Gestational Exposure To Oxyfluorfen, A Newly-Identified Thyroid Disruptor: Effects In Pregnant Rats And Their Progeny.

Many environmental contaminants reduce circulating levels of thyroid hormones (TH). EPA has developed a suite of high-throughput in vitro assays to identify potential target sites within the thyroid axis. One important target site is the sodium iodine symporter (NIS), a transport protein that co-transports sodium and iodine from the blood into the thyroid gland, the first key step of TH synthesis. Chemicals like perchlorate, a strong in vitro NIS inhibitor also reduce serum TH in rats and humans. Oxyfluorfen is an herbicide recently found to inhibit iodide uptake in both a human NIS and rat thyroid cell line and suppress thyroxine in juvenile rats (Murr et al, 2020; Wang et al., 2019; Buckalew et al., 2020). As THs play a direct role in fetal brain development, this study was designed to assess the adverse effects of oxyfluorfen in pregnant rats and their progeny.  Time-pregnant Long Evans rats (n=8-11/group) were placed on a controlled iodine diet on GD4. Oxyfluorfen or methyl cellulose vehicle (0, 125, 250 mg/kg/day) was administered once daily by gavage from GD6-GD19. Blood was collected from dams on GD16 and from dams and fetuses at study termination (GD20). Exposure was confirmed by dose-dependent increases in serum oxyfluorfen in the dam and fetus. Thyroid gland weights were unchanged in dam and fetus. Dam serum T4 was dose-dependently reduced (35-50%) with modest reductions in T3 (15-20%) and no change in TSH. Fetal serum TH and expression of forebrain TH-responsive gene are pending. Expression of genes involved in TH synthesis was largely unchanged (Nis, Tpo, Tg, Tshr) in fetal and maternal thyroid glands, with the exception of an upregulation of pendrin in the fetal thyroid. Further studies are planned investigating TH-dependent changes in the brain to evaluate predictive power of in vitro screens for thyroid disruption to altered neurodevelopment.   Does not reflect EPA policy

Impact/Purpose

Highthroughput screening assays for thyroid disruption have identified a suite of environmental chemicals that interfere with the sodium-iodine symporter. (NIS) We know that this target site has downstream consequences for brain development. This study links a chemical acting at this molecular initiating event from highthroughput testing to test predictions based in in vitro bioactivity to in vivo intermediate (thyroid hormone changes) and downstream key events (neurodevelopmental sequalae) in an AOP of NIS inhibition. This work is essential for the validation of in vitro screens for endocrine disruption.

Citation

Hawks, M., T. Stoker, A. Murr, J. Ford, C. Wood, T. Beasley, A. Yackley, D. Jenkins-Hill, AND M. Gilbert. Gestational Exposure To Oxyfluorfen, A Newly-Identified Thyroid Disruptor: Effects In Pregnant Rats And Their Progeny. NC Society of Toxicology Annual Meeting, Durham, NC, October 18, 2022.