BPP disrupts spermatogenesis via mitochondrial-ER stress-mediated autophagic flux blockade in mice.

Endocrine-disrupting chemicals (EDCs), particularly bisphenol A (BPA) and its analogs, have been extensively linked to male reproductive toxicity. However, the biological effects of bisphenol P (BPP), an increasingly used BPA substitute, remain poorly characterized. Through integrated in vivo and in vitro investigations, this study systematically evaluated the effects of chronic BPP exposure on male reproductive function in mice. Our findings demonstrate that BPP significantly impaired spermatogenesis and sperm quality, and suppressed serum testosterone and follicle-stimulating hormone (FSH) levels despite unaltered luteinizing hormone (LH). These effects were accompanied by the downregulation of key steroidogenic genes and the androgen receptor (Ar) at the mRNA level, demonstrating comprehensive endocrine disruption. It also caused dose-dependent genotoxic stress, apoptosis in testicular cells, leading to impaired male fertility. Critically, these adverse effects manifested at an exposure level of 30 μg/kg bw/day. Mechanistically, BPP simultaneously targeted somatic and germ cells: in Leydig cells, it induces mitochondrial dysfunction and endoplasmic reticulum stress (ERS), leading to decreased testosterone secretion; in Sertoli cells, it similarly induced these stressors, leading to blood-testis barrier (BTB) disruption. Concurrently, BPP triggers a self-reinforcing cycle in mouse spermatocytes, manifested as mutually reinforcing mitochondrial dysfunction and ERS that not only exacerbate each other but also suppress the mitophagy and autophagic flux required for their resolution. Considering the prevalence of BPP in humans and its comparable or even superior toxicity relative to BPA in sensitive biological models, these findings firmly establish BPP as a "regrettable substitution" that warrants urgent regulatory reassessment.