene expression in the fetal cortex; HES1 was identified as a putative thyroid hormone responsive gene in the fetal cortex. Using in situ hybridization, we now confirm that thyroid hormone administration to pregnant rats can increase the abundance of HES1 mRNA in the fetal cortex on gestational day 16 (G16). In separate experiments, we found that maternal exposure to polychlorinated biphenyls (PCBs) increases HES expression similarly. Western analysis of proteins extracted from fetal cortex did not confirm that Notch-1 or Notch-3 activation was associated with treatment effects on HES expression. However, considering the role of HES proteins in fate specification of cortical neurons, these findings suggest that thyroid hormone, and PCB exposure, may influence fate specification of cortical neurons.

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 (T3) and thyroxine (T4) in pregnant rats but increased the expression of several TH-responsive 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.

BackgroundIncreasing data on early biological changes from chemical exposures requires new interpretation tools to support decision-making.ObjectivesTo test the possibility of applying a quantitative approach using human data linking chemical exposures and upstream biological perturbations to overt downstream outcomes.MethodsUsing polychlorinated biphenyl (PCB) exposures and maternal thyroid hormone (TH) perturbations as a case study, we model three relationships: (1) prenatal PCB exposures and TH changes, using free T(4) (FT(4)); (2) prenatal TH and childhood neurodevelopmental outcomes; and (3) prenatal PCB exposures and childhood neurodevelopmental outcomes (IQ). We surveyed the epidemiological literature; extracted relevant quantitative data; and developed models for each relationship, applying meta-analysis where appropriate.ResultsFor relationship 1, a meta-analysis of 3 studies gives a coefficient of -0.27 pg/mL FT(4) per ln(sum of PCBs) (95% confidence interval [CI] -0.82 to 0.27). For relationship 2, regression coefficients from three studies of maternal FT(4) levels and cognitive scores ranged between 0.99 IQ points/(pg/mL FT(4)) (95% CI -0.31 to 2.2) and 7.6 points/(pg/mL FT(4)) (95% CI 1.2 to 16.3). For relationship 3, a meta-analysis of five studies produces a coefficient of -1.98 IQ points (95% CI -4.46 to 0.50) per unit increase in ln(sum of PCBs). Combining relationships 1 and 2 yields an estimate of -2.0 to -0.27 points of IQ per unit increase in ln(sum of PCBs).ConclusionsCombining analysis of chemical exposures and early biological perturbations (PCBs and FT(4)) with analysis of early biological perturbations and downstream overt effects (FT(4) and IQ) yields estimates within the range of studies of exposures and overt effects (PCBs and IQ). This is an example approach using upstream biological perturbations for effect prediction.

There is a growing need for quantitative approaches to extrapolate relationships between chemical exposures and early biological perturbations from animals to humans given increasing use of biological assays to evaluate toxicity pathways. We have developed such an approach using polychlorinated biphenyls (PCBs) and thyroid hormone (TH) disruption as a case study. We reviewed and identified experimental animal literature from which we developed a low-dose, linear model of PCB body burdens and decrements in free thyroxine (FT(4)) and total thyroxine (TT(4)), accounting for 33 PCB congeners; extrapolated the dose-response from animals to humans; and compared the animal dose-response to the dose-response of PCB body burdens and TH changes from eleven human epidemiological studies. We estimated a range of potencies for PCB congeners (over 4 orders of magnitude), with the strongest for PCB 126. Our approach to developing toxic equivalency models produced relative potencies similar to the toxicity equivalency factors (TEFs) from the World Health Organization (WHO). We generally found that the dose-response extrapolated from the animal studies tends to under-predict the dose-response estimated from human epidemiological studies. A quantitative approach to evaluating the relationship between chemical exposures and TH perturbations, based on animal data can be used to assess human health consequences of thyroid toxicity and inform decision-making.

BACKGROUND: Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) signaling by reducing TH levels in blood, by exerting direct effects on TH receptors (TRs), or both. OBJECTIVE: Our objective was to identify individual PCBs that directly affect TH signaling by acting on the TR. METHODS: We administered a mixture of six PCB congeners based on their ortho substitution pattern, including PCBs 77 and 126 (non-ortho), PCBs 105 and 118 (mono-ortho), and PCBs 138 and 153 (di-ortho), to pregnant Sprague-Dawley rats from gestational days (G) 6 to 16. This mixture, or various combinations of the components, was also evaluated in a transient transfection system using GH3 cells. RESULTS: The mixture reduced serum TH levels in pregnant rats on G16 but simultaneously up-regulated the expression of malic enzyme in liver. It also functioned as a TR agonist in vitro; however, none of the individual PCB congeners comprising this mixture were active in this system. Using the aryl hydrocarbon receptor (AhR) antagonist cc-naphthoflavone, and the cytochrome P450 (CYP)1A1 antagonist ellipticine, we show that the effect of the mixture on the thyroid hormone response element required AhR and CYP1A1. CONCLUSIONS: We propose that PCB 126 induces CYP1A1 through the AhR in GH3 cells, and that CYP1A1 activates PCB 105 and/or 118 to a form a compound that acts as a TR agonist. These data suggest that some tissues may be especially vulnerable to PCBs interfering directly with TH signaling due to their capacity to express CYP1A1 in response to coplanar PCBs (or other dioxin-like molecules) if sufficient mono-ortho PCBs are present. [ABSTRACT FROM AUTHOR]

An increasing incorporation of mode of action (MOA) information into risk assessments has led to examination of animal MOAs to determine relevance to humans. We examined a specific MOA for developmental neurotoxicity using the MOA/Human Relevance Framework (Meek et al., 2003). The postulated MOA of ototoxicity in rats involves early postnatal exposure to polychlorinated biphenyls (PCBs) via lactation, an upregulation of hepatic uridine diphosphoglucuronyltransferases (UGTs), and subsequent hypothyroxinemia during a critical period of cochlear development, with the ultimate neurotoxic consequence of hearing loss. This review concludes with high confidence in the animal MOA and medium confidence for the interspecies concordance for the key events in the MOA. Possible interspecies differences in toxicodynamic factors moderate confidence in some key events. In addition, there is a question of whether ambient human exposures are large enough to cause human fetal hypothyroxinemia to the degree needed to cause hearing loss. Data gaps identified by this analysis include a need to characterize the induciblity of human fetal UGTs and the comparative sensitivity of UGT induction by xenobiotics in rats and humans. Research on these areas of uncertainty will increase confidence that this MOA for PCBs is not likely to not occur in humans, assuming normal conditions of limited ambient exposure. [ABSTRACT FROM AUTHOR]