Analysis by Metabolomics and Transcriptomics for the Energy Metabolism Disorder and the Aryl Hydrocarbon Receptor Activation in Male Reproduction of Mice and GC-2spd Cells Exposed to PM.

Fine particulate matter (PM)-induced male reproductive toxicity arouses global public health concerns. However, the mechanisms of toxicity remain unclear. This study aimed to further investigate toxicity pathways by exposure to PMandthrough the application of metabolomics and transcriptomics., spermatocyte-derived GC-2spd cells were treated with 0, 25, 50, 100 μg/mL PMfor 48 h., the real-world exposure of PMfor mouse was established. Forty-five male C57BL/6 mice were exposed to filtered air, unfiltered air, and concentrated ambient PMin Tangshan of China for 8 weeks, respectively. The resultsandshowed that PMexposure inhibited GC-2spd cell proliferation and reduced sperm motility. Mitochondrial damage was observed after PMtreatment. Increased Humanin and MOTS-c levels and decreased mitochondrial respiratory indicated that mitochondrial function was disturbed. Furthermore, nontargeted metabolomics analysis revealed that PMexposure could disturb the citrate cycle (TCA cycle) and reduce amino acids and nucleotide synthesis. Mechanically, the aryl hydrocarbon receptor (AhR) pathway was activated after exposure to PM, with a significant increase in CYP1A1 expression. Further studies showed that PMexposure significantly increased both intracellular and mitochondrial reactive oxygen species (ROS) and activated NRF2 antioxidative pathway. With the RNA-sequencing technique, the differentially expressed genes induced by PMexposure were mainly enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, of whichwas the most significantly changed gene. Our findings demonstrated that PMexposure could induce spermatocyte damage and energy metabolism disorder. The activation of the aryl hydrocarbon receptor might be involved in the mechanism of male reproductive toxicity.