PAK1 mediates ivermectin-induced DNA damage in porcine oocytes during meiotic maturation

Ivermectin (IVM), a broad-spectrum antiparasitic agent, is widely utilized in agriculture and Animal Husbandry. However, the presence of its residues in the environment and food sources may pose potential risks to animal health. Although various cytotoxic effects of IVM have been reported, there is limited information available regarding whether IVM exposure can exert toxic effects on mammalian oocytes. In this study, porcine oocytes were exposed to varying concentrations of IVM for 44 h during in vitro maturation. The results showed that 10 μM IVM significantly inhibited oocyte maturation, as evidenced by the inhibition of first polar body (PB1) extrusion, cytoskeletal disorganization, and meiotic progression arrest. Furthermore, IVM treatment increased expression of γ-H₂AX but decreased p21-Activated Kinase 1 (PAK1) in oocytes, while inhibiting DNA homologous recombination (HR) repair process. Interestingly, these negative effects of IVM were significantly alleviated by the increased expression of PAK1. However, co-treatment with Mirin, an inhibitor of HR repair, reversed the alleviating effect of PAK1 overexpression on oocyte meiotic maturation and DNA damage. In conclusion, IVM exposure adversely affects the maturation of porcine oocytes and induced DNA damage. Additionally, PAK1 is involved in IVM-induced DNA damage in oocytes, and its mediating role is closely related to the regulation of HR repair.

DNA damage; Homologous recombination repair; Ivermectin; Oocyte; PAK1.