Identifying in utero risk factors associated with male reproductive malformation

Date
2014
Authors
Pike, Jack W.
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Publisher
University of Delaware
Abstract
Male reproductive development is mediated by hormone signaling events. A surge of testis testosterone production occurs during a critical window: gestational days 15-18 in the rat and gestational weeks 10-22 in the human. This period of development corresponds with many of the reproductive masculinization events that are required for normal formation. Disruption of steroidogenesis during this time can lead to malformations in the male reproductive system in the forms of hypospadias, cryptorchidism, and decreased anogenital distance. Steroidogenesis can be disrupted by many factors including environmental chemical exposure, genetic predisposition, or in utero conditions. Dibutyl phthalate is a plasticizer used in food packaging, medical devices, and cosmetics. In rats it has been shown to disrupt in utero testosterone production and cause reproductive malformations. Human sensitivities to this compound, however, have not been well established. Another factor that has been linked to fetal testis steroidogenic disruption is in utero growth restriction. When a fetus receives insufficient nutrients due to placental insufficiency, genetic predisposition, or maternal nutritional deficits, an increased prevalence of reproductive malformations that are associated with insufficient androgen signaling is observed. This study has examined the effects of in utero dibutyl phthalate exposure on rat foreskin gene expression. Several genes were selected for analysis by qRT-PCR from a pool of significantly altered genes, as identified by microarray analysis. Marcks, Pum1, and Penk expression were decreased and Nupr1 expression was increased in rat foreskin of offspring of dibutyl phthalate treated pregnant rats. Following prenatal exposure, gene expression changes persisted several days after birth and as such, could serve as potential markers of chemical exposure and biological response. Moreover, in utero growth restriction was assessed to determine its effects on fetal testis steroidogenesis. Growth restriction was elicited by means of maternal food restriction and caused a significant decrease in testicular gene expression of key genes involved in testosterone steroidogenesis including Scarb1, Star, Cyp11a1, and Cyp17a1. Moreover, testosterone production was reduced by 40% following maternal food restriction. We then assessed the potential cooperative effects of dibutyl phthalate with in utero growth restriction on gene expression. There was a significant decrease in testis steroidogenic gene expression in the combined growth restriction and dibutyl phthalate group as compared to either individual treatment. The combined treatment resulted in a 70% reduction in testosterone whereas there was only a 40% reduction for either individual treatment. Postnatally, the combined treatment resulted into numerous reproductive abnormalities. Interestingly, however, IUGR seemed to provide a protective effect wherein fetuses with DBP alone experienced a greater incidence of reproductive malformation than those in the DBP IUGR combined exposure group. Collectively, these findings can help in the risk assessment of dibutyl phthalate and in utero growth restriction while also demonstrating the potential interaction among these treatments. Prenatal studies indicate a cooperative disruption in steroidogenesis; however, postnatal analysis suggests a protective effect. The effects of IUGR on reproductive masculinization are clearly complicated. This study suggests that an interaction, whether preventative or compounding, may exist between IUGR and in utero exposure to the environmental antiandrogen, DBP.
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