Citation:

Gilbert, M., S. Thomas, Katherine OShaughnessy, I. Hassan, C. Riutta, J. Ford, A. Smith, W. Oshiro, AND C. Wood. Thyroid Toxicants and Neurodevelopment: Molecular Initiating Event may be an Important Consideration- DNTS. Developmental Neurotoxicology Society (DNTS), San Diego, CA, June 23 - 26, 2019.

Impact/Purpose:

Thyroid hormones (TH) are critical for brain development. Serum measures of TH are used for regulatory decision-making purposes because of concern for neurodevelopmental disorders and serum T4 represents a key integrator node in the Adverse Outcome Pathway (AOP) upstream from impaired neurodevelopment. This abstract examines two chemicals that reduce serum T4 in rat dams and offspring by their purported action at extrathyroidal sites (ie., liver and serum binding proteins). Pregnant dams were exposed to vehicle, triclosan (300mg/kg/day) or perfluorohexane sulfonate (PFHxS, 50 mg/kg/day) from early gestation until weaning of pups. Serum TH profiles were examined across multiple ages in dams and offspring and markers of developmental neurotoxicity assessed. This work addresses Chemical Safety for Sustainability (CSS) Adverse Outcome Pathway Discovery and Development (AOPDD 17.01), Thyroid Related AOPs and is relevant to OPPTS and OW needs for decision making. Both chemicals reduced serum total and/or free T4 in the dam (GD20 and PN21) and pup (PN0, PN2, PN6, PN14) to varying degrees; however, thyroid stimulating hormone (TSH) was unchanged. In the neonatal brain, no gene expression changes associated with TH dysfunction were detected, and there was no evidence of a TH-dependent phenotype (heterotopia). Neither were behavioral tests of learning and memory (trace fear conditioning) or sensory motor function (prepulse inhibition of acoustic startle) impaired in adult offspring. These data suggest that despite reductions in serum T4 in dams and offspring, according to these metrics, the developing brain does not appear to be adversely affected by triclosan or PFHxS. Future studies describing the quantitative relationship between THs in the serum and brain and more sensitive measures of neurodevelopmental impairment are needed to more fully characterize the risk of these chemicals and others with similar mode(s) of action. These findings indicate that more sensitive metrics of TH-mediated neurodevelopmental impairment are needed for the further development and refinement of quantitative AOPs for thyroid disruption. In their absence, the use of serum TH appears to be protective of the fetus and developing neonate.

Description:

Developmental neurotoxicity is a primary concern for thyroid disrupting chemicals (TDCs). Many environmental TDCs include pesticides, flame retardants, and perfluorinated compounds. These TDCs reduce circulating levels of thyroid hormones (THs) by distinct and/or overlapping mechanisms, many of which are not well characterized. It is unclear if these chemicals also reduce THs in the brain and cause neurodevelopment defects. This study investigated the potential neurotoxicological effects of two TDCs triclosan (an antimicrobial agent), and perfluorohexaACne sulfonate (PFHxS, a perflourinated compound), which reduce serum TH by altering liver clearance and/or interference with serum binding proteins. Pregnant rats were dosed by gavage (triclosan: 300 mg/kg/day, PFHxS: 50 mg/kg/day, controls: vehicle) from gestational day 6 (GD6) to postnatal day 21 (PN21). Results show that neither treatment group induced changes in litter size or pup body weight. No effects were seen on liver weight or body:liver weight ratios in dams or pups but liver metabolism genes were increased in expression. Both chemicals reduced serum total and free T4 in the dam (GD20 and PN21) and pup (PN0, PN2, PN6, PN14) to varying degrees; however, thyroid stimulating hormone (TSH) was unchanged. In the neonatal brain, no gene expression changes associated with TH dysfunction were detected, and there was no evidence of a TH-dependent phenotype (heterotopia). Neither were behavioral tests of learning and memory (trace fear conditioning) or sensory motor function (prepulse inhibition) impaired in adult offspring. These data suggest that despite reductions in serum T4 in dams and offspring, according to these metrics, the developing brain does not appear to be adversely affected by triclosan or PFHxS. Future studies describing the quantitative relationship between THs in the serum and brain and more sensitive measures of neurodevelopmental impairment are needed to more fully characterize the risk of these chemicals and others with similar mode(s) of action. This work does not reflect EPA policy.

Record Details: