The Role of Death Receptor Signaling in Testicular Germ-Cell Apoptosis Triggered by Mono-(2-ethylhexyl) Phthalate (MEHP)-Induced Sertoli Cell Injury and Its Implications for Risk Assessment

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Abstract
The focus of this review is to highlight the participation of members of the tumor necrosis factor (TNF) superfamily of proteins, particularly FasL and Fas, in triggering apoptosis of distinct testicular germ-cell subtypes after mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury. Despite the well-recognized expression of FasL and Fas in the testis, their functional role in this tissue and the cellular mechanisms that regulate germ-cell apoptosis in the testis remain poorly characterized. Over the last several years, evidence has been accumulating indicating the participation of the FasL/Fas signaling pathway in the testis as a key signaling event for triggering germ-cell apoptosis consequent to MEHP-induced Sertoli cell injury. It has also recently been revealed that the stability of the c-FLIP protein, a direct inhibitor of Fas signaling, in germ cells appears to be dependent on the activity of the p53 protein. Increased degradation of the c-FLIP protein is proposed to occur in distinct germ-cell subtypes as a secondary consequence to MEHP-induced Sertoli cell injury and may account for their sensitivity to undergo apoptosis. Taken together, these findings form the basis for our current hypothesis that MEHP-induced injury to Sertoli cells results in early increases in its expression of FasL and secondary changes in the regulation of Fas in germ cells as a result of p53 activation. An understanding of the primary cellular site of phthalate action in the Sertoli cell and of the extent of the resulting adverse outcomes that arise from this injury are required for an accurate appraisal of the risks of environmental phthalate exposure on human reproductive health during all phases of life.