Determinants of Fetal Male Rat Germ Cell Vulnerability to Phthalate EstersEPA Grant Number: R830766
Title: Determinants of Fetal Male Rat Germ Cell Vulnerability to Phthalate Esters
Investigators: Gaido, Kevin
Institution: The Hamner Institutes
EPA Project Officer: Klieforth, Barbara I
Project Period: February 24, 2003 through February 23, 2006 (Extended to March 31, 2007)
Project Amount: $725,736
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health , Health Effects , Health
The objective of this proposal is to identify key molecular events associated with germ cell development in the male rat testes that are targets for endocrine active chemicals following in utero exposure. Phthalate esters represent an important class of environmental chemicals to which humans are widely exposed and to which the developing male rat reproductive tract is highly vulnerable. In utero exposure of male rats to phthalate esters results in hypospadias, cryptorchidism, fetal gonocyte degeneration, and permanent reduction in post-pubertal sperm production and fertility. The mechanism by which phthalates cause these effects remains to be determined. We hypothesize that phthalates alter expression of key genes necessary for gonocyte survival in the developing testes resulting in permanent changes in testis function and germ cell development.
This hypothesis will be tested by investigating the following specific aims: 1) identify key cellular and molecular pathways involved in germ cell development in the male rat that are targets for DBP following in utero exposure; 2) determine the effect of in utero exposure to DBP on germ cell responsiveness to cell proliferation and survival factors; and 3) link DBP-induced changes in gonocyte gene expression with phthalate ester-induced germ cell toxicity by comparing the effect of in utero exposure of DBP with in utero exposure to another male reproductive toxic phthalate (DEHP) and a non-toxic phthalate (DEP).
The proposed studies will identify critical genes and pathways associated with male germ cell development that are targets for phthalate esters in the male rat testes in utero. This information will be critical for the determination of whether phthalate esters can act similarly in humans.