Epidemiological and experimental studies suggest that disruption of embryonic programming and gonadal development during human fetal life can result in testicular dysgenesis, manifested as undescended testis, hypospadias, poor semen quality, and testicular cancer. Preliminary data indicates that exposure of Leydig cells to low and environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) in vivo and mono-ethylhexyl phthalate (MEHP) in vitro altered the genomic and proteomic profile of the cells in a manner that parallels the inhibition of hormone-dependent steroid formation and the induction of Leydig cell hyperplasia. The central objective of this proposal is to gain greater understanding of the fetal basis of male reproductive disorders by elucidating the mechanisms by which exposure of the fetus to the environmental antiandrogen DEHP suppresses fetal testosterone production and later, testosterone and estradiol production by the adult. Our major goals are to identify the cellular targets and the molecular mechanisms underlying the responses of the fetus to DEHP, and to reveal the mechanisms by which effects on the fetus lead to pathologies of the male reproductive tract in the adult. The overarching hypothesis is that in utero exposures to DEHP suppress fetal testosterone production by direct effects on fetal Leydig cells and/or on the mesenchymal cells that are the precursors of adult Leydig cells, and by doing so, suppresses postnatal development and function of the adult Leydig cell population. We will test this hypothesis with the following specific aims: (1) identify the cellular and molecular targets of gestational DEHP in the fetal testis; (2) identify the mechanism(s) by which gestational exposure to DEHP results in reduced testosterone production by the fetal testis; and (3) determine the effects of fetal exposure to DEHP on the formation and function of the adult population of Leydig cells and its impact on testicular function in the immature and adult testis. We believe that these Aims will identify the molecular signaling pathways and characterize their role in mediating the hyperplasic and antiandrogenic effect of phthalates leading to testicular dysgenesis in the adult. Taken together the proposed studies will unveil the endocrine disruptor-sensitive steps in the steroidogenic pathway that are affected by this antiandrogen, and the mechanisms and consequences of endocrine disruption on the endocrine milieu of the adult. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013495-05
Application #
7409634
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Heindel, Jerrold
Project Start
2005-08-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$241,592
Indirect Cost
Name
Mcgill University Health Center Research Institute
Department
Type
DUNS #
201923179
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 2-R9
Martinez-Arguelles, Daniel B; Guichard, Theodore; Culty, Martine et al. (2011) In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod 85:51-61
Fan, Jinjiang; Traore, Kassim; Li, Wenping et al. (2010) Molecular mechanisms mediating the effect of mono-(2-ethylhexyl) phthalate on hormone-stimulated steroidogenesis in MA-10 mouse tumor Leydig cells. Endocrinology 151:3348-62
Martinez-Arguelles, Daniel B; Papadopoulos, Vassilios (2010) Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action. Steroids 75:467-76
Martinez-Arguelles, D B; Culty, M; Zirkin, B R et al. (2009) In utero exposure to di-(2-ethylhexyl) phthalate decreases mineralocorticoid receptor expression in the adult testis. Endocrinology 150:5575-85
Rosenberg, Brian G; Chen, Haolin; Folmer, Janet et al. (2008) Gestational exposure to atrazine: effects on the postnatal development of male offspring. J Androl 29:304-11
Culty, Martine; Thuillier, Raphael; Li, Wenping et al. (2008) In utero exposure to di-(2-ethylhexyl) phthalate exerts both short-term and long-lasting suppressive effects on testosterone production in the rat. Biol Reprod 78:1018-28