Meiosis-mediated reproductive toxicity by fenitrothion in Caenorhabditis elegans from metabolomic perspective

Fenitrothion (FNT), an organophosphorus insecticide, is widely detected in the living environment. The reproductive and endocrine toxicity of FNT to biological communities has been ever reported, but potential mechanism and reproductive toxicity dose effect remain unclear. In our study, we constructed Caenorhabditis elegans model to analyze the reproductive toxicity mechanism of FNT based on metabolomics and evaluated its reproductive toxicity dose effect using benchmark dose (BMD)method. Our results showed that FNT exposure significantly reduced brood size, number of germ cells, and delayed gonadal development in nematodes. Non-targeted metabolomics revealed that FNT exposure caused significant metabolic disturbances in nematodes, leading to a significant reduction in the synthesis of cortisol and melatonin, and the latter played a mediating role in the effects of FNT on number of germ cells. We further found that the levels of these two hormones were significantly negative correlated with the expression of the androgen receptor nhr-69 and affected the meiosis of germ cells by regulating the nhr-69/ fbf-1/2 /gld-3 /fog-1/3 pathway. Meanwhile, the study found the BMDL10s for N2 and him-5 mutant were 0.411 μg/L by number of germ cells and 0.396 μg/L by number of germ cells in the meiotic zone, respectively, providing a more protective reference dose for ecological risk assessment of FNT. This study suggested that FNT can affect androgen receptor expression by inhibiting cortisol and melatonin secretion, which further mediate the meiotic pathway to affect sperm formation and exert reproductive toxicity, and provides a basis for setting reproductive toxicity limits for FNT.