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

Abstract 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.