The role of cells of the innate immune system in mediating testicular toxicity

Caitlin Murphy

Caitlin Murphy, Ph.D.
Post-doctoral Fellow

In this research project we appraise the contribution of the innate immune system in the mechanism responsible for the loss of germ cells (GC) via apoptosis in the postnatal male testis after exposure to mono-(2-ethylhexyl) phthalate (MEHP). Phthalates are a class of compounds that are incorporated into cosmetics, food packaging, biomedical devices, and PVC products to impart flexibility. Since these agents are not covalently bound to the final product they readily leach out of these products and, as a result, are found widely distributed in the environment and human tissues. The most abundantly produced and studied phthalate is di-(2-ethylhexyl) phthalate (DEHP) that is rapidly hydrolyzed in the gastrointestinal tract, liver and blood, by nonspecific esterases to produce its corresponding toxic monoester, MEHP. Although the collective human median phthalate exposure level is estimated to be ~30 µg/kg/bw/day, certain individual populations, such as young children receiving parenteral fluids via polyvinyl-chloride based tubing, show levels of 10-20 mg/kg/day. It is widely recognized that peripubertal rodents (~postnatal day, PND, 14-28) are more sensitive than adults to testicular injury by phthalates . The work of this research project is anticipated to  provide  key  insights into the mechanisms that account for the age-dependent susceptibility to phthalate-induced testicular injury.

While certain phthalate monoesters have long been recognized as male reproductive toxicants, only a scant number of studies have evaluated their effects on the immune system. We have previously revealed a role for the cytokine, soluble tumor necrosis factor-a (sTNFalpha), in upregulating Fas/FasL signaling and GC apoptosis after MEHP exposure. In addition, our recent observations show that the extent of infiltration of CD11b+ leukocytes into the testis strongly coincides with the known differences in MEHP-induced GC apoptosis between the sensitive rats and the less responsive mice, and between peripubertal and adult rodents. The goal of this project is to decipher the cellular signals that instigate leukocyte infiltration into the testis after exposure to mono-(2-ethylhexyl) phthalate (MEHP) and to determine the functional significance of these cells in the pathogenesis of MEHP-induced germ cell apoptosis. It is predicted that insights gained from this work will be useful for predicting susceptible individuals and preventing human reproductive health risks this class of chemicals.

Relevant Manuscripts:

Murphy, CJ, Stermer, AR and Richburg, JH (2014). Age- and species-dependent infiltration of macrophages into the testis of rats and mice exposed to mono-(2-ethylyhexyl) phthalate (MEHP). Biology of Reproduction. 91(1):18, 1-11.

Yao, P-L, Lin, Y-C and Richburg, JH (2012). Mono-(2-ethylhexyl) phthalate promotes invasion and migration of human testicular embryonal carcinoma cells. Biology of Reproduction 86(5): 160, 1-10

Yao, P-L, Lin, Y-C and Richburg, JH (2011). Transcriptional suppression of Sertoli cell Timp2 in rodents following mono-(2-ethylhexyl) phthalate exposure is regulated by CEBPA and MYC. Biology of Reproduction 85(6): 1203-15.

Yao, P-L, Lin Y-C and Richburg, JH (2010). Mono-(2-ethylhexyl) phthalate-induced disruption of junctional complexes in the seminiferous epithelium of the rodent testis is mediated by MMP2. Biology of Reproduction 82: (3) 516-527.

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