LHCGR disruption and downregulation by bisphenol PH impairs ovarian function and establishes a prioritization framework for endocrine disruptors.

Abstract

INTRODUCTION: Bisphenol analogs (BPs) are recognized endocrine-disrupting chemicals (EDCs) significantly threaten ovarian health; however, the characterization of high-risk compounds, molecular initiating events (MIEs), and toxicity mechanisms associated with specific diseases remains insufficient. OBJECTIVES: This study aims to systematically evaluate the ovarian hazards of BPs, identify high-risk compounds and their MIEs, and elucidate the underlying toxicity mechanisms. METHODS: A tiered strategy integrating computational toxicology models, high-throughput in vitro screening, and in vivo validation using a murine exposure model was employed. Transcriptomic, immunoblotting, and immunohistochemical analyses were conducted to elucidate the mechanisms of BP-induced ovarian injuries. Molecular dynamics simulations, and cellular thermal shift assays were performed to investigate the direct target binding of BPs and MIEs. RESULTS: High- throughput screening highlighted Bisphenol PH (BPPH) as a high-risk compound. Animal studies demonstrated that BPPH induced endocrine dysfunction and reduced ovarian reserve. Transcriptomic analysis indicated that both compounds disrupted steroidogenic pathways, pinpointing luteinizing hormone/choriogonadotropin receptor (LHCGR) as a critical target. Protein analyses corroborated the suppression of LHCGR expression. BPPH was shown to directly bind to and disrupt LHCGR. Agonist validation experiments affirmed that BPs disrupt steroid hormone biosynthesis by binding to LHCGR and dysregulating its expression. CONCLUSION: Results delineate the molecular pathogenesis by which BPs, particularly BPPH, induce ovarian insufficiency through binding and dysregulation of LHCGR. This study establishes a translatable framework for prioritizing hazardous EDCs, providing critical insights for regulatory decision-making and intervention strategies. SYNOPSIS: High-throughput screening identified Bisphenol PH (BPPH) as a high-risk compound. Both BPPH and BPA can directly bind to LHCGR, causing structural alternation and dysregulation of steroidogenic pathways, thereby resulting in diminished ovarian reserve.

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