PM2.5 exposure at different concentrations and modes induces reproductive toxicity in male rats mediated by oxidative and endoplasmic reticulum stress

The molecular mechanisms of PM2.5 exposure in the male reproductive system, have scarcely been studied. Here, we demonstrate the possible relationship and molecular mechanisms between endoplasmic reticulum stress (ERS), oxidative stress, and reproductive toxicity caused by PM2.5. A "PM2.5 real-time online concentrated animal whole-body exposure system" was employed to expose male Wistar rats to PM2.5 for 12 weeks, which could induce sperm quality decline, apoptosis, inflammation, oxidative stress, ERS, and histopathological damage in the testis. In vitro study on cultured primary testicular spermatogonia and Leydig cells confirmed that treatment with PM2.5 (0–320 μg/mL) for 24 h decreased cell survival rate, increased reactive oxygen species, lactate dehydrogenase and 8-hydroxydeoxyguanosine levels, induced DNA damage, ERS and apoptosis, and inhibit the secretion and synthesis of testosterone in Leydig cells. These results clarified that ERS pathways triggered by oxidative stress could significantly induce CHOP and caspase-12 activation, which are significantly associated with cell apoptosis. However, oxidative stress and ERS inhibitors significantly inhibited the occurrence of these injuries. In conclusion, PM2.5 triggers the ERS pathway and induces DNA damage in rat testicular cells through oxidative stress, ultimately leading to cellular apoptosis. Furthermore, high-concentration intermittent inhalation was more harmful than low-concentration continuous inhalation when the total mass of PM2.5 exposure was the same. [Display omitted] •PM2.5 can cause reproductive toxicity in male Wistar rats.•PM2.5 can cause DNA damage and ERS in male rat germ cells through oxidative stress.•PM2.5 can activate ERS-mediated CHOP and Caspase-12 apoptosis pathways.•PM2.5 can activate the DNA damage-mediated mitochondrial apoptosis pathway.•High-dose PM2.5 intermittent exposure is more toxic than low-dose continuous exposure.