Synergistic assault of DEHP and MPs: Unmasking the ER stress-triggered autophagic injury male fertility

As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress via the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.