Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero.
Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function. Pregnant Long-Evans female rats received vehicle (corn oil) or DEHP at 10, 100, or 750 mg/kg by oral gavage from gestational day (GD)2-20. At GD21, T production, FLC numbers and distribution, and testicular gene expression were examined. The percentage of FLC clusters containing 6-30 cells increased in all treatment 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 were 33% and 39% lower than control after exposures to 100 and 750 mg/kg DEHP, respectively. At these doses, mRNA levels of leukemia inhibitory factor (LIF) increased. LIF was found to induce cell aggregation in FLCs in vitro, consistent with the hypothesis that DEHP induced FLC aggregation. Testicular T levels were doubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNA levels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kg DEHP. These results, taken together, indicate that fetal exposures to DEHP have effects on FLC number, distribution, and most importantly, steroidogenic capacity and suggest that abnormal expressions of IGF1, KITL, and LIF genes may contribute to the reproductive toxicity of phthalates.
Lin
Han
H
Population Council and the Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Ge
Ren-Shan
RS
Chen
Guo-Rong
GR
Hu
Guo-Xin
GX
Dong
Lei
L
Lian
Qing-Quan
QQ
Hardy
Dianne O
DO
Sottas
Chantal M
CM
Li
Xiao-Kun
XK
Hardy
Matthew P
MP
D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis; D007985:Leydig Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D019089:Stem Cell Factor / Q000378:metabolism
D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D019089:Stem Cell Factor; D007334:Insulin-Like Growth Factor I; D004051:Diethylhexyl Phthalate