Exposure to multiple pyrethroid insecticides affects ovarian follicular development via modifying microRNA expression

Abstract

Pyrethroids, a class of insecticides widely used in agriculture and residential pest control, have been considered as endocrine-disrupting chemicals (EDCs). Our previous epidemiological study reported a positive association of urinary levels of pyrethroid metabolites with the risk of primary ovarian insufficiency in women, suggesting that pyrethroid exposure may be a potential risk factor for female ovarian health. In this study, female mice at gestational, lactational or peripubertal stages were exposed to eight most commonly used pyrethroids at the doses of acceptable daily intake (ADI) recommended by the World Health Organization (WHO). Gestational exposure to eight pyrethroids at ADI doses led to a significant decrease in the number of primary follicles in female offspring on postnatal day (PND) 3, and an increase in the number of atretic follicles and granulosa cell apoptosis, as well as lower estrogen and higher follicle-stimulating hormone (FSH) levels in adult female offspring. Lactational and peripubertal exposure to pyrethroid mixture had no significant effects on follicular development and ovarian functions. The data of high-throughput microRNA (miRNA) sequencing showed that 23 miRNAs were differentially expressed in the ovaries of female offspring mice on PND 1 after gestational exposure to pyrethroid mixture. The results of qPCR confirmed that miR-152-3p, miR-450b-3p and miR-196a-5p were significantly upregulated in the neonatal ovaries in the exposed group. The bioinformatic analysis indicates that the modification of the expression of ovarian miRNAs by pyrethroid exposure may disrupt the key biological processes (such as mRNA processing) and major signaling pathways (such as PI3K/Akt pathway, adipocytokine pathway and GnRH pathway) governing follicular development and ovarian functions. This study first reported that gestational exposure of female mice to multiple pyrethroids at the recommended human safe doses had irreversible adverse effects on the ovaries in female offspring in adulthood through regulating the expression of miRNAs during early developmental stages.