A Mechanistic Insight into the Autophagy Induced by Cadmium and Other Heavy Metals in Testes

In testicular pathologies mediated by heavy metals, especially cadmium, defective and overactive autophagy have been reported previously. Additionally, it has been demonstrated to work in a way that is either pro-death or pro-survival by promoting, opposing, or cooperating with apoptosis. As a result, there is still much debate over the most basic question in toxicological research, how autophagy in testicular tissue functions as both a protector and an executor of cell death. The present review is an attempt to delineate the molecular mechanism of autophagy induced by heavy metals, especially cadmium, in testicular cells of different species. Understanding the mechanism of action will pave the way towards the development of new strategies to offset the Cd and other heavy metals mediated testicular toxicity. Cadmium and other heavy metals induced autophagic cell death in testes mediated via mechanism involving DNA damage, endoplasmic reticulum (ER) stress, disrupted integrity of blood-testis-barrier, and disruption of mitophagy. Primarily ATM/AMPK/mTOR axis and Rictor/mTOR2 pathway has been shown to involve into the autophagic process in testicular tissue upon exposure to heavy metals, particularly cadmium. However, depending on the circumstances, autophagy can also have pro-survival effects. Probably, the dosage and duration of heavy metals treatment may have varying effects on the autophagic activities of testicular cells. In this regard, cross-talk between autophagy and other cell death mechanisms like apoptosis is of particular interest, and thus further studies should focus more on this aspect.