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Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework
Hassan, I., H. El-Masri, Pat Kosian, J. Ford, S. Degitz, AND M. Gilbert. Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 160(1):57-73, (2017).
Regulatory toxicology is challenged by the need to assess the safety of an increasing number of chemicals. The EPA has adopted an Adverse Outcome Pathway (AOP) framework to meet this challenge to evaluate toxicity of chemicals. The adverse outcome pathway (AOP) is conceptual construct intended to organize molecular toxicological data to inform regulatory-decision making. AOPs link molecular, cellular, organ and organism level effects across complex biological systems. A quantitative AOP (qAOP) enhances the description of predictive/causal linkages by augmenting descriptive, qualitative biological linkages with quantitative information on these key events in the biological pathway. Thyroid hormones are crucial for brain development and modest disruption of the thyroid axis during pregnancy is associated with adverse neurodevelopment outcomes. While environmental chemicals have been linked to thyroid axis perturbation, limited studies have explored the impact of exposure to low doses of TH disrupting compounds and neuroanatomical impairment. Therefore, we developed a qAOP linking TH disruption to neuroanatomical impairment previously described by our lab. This malformation, a heterotopia, requires prenatal thyroid hormone insufficiency for its formation, its size and incidence is dose-dependent, and it persists in the brain to adulthood. Heterotopias when present in humans and animal models are associated with a number of developmental disabilities including epilepsy, mental retardation, autism, learning impairments. To generate dose-response data, pregnant rats were exposed to 0, 0.1, 0.5, 1, 2, or 3 ppm PTU in drinking water from early gestation (GD6) until just before birth on GD20. Serum from the fetus and dam and thyroid gland from the dam were collected. Dams exhibited significant decreases in serum T4 at higher doses than did the fetus, suggesting that the fetus is more sensitive to PTU exposure than the dam. Moreover, at higher doses, fetal serum T3 concentration decreased, but levels in the dam did not change. As expected, the levels of PTU increased in the maternal and fetal serum and in the maternal thyroid gland. Concentration of thyroid hormone analytes in the maternal gland were also decreased indicative of TPO inhibition reduced hormone synthesis. Empirical modeling was used to describe the relationship between exposure and dosimetry, to the thyroid gland of the dam and estimate the degree of TPO inhibition associated with a given serum concentration of PTU. Results of modeling clearly demonstrate the increased vulnerability of the fetus to hormone disruption from TPO inhibition and that fetal brain T4 deficits occur in the absence of any indication of hormone decrements in the dam Reductions of 25% in fetal serum T4, and less than 10% drops in dam serum T4 were associated with volumes of heterotopia in excess of that seen in controls. Our study shows the feasibility of using computational modeling approach to describe dose-response data for translating high-throughput screening into biologically based predictions for TH hormone insufficiency and adverse neurological outcomes. We have also established analytical tools to measure internal metrics of exposure that can be generalized to other TPO inhibitors.
Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures and decline in serum TH resulting in neurodevelopmental impairment is poorly understood. The present study developed a quantitative adverse outcome pathway (qAOP) where serum thyroxin (T4) reduction following inhibition of thyroperoxidase in the thyroid gland are described and related to deficits in fetal brain TH and the development of a brain malformation, subcortical band heterotopia. Pregnant dams were exposed to 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 ppm) from gestational day 6-20, increasing PTU concentrations in maternal thyroid gland and serum as well as in fetal serum. Dams exposed to 0.5 ppm PTU and higher exhibited dose-dependent decreases in thyroidal T4. Serum T4 levels in the dam were significantly decreased with exposure to 2 and 3 ppm PTU. In the fetus, T4 decrements were first observed at a lower dose of 0.5 ppm PTU. Based on these data, fetal brain T4 levels were estimated from published literature sources, and quantitatively linked to increases in the size of the heterotopia present in the brains of offspring. These data show the potential of in vivo assessments and computational descriptions of biological responses to predict the development of this structural brain malformation and use of qAOP approach to evaluate brain deficits that may result from exposure to other TH disruptors.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
TOXICOLOGY ASSESSMENT DIVISION
ENDOCRINE TOXICOLOGY BRANCH