Sex-Dependent Environmental Health Risk Analysis of Flupyradifurone

Pesticides are used in agricultural production worldwide, resulting in widespread environmental pollution. Many diseases are closely related to exposure to pesticide residues. In this study, the association between exposure to the pesticide flupyradifurone (FPF), a substitute for neonicotinoids, and sex-dependent thyroid dysfunction was explored for the first time. Exposure using rat models revealed that the FPF metabolism is sex-dependent, with males preferring N-dealkylation and hydrolytic metabolism and females preferring hydroxylation. In particular, novel chloropyridine-site hydroxylation I and II metabolic pathways of FPF were discovered. More importantly, differential metabolic pathways of FPF induced sex-based dysregulation of the hypothalamic-pituitary-thyroid axis, in which females exhibited subclinical hyperthyroidism, while males displayed abnormal hypothyroidism. This may be attributed to the potential agonistic or antagonistic effect of FPF sex-dependent metabolites on liver thyroid hormone receptors. Furthermore, FPF exposure further mediated sex-specific dysregulation of cellular lipid homeostasis, with abnormal fatty acid β-oxidation and excessive energy expenditure in females and the risk of excessive accumulation of triglycerides in males. These results illustrate the potential risk of sex-related thyroid metabolic diseases caused by FPF and provide an important basis and support for further studies of FPF on human health and as an environmental pollutant.