Unveiling polycyclic aromatic hydrocarbons exposure and female infertility risk in southern China: An integrated epidemiologic and network toxicology approach.

The relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and female infertility (FI) remains unclear, particularly regarding mixed PAH exposures. This study aimed to investigate the association between individual and mixed PAH exposures and FI by integrating epidemiological and network toxicological approaches. A case-control study was conducted involving 83 infertile patients and 272 non-infertile controls in Guangdong Province, China. Three statistical models were applied to assess the effects of eight urinary hydroxylated-PAHs (OH-PAHs) metabolites on FI. Network toxicology analysis was utilized to identify common genes, potential pathways, and key targets. After adjusting for potential confounders, 3-OHFLU and 2-OHPHE were significantly associated with an increased risk of FI, with 3-OHFLU identified as the predominant risk factor (OR [95 % CI]: 1.92 [1.42, 2.69]). Mixture analysis revealed a positive association between mixed OH-PAHs and FI risk, with 3-OHFLU contributing the most. Based on network toxicology analysis, we propose a potential mechanism: PAHs exposure may activate the TNF signaling pathway, which could trigger an inflammatory response, potentially altering AKT1 expression via the PI3K-Akt pathway. This might lead to reduced cell survival, promoted oocyte apoptosis, and ultimately contribute to FI. These findings indicate that mixed PAHs exposure increases the risk of FI, with 3-OHFLU identified as the predominant contributing factor and the TNF signaling pathway serving as a potential underlying mechanism. Further longitudinal studies are needed to validate these results.