Abstract
Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero
Lin,Han; Ge,Renshan; Chen,Guo-Rong; Hu,Guo-Xin; Dong,Lei; Lian,Qing-Quan; Hardy,Dianne O.; Sottas,Chantal M.; Li,Xiao-Kun; Hardy,Matthew P.
Proceedings of the National Academy of Sciences of the United States of America 105(20): 7218-7222
Publication date: 2008
Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shownto be associated with decreased adult testosterone (T) levelsand increased Leydig cell numbers. As yet, little is known aboutDEHP effects in utero on fetal Leydig cells (FLC). The presentstudy investigated effects of DEHP on FLC function. PregnantLong-Evans female rats received vehicle (corn oil) orDEHP at 10, 100, or 750 mg/kg by oral gavage from gestationalday (GD)2-20. At GD21, T production, FLC numbers and distribution,and testicular gene expression were examined. The percentageof FLC clusters containing 6-30 cells increased in alltreatment groups, with 29 ± 2% in control vs. 37 ±3, 35 ± 3, and 56 ± 4% in rats receiving 10, 100,and 750 mg/kg DEHP, respectively. In contrast, FLC numbers were33% and 39% lower than control after exposures to 100 and 750mg/kg DEHP, respectively. At these doses, mRNA levels of leukemiainhibitory factor (LIF) increased. LIF was found to induce cellaggregation in FLCs in vitro, consistent with the hypothesisthat DEHP induced FLC aggregation. Testicular T levels weredoubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNAlevels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kgDEHP. These results, taken together, indicate that fetal exposuresto DEHP have effects on FLC number, distribution, and most importantly,steroidogenic capacity and suggest that abnormal expressionsof IGF1, KITL, and LIF genes may contribute to the reproductivetoxicity of phthalates.
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