This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Reproductive tract malformations are the most common male congenital defects in developed countries, and data suggest a rising incidence in recent decades. In the United States and other industrialized countries, cryptorchidism (undescended testis) affects 2 to 3% of male newborns, while hypospadias (abnormal penile development) presents in 1 out of 125 male newborns. In most cases, the etiology of reproductive tract disorders is unknown, but the reported rise in prevalence suggests environmental factors are major contributors. Indeed, in utero exposure of animal models to environmental chemicals called """"""""endocrine disruptors"""""""" recapitulates the suite of reproductive malformations observed in humans. These laboratory experiments have led researchers to propose a causative role of endocrine disrupting chemicals in human male reproductive abnormalities. However, there is little if any human data linking environmental chemical exposure with human male reproductive tract malformations. While human exposure to endocrine disruptors and the effects of endocrine disruptors in animal models are two relatively easy approaches to assay, linking human endocrine disruptor exposure to human reproductive malformations has proven difficult. Participants at a recent National Institutes of Health-sponsored workshop addressing this knowledge gap concluded that the field is constrained by a lack of validated molecular biomarkers of endocrine disruptor exposure and adverse effect that can be translated to human epidemiology studies. This is the important knowledge gap we propose to close. Chemical plasticizers termed phthalates are one class of endocrine disruptors producing cryptorchidism and hypospadias in animal models, and human phthalate exposure is daily and ubiquitous. During rat in utero exposure, phthalates disrupt fetal testis expression of lipid metabolism genes responsible for producing hormones leading to maldevelopment of hormone-dependent reproductive tissues. However, phthalates alter gene expression in several testis cell types as well as other tissues. We will use this promiscuity to develop biomarkers of phthalate exposure and, more importantly, adverse effect in perinatal reproductive tissues that can be readily obtained from humans (placenta and foreskin). These tissues are excellent choices for biomarker development because 1) placenta expresses steroidogenic genes, altered placental function or weight is linked to male reproductive malformations, and in vitro phthalate exposure perturbs placental cell function, and 2) foreskin expresses androgen receptor and its separation from the glans penis at puberty is androgen-dependent and delayed by endocrine disruptor (phthalate and estrogen) exposure. In preliminary gene expression profiling of the rat placenta after phthalate exposure, we have observed changes in several hundred genes;similar to testis, the lipid metabolism pathway was significantly altered in placenta. Based upon these data, we hypothesize that candidate genomic biomarkers of low dose level phthalate exposure and adverse effect can be derived from gene profiling rat placenta and foreskin.
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