Citation:

Gilbert, Mary E., K. OShaughnessy, S. Thomas, C. Riutta, C. Wood, A. Smith, W. Oshiro, J. Ford, A. Hotchkiss, I. Hassan, AND R. Ford. Thyroid Disruptors: Extrathyroidal Sites of Chemical Action and Neurodevelopmental Outcome-An Examination Using Triclosan and Perfluorohexane Sulfonate. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 183(6):195-213, (2021). https://doi.org/10.1093/toxsci/kfab080

Impact/Purpose:

Background/Overview: 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. Serum T4 represents a key integrator node in the Adverse Outcome Pathway (AOP), upstream from impaired neurodevelopment. Predictions stemming from altered T4 in this AOP are largely based on data from agents known to disrupt the thyroid system by inhibiting TH synthesis at the level of the thyroid gland. Many other chemicals with distinct modes of action are also capable of reducing serum T4, but confirmation of their link to neurodevelopmental deficits has remained elusive. Relevancy to EPA Program/Regional Research Needs/Priorities: Currently serum TH measures are recommended and/or required endpoints in US EPA and OECD testing guidelines, and sound interpretation of this biomarker is critical for chemical evaluation. This paper examines two chemicals that reduce serum T4 in rat dams and offspring by their purported action at extrathyroidal sites. Serum TH profiles were examined across multiple ages 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, Neurotoxicity of PFAS chemicals. It is relevant to OPPTS, OW, and CPHEA needs for decision making. Study Description: Pregnant rats were dosed with vehicle, 300 mg/kg/day of the antimicrobial triclosan, or 50 mg/kg/day the perflourinated compound, perfluorohexane sulfonate (PFHxS) from gestational day 6 until postnatal day 21. Dam and pup serum TH were profiled. Thyroid gland, liver and brain were examined for gene expression. Brains of pups at PN14 evaluated for presence of a cortical malformation, behavioral measures including trace fear conditioning and prepulse inhibition of the acoustic startle response were assessed in offspring as adults. Major Observations and Results: Both chemicals reduced serum total and/or free T4 in the dam and pup, however, thyroid stimulating hormone (TSH) was unchanged. Brain T4 was modestly reduced the pup brain on PN0 and PN2, but not on PN6 or PN14. No gene expression changes associated with serum TH dysfunction were detected at the time assessed, consistent with a lack of effect on brain hormone at these ages. There was no evidence of a TH-dependent anatomical phenotype (heterotopia) or impairment in behavioral tests of learning and memory (trace fear conditioning) or sensory motor gaiting (prepulse inhibition of acoustic startle). Impact/Potential Implications of the Findings: These data suggest that despite reductions in serum T4 in dams and offspring, 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. Findings Advancing Existing Scientific Knowledge: These findings measure brain hormones, hormone action, and known thyroid-dependent neurodevelopmental phenotypes. This is a more comprehensive evaluation of the potential thyroid-mediated neurotoxicity of PFHxS and Triclosan than has appeared in the literature to date. Findings indicate that more sensitive or different metrics of TH-mediated neurodevelopmental impairment may be needed for further development/refinement of quantitative AOPs for thyroid disruption, yet in their absence, serum TH appears to be protective of the fetus and developing neonate.

Description:

Many xenobiotics are identified as potential thyroid disruptors due to their action to reduce circulating levels of thyroid hormone, most notably thyroxine (T4). Developmental neurotoxicity is a primary concern for thyroid disrupting chemicals yet correlating the impact of chemically induced changes in serum T4 to perturbed brain development remains elusive. A number of thyroid-specific neurodevelopmental assays have been proposed, based largely on the model thyroid hormone synthesis inhibitor propylthiouracil (PTU). This study examined whether thyroid disrupting chemicals acting distinct from synthesis inhibition would result in the same alterations in brain as expected with PTU. The perfluoroalkyl substance perfluorohexane sulfonate (50 mg/kg/day) and the antimicrobial Triclosan (300 mg/kg/day) were administered to pregnant rats from gestational day 6 to postnatal day (PN) 21, and a number of PTU-defined assays for neurotoxicity evaluated. Both chemicals reduced serum T4 but did not increase thyroid stimulating hormone. Both chemicals increased expression of hepatic metabolism genes, while thyroid hormone-responsive genes in the liver, thyroid gland, and brain were largely unchanged. Brain tissue T4 was reduced in newborns, but despite persistent T4 reductions in serum, had recovered in the PN6 pup brain. Neither treatment resulted in a low dose PTU-like phenotype in either brain morphology or neurobehavior, raising questions for the interpretation of serum biomarkers in regulatory toxicology. They further suggest that reliance on serum hormones as prescriptive of specific neurodevelopmental outcomes may be too simplistic and to understand thyroid-mediated neurotoxicity we must expand our thinking beyond that which follows thyroid hormone synthesis inhibition.

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