The phthalate ester, diethylhexylphthalate (DEHP), is a constituent chemical of many plastics, conferring their flexibility. Plastics are used ubiquitously in the United States and most industrialized countries and DEHP, which is not chemically bound to the plastic matrix, leaches out over time: human exposure is therefore widespread. Exposure to DEHP is associated with disruption of male sexual development and decreased fertility. Studies by Earl Gray and colleagues have shown that DEHP is anti-androgenic, and that its mechanism of male reproductive toxicity is not through direct interference at the level of the androgen receptor. The P.I. and others have shown that androgen secretion by rat Leydig cells is compromised after in vivo exposures to DEHP. This leads to the hypothesis providing the overall theme to the present application, that the endocrine disrupting properties of DEHP result from adverse effects on Leydig cell development with consequent decreases in androgen secretion. Consistent with this hypothesis, recent data from the P.l.'s lab demonstrate the existence of a critical window of sensitivity for impairment of Leydig cell steroidogenesis in younger animals. In the experiments described for this renewal application, we will analyze the potential for DEHP exposures: I. to suppress expression levels of steroidogenic factor-I, a key nuclear transcription factor that regulates differentiation of Leydig cells and pituitary gonadotropes, and decrease the action of Mullerian inhibiting substance, an SF-1 regulated growth factor that limits Leydig cell division; II. to inhibit proliferation of progenitor Leydig cells; and III. to delay acquisition of steroidogenic enzyme gene expression and steroidogenic capacity. Chronic postnatal exposures to DEHP induced increased levels of gonadotropic secretion by the pituitary and elevated serum testosterone and estradiol levels, which were associated with Leydig cell hyperplasia, a precursor to tumorigenesis. Formation of Leydig cell tumors is commonly observed in DEHP-treated rats. We will describe the time course of DEHP induced Leydig cell hyperplasia and analyze the role of LH, testosterone, and estradiol in the development of tumorigenesis. These studies will be the first to define the involvement of Leydig cells in the endocrine disrupting effects of DEHP. Our data will facilitate identification of biomarkers of exposure to environmental pollutants, and provide information to regulatory agencies in setting limits for the use of DEHP and phthalates in consumer products ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010233-07
Application #
7213368
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
1999-07-01
Project End
2009-01-31
Budget Start
2007-04-25
Budget End
2009-01-31
Support Year
7
Fiscal Year
2007
Total Cost
$232,657
Indirect Cost
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
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Lin, Han; Lian, Qing-Quan; Hu, Guo-Xin et al. (2009) In utero and lactational exposures to diethylhexyl-phthalate affect two populations of Leydig cells in male Long-Evans rats. Biol Reprod 80:882-8
Ge, Renshan; Chen, Guorong; Hardy, Matthew P (2008) The role of the Leydig cell in spermatogenic function. Adv Exp Med Biol 636:255-69
Lin, Han; Ge, Ren-Shan; Chen, Guo-Rong et al. (2008) Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero. Proc Natl Acad Sci U S A 105:7218-22
Ge, Ren-Shan; Chen, Guo-Rong; Tanrikut, Cigdem et al. (2007) Phthalate ester toxicity in Leydig cells: developmental timing and dosage considerations. Reprod Toxicol 23:366-73
Ge, Ren-Shan; Chen, Guo-Rong; Dong, Qiang et al. (2007) Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats. J Androl 28:513-20
Akingbemi, Benson T (2005) Estrogen regulation of testicular function. Reprod Biol Endocrinol 3:51
Akingbemi, Benson T; Ge, Renshan; Klinefelter, Gary R et al. (2004) Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc Natl Acad Sci U S A 101:775-80
Akingbemi, Benson T; Sottas, Chantal M; Koulova, Anna I et al. (2004) Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells. Endocrinology 145:592-603
Akingbemi, Benson T; Ge, Renshan; Rosenfeld, Cheryl S et al. (2003) Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell. Endocrinology 144:84-93

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