The overall objective of this proposal is to use a genomic approach to investigate the molecular mechanisms by which phthalate esters exert their toxic effects on the developing male reproductive tract. Phthalate esters are a class of environmental chemicals to which humans are highly exposed and which cause antiandrogenic effects on the developing male reproductive tract in rats. The mechanisms by which phthalate esters cause their effects remain to be determined. In preliminary studies, global changes in gene expression in the developing rat testis following in utero exposure to di(n-Butyl) phthalate (DBP) were examined. A significant finding was that the antiandrogenic effects of DBP appeared to be due to a coordinated downregulation in expression of genes involved in cholesterol transport and steroidogenesis. We hypothesize that developmentally toxic phthalate esters have similar gene expression patterns in developing fetal testes and that we can elucidate the mechanism of action of phthalate esters on the developing male reproductive tract by comparing expression patterns. This hypothesis will be tested by investigating the following specific aims: (1) characterize the molecular events in the developing rat testis that are targets for disruption following in utero exposure to a phthalate toxic to male reproductive development and to a nondevelopmentally toxic phthalate compared with results obtained with DBP and identify key target genes for developmental toxicity and (2) link expression of key target genes identified in Specific Aim 1 with adverse response in developing rat fetal testes across a range of doses of a developmental toxic phthalate ester. The methods are to use cDNA microarrays to compare global changes in gene expression patterns in fetal testes exposed in utero to toxic and nontoxic phthalates. Confirm results using quantitative RT-PCR, and determine gene expression in the fetal testes across a range of doses of DBP to identify precursor events and to link gene expression with adverse response. The proposed studies present a unique means for studying hormonally controlled events in the developing male reproductive tract in the absence of hormonal effects on the dam and have the potential to identify novel mechanisms of action of environmental chamicals on male reproductive development. These studies will establish a molecular mechanism for future, more focused studies on the mechanisms of action by which phthalate esters exert their effects on the developing male reproductive tract.
| Liu, Kejun; Lehmann, Kim P; Sar, Madhabananda et al. (2005) Gene expression profiling following in utero exposure to phthalate esters reveals new gene targets in the etiology of testicular dysgenesis. Biol Reprod 73:180-92 |
| Lehmann, Kim P; Phillips, Suzanne; Sar, Madhabananda et al. (2004) Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate. Toxicol Sci 81:60-8 |
