[4-nonylphenol combined with bisphenol A induces testicular autophagy and spermatogenic impairment by inhibiting the Akt/mTOR pathway in F1 male offspring rats].

ABSTRACT

OBJECTIVE: To study the impacts of exposure of F0 generation rats to 4-nonylphenol (4-NP) and bisphenal A (BPA) on the autophagy of testicular cells and key gene expressions of the Akt/mTOR pathway in the F1 generation offspring rats. METHODS: Using a 2×2 factorial design, F0 female and male rats were randomly assigned to receive intragastrically sigma vegetable oil (the control), BPA at 0.5 mg/kg, 4-NP at 5 mg/kg, and BPA+4-NP both at 0.5 mg/kg, respectively, qd alt for 30 days. Then the rats in each group were mated at a ratio of 1∶3. After pregnancy, the female rats continued the above intragastrical administration till delivery. The F1 generation male offspring rats were killed at 60 postnatal days, and their testes harvested for sperm count, observation of the morphological and autophagic changes of the testis, and determination of the relative mRNA expression levels of Akt, mTOR, 4EBP1 and p70S6K and protein expression levels of LC3-I and LC3-II. RESULTS: The sperm count of the F1 generation male offspring rats was markedly decreased in the BPA and BPA+4-NP groups compared with that in the control (P < 0.05) but no significant interactive effect was observed between BPA and 4-NP (P > 0.05). The ratio of LC3-II / LC3-I was remarkably increased in the 4-NP, BPA and BPA+4-NP groups in comparison with that in the control (P < 0.05), and a significant interactive effect was shown between BPA and 4-NP (P < 0.05). The cells in the seminiferous tubules of the rats in the 4-NP, BPA and BPA+4-NP groups were loosely arranged, with a decreased count of sperm and increased number of autophagic vacuoles. Significant down-regulation was observed in the relative mRNA expression of p70S6K in the 4-NP group, as well as in that of mTOR in the BPA group and Akt in the BPA+4-NP group (all P < 0.05). A remarkably up-regulated expression of 4EBP1 mRNA was found in all the three intervention groups (P < 0.05), with a significant interactive effect between BPA and 4-NP on the expressions of Akt and 4EBP1 mRNA (P < 0.05). CONCLUSION: Long-term exposure to low-concentration BPA and 4-NP impairs the testicular function of the F1 generation male offspring rats, which is closely related to the autophagy of testicular cells and changes of the Akt/mTOR pathway.