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* To whom correspondence should be addressed. E-mail: m-hardy{at}popcbr.rockefeller.edu.
Phthalate esters such as di(2-ethylhexyl)phthalate (DEHP), which are commonly found in cosmetics and used in flexible plastics distributed by the food, construction and medical products industries, have been classified as anti-androgens. High dose DEHP exposure in utero is associated with decreased androgen levels. However, when administered after birth, low doses of DEHP (e.g., 10 mg/kg body weight) may stimulate androgen production. In the present study, the potential of phthalate exposures to advance or delay the timing of puberty was assessed. Male Long Evans rat pups were chronically subjected to low or high doses of DEHP, with the androgen-driven process of preputial separation serving as an index of pubertal timing. Rats were treated with 0, 10, 500 or 750 mg/kg body weight DEHP for 28 days starting at day 21 postpartum. The average age at which the animals completed preputial separation was measured in each group. The age of preputial separation was 41.5 ± 0.1 days postpartum in controls (vehicle). The 10 mg/kg DEHP dose advanced pubertal onset significantly to 39.7 ± 0.1 days postpartum, whereas 750 mg/kg DEHP dose delayed pubertal onset to 46.3 ± 0.1 days postpartum. The 10 mg/kg DEHP dose also significantly increased serum testosterone(T)levels (3.13 ± 0.37 ng/ml) and seminal vesicle weights (0.33 ± 0.02 g) compared to control serum T (1.98 ± 0.20 ng/ml) and seminal vesicle weight (0.26 ± 0.02 g), while the 750 mg/kg dose decreased serum T (1.18 ± 0.18 ng/ml)as well as testis and body weights. Direct action of the DEHP metabolite, monoethylhexylphthalate (MEHP), on Leydig cell steroidogenic capacity was investigated in vitro. MEHP treatment at a low concentration (100 mM) increased LH-stimulated T production, whereas 10 mM concentrations were inhibitory. In conclusion, data from the present study indicate that DEHP has a biphasic effect on Leydig cell function, with low dose exposures advancing the onset of puberty. High doses of DEHP, which are antiandrogenic, may also be outside the range of real environmental exposure levels.
Key words: Androgen •
Puberty •
Steroidogenesis •
Testis •
Endocrine Disruptor •
Toxicology
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