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R Thomas Zoeller

Publications and source records attributed to R Thomas Zoeller.

At least 19 recordsLinked to original sources
PubMed2006

4-Hydroxy-PCB106 acts as a direct thyroid hormone receptor agonist in rat GH3 cells.

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.

Animals↗
PubMed2006

Collision of basic and applied approaches to risk assessment of thyroid toxicants.

Thyroid hormone (TH) is essential for normal brain development; therefore, any environmental chemical that interferes sufficiently with thyroid function, TH metabolism, or TH action may exert adverse effects on brain development. Important known differences in aspects of thyroid endocrinology between the fetus, infant, and adult allow us to identify age-dependent vulnerabilities to thyroid toxicants with some confidence. These differences include the size of the hormone pool stored in the thyroid gland at different ages as well as the age-dependent sensitivity to mild TH insufficiency. Several recent studies that describe risk assessments of the environmental contaminant, ammonium perchlorate, provide good examples of conclusions based on the selective consideration of these known aspects of the thyroid system. Specifically, authors who consider age-dependent differences in thyroid endocrinology suggest that safe levels of perchlorate should be set at relatively low levels (low parts per billion). In contrast, authors who do not consider these known age-dependent differences in thyroid endocrinology recommend safe levels of perchlorate at high (hundreds) parts per billion to parts per million. Emerging evidence indicates that a variety of high production volume chemicals can directly interact with the TH receptor. As testing paradigms are designed by regulatory agencies, these age-dependent differences in thyroid endocrinology must be considered.

Adult↗
PubMed2005

Polychlorinated biphenyls exert selective effects on cellular composition of white matter in a manner inconsistent with thyroid hormone insufficiency.

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.

Analysis of Variance↗
PubMed2005

Environmental chemicals as thyroid hormone analogues: new studies indicate that thyroid hormone receptors are targets of industrial chemicals?

Thyroid hormone (TH) is essential for normal brain development, but the specific actions of TH differ across developmental time and brain region. These actions of TH are mediated largely by a combination of thyroid hormone receptor (TR) isoforms that exhibit specific temporal and spatial patterns of expression during animal and human brain development. In addition, TR action is influenced by different co-factors, proteins that directly link the TR protein to functional changes in gene expression. Several recent studies now show that TRs may be unintended targets of chemicals manufactured for industrial purposes, and to which humans and wildlife are routinely exposed. Polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and bisphenol-A (BPA), and specific halogenated derivatives and metabolites of these compounds, have been shown to bind to TRs and perhaps have selective effects on TR functions. A number of common chemicals including polybrominated biphenyls (PBBs) and phthalates may also exert such effects. Considering the importance of TH in brain development, it will be important to pursue the possibilities that these chemicals - or interactions among chemical classes - are affecting children's health by influencing TH signaling in the developing brain.

Animals↗
PubMed2005

Maternal thyroid hormone increases HES expression in the fetal rat brain: an effect mimicked by exposure to a mixture of polychlorinated biphenyls (PCBs).

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.

Analysis of Variance↗
PubMed2004

Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain.

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.

Air Pollutants, Occupational↗
PubMed2004

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

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.

Animals↗
PubMed2003

Challenges confronting risk analysis of potential thyroid toxicants.

Screening and testing for potential thyroid toxicants using endpoints of thyroid function, including circulating levels of thyroid hormones and thyrotropin, will not capture toxicants that directly interfere with thyroid hormone action at the receptor. The goals of the present review are to provide a critique of the literature focused on thyroid hormone and brain development as it relates to testing and evaluating thyroid toxicants, and to propose possible solutions to this perceived dilemma.

Animals↗
PubMed2002

Differential display identifies neuroendocrine-specific protein-A (NSP-A) and interferon-inducible protein 10 (IP-10) as ethanol-responsive genes in the fetal rat brain.

Fetal alcohol exposure is the most common nonhereditary cause of mental retardation in the western world. Rats prenatally treated with ethanol liquid diet exhibit extensive defects in the brain that accurately model those observed in humans. To analyze the ethanol effects on gene expression during brain development, we performed mRNA differential display and two-dimensional electrophoresis on gestational day (G) 13 and G 16 brain from rats treated with ethanol liquid diet. Using mRNA differential display followed by a variety of quantitative analyses, three genes were confirmed to be ethanol-responsive. Among them was Neuroendocrine-Specific Protein-A (NSP-A), which is known to be affected by thyroid hormone in the cortex at this developmental time. However, two additional genes known to be thyroid hormone-responsive were unaffected by ethanol, indicating that interference with thyroid hormone action may not be a predominant pathway by which alcohol induces damage in the fetal brain. The observation that interferon-inducible protein-10 (IP-10) is up-regulated in ethanol-treated fetal brain may indicate the presence of a disease process recruiting CD8+ T-cells capable of interfering with myelination. The result of two-dimensional (2D) electrophoresis and Western analyses demonstrated that few changes in the abundance of individual proteins or the phosphorylation of proteins at threonine and tyrosine were induced by prenatal ethanol exposure. A critical analysis of the approaches used in the present study may be important for future studies in this field.

Animals↗