Several agents have been identified as Leydig cell toxicants, including ethanol, ethane 1,2 dimethanesulphonate (EDS), 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCCD), and steroid hormone receptor antagonists. These toxicants can damage Leydig cells in three ways: overstimulation or inhibition of steroidogenesis, induction of tumor formation, and promotion of cell death. Leydig cells are vulnerable to several toxins through direct actions and/or by disruption of the hypothalamic-pituitary axis.
Toxicants, such as ethanol, interfere with Leydig cell steroidogenesis by interfering with LH secretion, LH receptor binding, intracellular signal transduction pathways, and steroidogenic enzyme activities. Ethanol, for example, decreases LH secretion and reduces LH receptor binding and intracellular cyclic guanosine 5'-monophosphate (GMP) levels. Hence, chronic alcohol abuse causes declines in testosterone levels (138-140). Tumor formation and cell death are also observed after toxicant exposures. Carcinogenesis is considered to be a consequence of multiple insults to the genome. Necrosis and apoptosis have both been implicated in the process of toxicant-related Leydig cell death, with ethylene dimethanesulfonate exposure as the experimental paradigm (141).
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