You are here:
Evaluation of the diphenyl herbicide, Oxyfluorfen, for effects on thyroid hormones in the juvenile rat.
Citation:
Stoker, T., G. DeVane, A. Buckalew, J. Bailey, J. Ford, AND A. Murr. Evaluation of the diphenyl herbicide, Oxyfluorfen, for effects on thyroid hormones in the juvenile rat. Current Research in Toxicology. Elsevier B.V., Amsterdam, Netherlands, 6:100146, (2023). https://doi.org/10.1016/j.crtox.2023.100146
Impact/Purpose:
The purpose of this study was to evaluate a recently identified NIS (sodium iodide symporter) inhibitor, oxyfluorfen, for in vivo effects on circulating thyroid hormones using two short-term juvenile rat models. Oxyfluorfen was previously identified as a potent inhibitor of NIS (IC50 of approximately 2uM) in our laboratory when we screened a large number of chemicals using our in vitro HTP human and rat NIS assay (Buckalew et al., 2020). The current in vivo evaluation of thyroid hormones with accompanied serum and thyroid gland chemical analysis provides quantitative data to build a predictive model (IVIVE) to inform adverse outcome pathway (AOP) development for potential health outcomes in humans . This study found a NOEL and LOEL for endocrine effects of oxyfluorfen for observed dose-dependent thyroid hormone suppression, with T4 as the most sensitive endpoint and the primary initial target for NIS inhibition in the thyroid gland. The NOEL for T4 was 1.625 mg/kg with a LOEL of 3.25 mg/kg based on the 8-day exposure. The confirmation of oxyfluorfen as an endocrine disrupting chemical attests that this approach of using in vitro HTP screening and prioritization for potential NIS inhibitors can be used to identify candidate chemicals that have effects on thyroid homeostasis in mammals.
Description:
Recently, oxyfluorfen, a pre- and post-emergent diphenyl ether herbicide, was identified in our laboratory as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), the first key step in the synthesis of thyroid hormones (THs). This inhibition was observed in vitro, using both a human NIS engineered cell line (hNIS-HEK293T-EPA) and a rat thyroid follicular cell line (FRTL-5). Oxyfluorfen was found to be a potent inhibitor of NIS activity with an EC50 of approximately 2 µM in both cell lines with no observed cytotoxicity at any concentration tested up to 100 μM. The current research tested the hypothesis that oxyfluorfen alters circulating concentrations of THs. This hypothesis was first tested in a pilot study with both juvenile male and female rats exposed to oxyfluorfen for 4 days at 0, 125, 250 and 500 mg/kg/day. Once we identified that this short-term 4-day oxyfluorfen exposure suppressed both total serum thyroxine (T4) and triiodothyronine (T3) at all doses, we tested seven lower concentrations of oxyfluorfen (0.8125 to 62.5 mg/kg day) in an 8-day exposure paradigm to more closely evaluate the dose-response. We found that oxyfluorfen suppressed serum T4 with a LOEL of 3.25 mg/kg/day and T3 with a LOEL 62.5 mg/kg/day. Analytical chemistry of the serum showed an accumulation over time following oral exposure to oxyfluorfen in both the 4- and 8-day groups. Analytical chemistry of the thyroid glands in the 8-day study revealed higher accumulation in the thyroid as compared to the serum (2 to 3- fold at 62.5 mg/kg). No changes in thyroid weight or serum TSH were observed following the 8-day exposure. This study is the first to demonstrate an effect of oxyfluorfen on serum thyroid hormones in the rat. Additional studies are needed to further evaluate the effects on thyroid homeostasis with extended exposures and the potential implications of the observed effects.