Nemours Biomedical Research
Male reproductive system development requires appropriate hormone (androgen) signaling intensity during a critical in utero time window, and improper signaling results in malformations affecting approximately 3% of male newborns.
The overarching goals of our research program are to identify mechanisms of normal male reproductive maturation and understand how these mechanisms are perturbed in instances of abnormal development such as hypospadias and cryptorchidism.
Associate Research Scientist, Nemours Biomedical Research
Research Assistant Professor, Department of Urology,
Thomas Jefferson University
Affiliated Scientist, Department of Biological Sciences, University of Delaware
The fetal environmental milieu contributes to male reproductive disease, but the environmental factors responsible for this effect are unknown. Our goals are to identify environmental factors involved and discover their mechanism of action. Once causative environmental factors are identified, exposure prevention will reduce the rate of congenital male reproductive malformations.
It is becoming clear that more than one type of environmental exposure contributes to disease, and our lab is examining the interaction of different exposures using animal models. In humans, an “environmental” exposure consistently associated with cryptorchidism and hypospadias is intrauterine growth restriction, which is generally caused by poor placental function. Likewise, exposure to chemical toxicants that perturb the fetal endocrine system is frequently invoked as a cause of cryptorchidism and hypospadias. In isolation, neither growth restriction nor exposure to a single toxicant causes these malformations. Instead, multiple exposures contribute to disease.
We are studying the interaction of fetal growth restriction and reproductive toxicant exposure on male reproductive development in utero. We hypothesize that fetal growth restriction and toxicant exposures individually inhibit fetal testis testosterone production and together have additive or synergistic effects resulting in cryptorchidism and hypospadias. These hypotheses are being tested in rodent models. In addition, we are determining if growth restricted neonates have altered male-specific morphological changes indicative of reduced fetal androgen signaling.
In the course of our research on environmental influences on male reproductive development, it became clear that insufficient information about normal fetal testis androgen production was impeding progress to decipher mechanisms of endocrine disruptor action and the etiology of male reproductive malformations. Therefore, we embarked on a project to discover novel factors regulating fetal testis steroidogenesis.
We used a comparative genomics method of various normal and endocrine disruptor-exposed tissues to isolate candidate genes controlling steroidogenesis. This research generated a list of approximately forty candidate genes. Using a mouse testis steroid producing cell line (MA-10), we are screening candidate genes using a high throughput gene knockdown (siRNA) approach for involvement in steroid production. In addition, we are performing additional functional studies on one particular gene candidates (Gramd1b) using a variety of in vitro and in vivo models. Once candidate genes with a steroidogenic function are identified, our goal is to screen human cases of male reproductive malformations for mutations in these genes.
Phone: (302) 651-6615
Fax: (302) 651-6539
Nemours/Alfred I. duPont Hospital for Children
1600 Rockland Road
Wilmington, DE 19803
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