Exposure to disinfection by-products and risk of diminished ovarian reserve: Case-control evidence and cellular metabolomic insights

Disinfection of drinking water is a critical measure for ensuring water safety and controlling waterborne infectious diseases. However, during the disinfection process, a variety of disinfection by-products (DBPs), some of which exhibit reproductive toxicity, are generated. This study aimed to assess whether DBP exposure contributes to the risk of diminished ovarian reserve (DOR) and explored the underlying metabolic mechanisms. A total of 182 participants, including 91 healthy women and 91 women with DOR, were recruited for a case-control study conducted between October 2023 and February 2024. Serum concentrations of DBPs, including dibromoacetic acid (DBAA), monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), chlorate, and perchlorate, were measured to evaluate DBP exposure. Key indicators for evaluating DOR included antral follicle count (AFC), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH). All six DBPs were higher in DOR patients (all p < 0.05). After controlling for covariates, all DBPs showed negative correlations with AMH and AFC, positive correlations with basal FSH, and a significant association with the risk of DOR (all p < 0.05). To further investigate the underlying mechanisms, we conducted an in vitro study using human ovarian granulosa cell line (KGN). KGN cells were exposed to DBAA and perchlorate for 48 hours, and metabolomic analysis was performed to identify altered metabolic pathways. Metabolomics data suggested that DBAA and perchlorate might have contributed to DOR by disrupting arginine biosynthesis and purine metabolism, respectively. In conclusion, DBPs exposure might have contributed to DOR risk by disrupting granulosa cell (GC) metabolism.