Adolescent cetylpyridinium chloride exposure impairs homologous recombination repair and induces granulosa cell apoptosis and follicular atresia via FOXM1/CREBBP complex suppression

Abstract

Cetylpyridinium chloride (CPC), a widely used surfactant, functions as an antimicrobial agent in pharmaceuticals and personal care products (PPCPs). However, its effect on the female reproductive system remains largely unknown. Herein, female mice were gavaged with 0.01, 0.1, or 1 mg CPC/kg body weight (bw)/d during adolescence. Results showed reduced body and ovarian weights, decreased primordial follicle numbers, and increased atretic follicles. Additionally, CPC disrupted serum hormone levels, reduced cell viability and proliferation, and increased apoptosis in granulosa cells. Transcriptomic analysis of primary granulosa cells revealed altered genes in homologous recombination (HR) repair pathway, including the downregulation of FOXM1 and the MRN complex. Further validation demonstrated decreased expression of HR repair components and increased DNA damage in both in vivo and in vitro. Mechanistically, CPC inhibited the FOXM1/CREBBP interaction and inhibited HR repair gene transcription, including MRE11 and NBS1. Finally, FOXM1 overexpression partially reversed the detrimental effects of CPC on HR repair and cell proliferation. These results indicate that CPC-induced ovarian dysfunction during adolescence is mediated through FOXM1/CREBBP complex inhibition and homologous recombination repair impairment, potentially increasing the risk for the development of diminished ovarian reserve (DOR) and providing new experimental evidence to assess the reproductive toxicity effects of CPC.