BDE-47 has cytotoxicity on human sperm by inducing apoptosis, mitochondrial dysfunction, and membrane damage

Persistent organic pollutants, including 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), pose significant threats to human health, with growing evidence linking their exposure to male reproductive toxicity. However, research directly addressing BDE-47 toxicity in ejaculated human sperm and integrating functional sperm endpoints, mechanistic markers, and in silico network toxicology remains limited. This study investigated the toxic effects of BDE-47 on human sperm in vitro. Exposure to BDE-47 (25, 50, 75, and 100 μM) impaired multiple sperm functional endpoints, including viability, total and progressive motility, and penetration into methylcellulose; BDE-47 also reduced computer-aided sperm analysis (CASA)-derived kinematic parameters in motile spermatozoa. Penetration into the methylcellulose medium was the most sensitive endpoint, being reduced at all concentrations, whereas decreases in viability and motility became evident only at higher concentrations. Moreover, BDE-47 induced mitochondrial dysfunction, as reflected by decreased mitochondrial membrane potential (MMP), and was accompanied by reduced total ATP levels. Additionally, BDE-47 increased malondialdehyde (MDA) levels, consistent with plasma membrane damage. Apoptosis-associated changes were observed, including loss of plasma membrane integrity and increased nuclear DNA fragmentation, accompanied by a pro-apoptotic shift in protein levels (increased Bax and decreased Bcl-2 protein levels). Network toxicology analysis further indicated biological processes related to apoptosis and cell death, along with mitochondrial dysfunction involved in BDE-47-induced toxicity. Collectively, these findings suggest that BDE-47 induces sperm toxicity through mitochondrial dysfunction, membrane damage, and apoptosis, leading to impaired function and viability. This study therefore extends previous PBDE studies in animals and cell models by providing direct evidence in ejaculated human sperm.