Effects of combined genistein and di-(2-ethylhexyl) phthalate on male reproductive development and function

Early life exposure to endocrine disruptors (EDs) is thought to contribute to reported declines in male reproductive potential and increased incidence of male reproductive abnormalities such as testicular cancer, crytorchidism and hypospadias. These aberrations, collectively termed testicular dysgenesis syndrome (TDS), are thought to arise from impaired development and reprogramming of progenitor cells during the developmentally sensitive fetal and neonatal windows. The hormonal dependence and developmental intricacy of the fetal period, in combination with a comparatively permeable fetal skin surface, minimal detoxifying capacity and lack of blood-testis barrier, make the developing gonads particularly sensitive to EDs capable of crossing the placenta. Although EDs have been extensively studied in the context of single high dose chemical exposures, few studies have examined the additive or synergistic effects of ED co-exposure during critical periods of development. In reality, humans and animals are exposed not to one, but a myriad of potentially harmful substances throughout their lifetimes. Two common early life exposures are those of genistein (GEN), a natural phytoestrogen found at high levels in soy based infant formula and other soy-derived products, and di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer used in the manufacturing of polyvinyl chloride (PVC) plastics. We hypothesized that in utero co-exposure to genistein and DEHP, at low doses relevant to human exposure could induce alterations in testis development different or potentially more harmful than exposure to a single chemical at the same dose. Such changes could lead to long term effects on fertility.Multiple rodent toxicological models demonstrated the ability of genistein and DEHP to present a long term male reproductive risk, acting in an additive or synergistic manner, below previously reported thresholds of toxicity, and involving different mechanisms of toxicity from perinatal ages through adulthood. Several vulnerable cell types were identified in perinatal and adult periods, along with potential mechanisms of toxicity.The present thesis challenges the long running doctrine of assessing chemical safety in the context of high dose, single exposure animal and cell based models. Results also highlight how short term studies may not be predictive of long term effects. The notion that these EDs do not follow classical dose-response effects with consistent mechanisms of toxicity from perinatal ages to adulthood further stresses the importance of assessing impacts across a range of doses during appropriate windows of exposure and at different ages. These are very pertinent concepts in the context of chemical risk assessment and the ability of regulatory agencies to determine safe exposure thresholds.

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