Transgenerational exposure to plastics-derived endocrine-disrupting bisphenol A and its analogs on male infertility: impact of gut dysbiosis and epigenetic regulation.

Global declines in male fertility, characterized by reduced sperm count, motility, and quality, raised concerns about environmental exposures to estrogen-mimicking endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), and reproductive dysfunction. BPA exposure in vivo has been shown to alter gut microbial composition, diversity, and metabolites, leading to dysbiosis. Such gut alterations modulate systemic inflammation, estrogen bioavailability, and the endocrine-immune axis, thereby affecting gonadal function. Even though the gut is the largest endocrine organ in the body, directly regulating multiple metabolites that reach the circulation and influence the functions of peripheral organs and systems, little is known about epigenetic perturbations due to exposure to plastic-derived endocrine-disrupting bisphenols and their role in gut dysbiosis and male infertility risks. Recent evidence on the fetal programming of bisphenol exposure suggests such events can also impact epimutation states beyond diet, potentially carrying across generations. BPA can diffuse across the membrane and enter the nucleus, altering transcription of target genes by modifying nuclear receptor activity and gene promoter methylation, similar to estradiol, a steroid hormone. The genomic imprint is modulated by gene-chemical interactions, which predominantly result in epigenetic alterations. In particular, BPA exposure in utero altered the epigenome, highlighting the urgent need for transgenerational assessment. This narrative review conducted a thorough review of the available data to emphasize the transgenerational impacts of BPA exposure on male infertility risk and the roles of the gut-reproductive axis, underscoring the importance of further research in this area.