Lactoferrin alleviates spermatogenesis dysfunction caused by bisphenol A and cadmium via ameliorating disordered autophagy, apoptosis and oxidative stress

Contaminants in food have severely threatened human health, and appropriate antioxidants derived from food could reduce impairment risk. Lactoferrin from milk could control iron concentration in the blood to ameliorate oxidative stress, which is also required for sperm maturation, but the underlying mechanisms remain unclear. The present study used mice with spermatogenetic dysfunction caused by bisphenol A (BPA) and cadmium (Cd) to evaluate the ameliorative effects of lactoferrin and milk (bioactive substances). BPA (50 mg/kg) and Cd (1.6 mg/kg) caused severe damage to testis, including globally decreased germ cell counts, poor sperm quality, disordered apoptosis, oxidative stress, and autophagy; however bioactive substances comprehensively ameliorated spermatogenetic dysfunction via mitigating the increased levels of BAX/BCL2, LC3II/LC3I, and P62. AMPK was involved in autophagic regulation, while ERK1/2 inhibition attenuated the protective effects of lactoferrin, including restimulating apoptosis, oxidative stress, and arrested autophagic flux. Notably, P62 was consistently stimulated with different ERK1/2 inhibitors, which was ubiquitin-dependent. The study provides evidence for the alleviative effects of lactoferrin and milk in mice with spermatogenetic dysfunction through ERK1/2 mediated the ubiquitin-dependent degradation of P62. The involved signals and molecules could be identified as novel therapeutic targets for male infertility, which contributes to expanding LF's interests in research and application.