MECHANISTIC BIOMARKERS OF ENDOCRINE DISRUPTION

Nemours Children'S Hospital, Delaware, Wilmington DE

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the United States, malformations of the reproductive tract are the most common male birth defect. Several pieces of evidence suggest the human environment is partially responsible for these birth defects, including the increasing prevalence of malformations and the ubiquitous exposure of humans to endocrine disrupting chemicals that, in animal models of exposure, recapitulate the suite of human malformations. One of these endocrine disrupting chemical classes is the phthalates. Exposure of fetal rats to dibutyl phthalate (DBP) reduces testicular Leydig cell hormone production leading to common human malformations: hypospadias (malformed penis) and cryptorchidism (undescended testis). The mouse is resistant to phthalate-induced endocrine disruption. This species-dependent sensitivity raises the question of whether or not the ubiquitous human phthalate exposure contributes to human male reproductive malformations, and answering this question is the long-term goal of this project. The scientific bottleneck to determining if phthalate exposure contributes to human male reproductive is the lack of validated molecular biomarkers of phthalate exposure and endocrine disruption that can be used in human epidemiological studies. Appropriate biomarkers have two characteristics. Biomarkers should be from a source readily available from humans and be associated with the mechanism of phthalate endocrine disruption. Here, mechanistically relevant, surrogate tissue phthalate endocrine disruption biomarkers will be developed from profiling expression of the placental genome in exposed rodents and exploration of the molecular mechanism of testicular phthalate endocrine disruption. Three main pieces of information have led to our hypothesis that placental biomarkers of phthalate exposure predict fetal testis endocrine disruption that requires testicular gonadotropin releasing hormone receptor (Gnrhr) signaling: 1) DBP exposure alters the genetic profile of rat placenta;2) Gnrhr signaling in testis disrupts testicular hormone production in rats (phthalate sensitive species) but not mice (phthalate insensitive species);and 3) rat DBP exposure induces testicular expression of Gnrhr and potential Gnrhr signaling molecules in rat, but not mouse, testis. Three specific aims will test the hypothesis. In the first aim, a machine learning algorithm will be applied to placental genomic expression data to define a surrogate biomarker set of genes predictive of testicular endocrine disruption. Using the species-dependent phthalate susceptibility as a tool in aim two, the role of Gnrhr signaling in phthalate endocrine disruption will be explored by determining the endocrine disruption phenotype in rat Leydig cells with disrupted Gnrhr signaling and in mouse Leydig cells with activated Gnrhr signaling. In the final aim, a Leydig cell-specific Gnrhr knockin mouse model will be used to ascertain if forced Gnrhr signaling in vivo sensitizes the mouse the endocrine disruption. Successful completion of these aims will lead to novel biomarkers of endocrine disruption to be used in future studies examining the role of phthalate exposure in human male reproductive birth defects.