Postnatal exposure to various benzophenones at environmentally relevant levels enhances the susceptibility of mammalian testes to cyclophosphamide-induced spermatogenic stress in adulthood.

Exploring the health damage caused by joint exposure in the real world is one of the hotspots in modern environmental toxicology. Recent studies indicate that environmental chemicals can heighten sensitivity to future stress or damage, potentially leading to various diseases. Benzophenone-type (BPs) chemicals, which are commonly used UV filters with estrogenic properties, have been shown to affect the development of male reproductive systems in aquatic animals, rodents, and humans. This study aims to determine whether BPs exposure during development increases the testes' susceptibility to stress in adulthood. Newborn male ICR mice were exposed to the three most common BPs (BP-1, BP-2, and BP-3) in the environment at concentrations of 10 nM (equivalent to 2.14, 2.46, and 2.28 μg/L, respectively) and 1000 nM (equivalent to 214, 246, and 228 μg/L, respectively) via breast milk and drinking water for 56 days (from postnatal day 1 to postnatal day 56), using diethylstilbestrol (DES) as a positive control. The results showed that BPs affected the integrity of the blood-testis barrier (BTB) and resulted in reduced mRNA levels of genes associated with reproduction, apoptosis and cytoskeleton in testicular tissue of mice at PND 56. Subsequently, intrapitoneal injection of 3 mg/kg cyclophosphamide (CTX) for 4 weeks was conducted to induce spermatogenic stress. It was found that the testes in the BPs pre-treated groups showed significant changes in decreased testicular organ coefficient, damaged seminiferous tubules, delayed spermatogenesis, reduced sperm quality, pro-apoptotic effect, and disrupted microfilament structure, but not in untreated ones. The study indicates that mice with historical low-dose BPs exposure are more susceptible to CTX-induced spermatogenic stress, resulting in severe reproductive issues, and suggests that chemical-induced reproductive harm should be taken seriously. It's the first study to examine BPs-induced reproductive risks from testicular stress susceptibility, offering a novel approach to identify environmental chemicals that may cause male reduced fertility and infertility.