Endocrine and systemic toxicity of pyriproxyfen in adult female zebrafish: disruption of the HPT axis and peripheral organ impairments.

Endocrine-disrupting chemicals (EDCs) can destabilize the hypothalamic-pituitary-thyroid (HPT) axis, a fundamental regulator of vertebrate development and metabolism. Pyriproxyfen (PPF), a juvenile hormone analog widely utilized in vector control, is recommended by the World Health Organization (WHO) for application at concentrations of up to 10 µg/L in drinking water; however, its safety profile for vertebrates remains a matter of concern. In this study, we investigated the endocrine and systemic impacts of PPF in adult female zebrafish exposed for 14 days to 1, 10, or 100 µg/L. Histological, hormonal, and transcriptional analyses across the thyroid, brain, liver, and kidney revealed a non-monotonic response centered on the WHO reference application concentration. The 10 µg/L group exhibited the most significant molecular impairment in the thyroid, characterized by the upregulation of slc5a5 (nis), nkx2.1, pax2a, and tshr, while repressing thyroglobulin (tg) expression. Consistent with these molecular alterations, thyroid epithelial disruption was observed at 1 and 10 µg/L. In contrast, exposure to 100 µg/L increased plasma TSH levels and the expression of pituitary tshb and hepatic dio1, suggesting a compensatory response of the HPT axis. Renal morphometry additionally revealed tubular alterations across all exposure groups. Overall, these findings demonstrate a non-monotonic concentration-response centered on 10 µg/L as a key mechanistic feature of PPF toxicity and support further evaluation of thyroid and renal endpoints in ecotoxicological risk assessment.