Fine particulate matter (PM_2.5)-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 PM_2.5in vitro and in vivo through the application of metabolomics and transcriptomics. In vitro, spermatocyte-derived GC-2spd cells were treated with 0, 25, 50, 100 μg/mL PM_2.5 for 48 h. In vivo, the real-world exposure of PM_2.5 for mouse was established. Forty-five male C57BL/6 mice were exposed to filtered air, unfiltered air, and concentrated ambient PM_2.5 in Tangshan of China for 8 weeks, respectively. The results in vitro and in vivo showed that PM_2.5 exposure inhibited GC-2spd cell proliferation and reduced sperm motility. Mitochondrial damage was observed after PM_2.5 treatment. Increased Humanin and MOTS-c levels and decreased mitochondrial respiratory indicated that mitochondrial function was disturbed. Furthermore, nontargeted metabolomics analysis revealed that PM_2.5 exposure 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_2.5, with a significant increase in CYP1A1 expression. Further studies showed that PM_2.5 exposure 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 PM_2.5 exposure were mainly enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, of which Cyp1a1 was the most significantly changed gene. Our findings demonstrated that PM_2.5 exposure 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.

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