Biphasic effects of postnatal exposure to diethylhexylphthalate on the timing of puberty in male rats

Ren Shan Ge, Guo Rong Chen, Qiang Dong, Benson Akingbemi, Chantal M. Sottas, Michelle Santos, Stuart C. Sealfon, Daniel J. Bernard, Matthew P. Hardy

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Phthalate esters such as di(2-ethylhexyl)phthalate (DEHP), which are commonly found in cosmetics and 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 (eg, 10 mg/kg body weight) may stimulate androgen production. In the present study, the potential of phthalate exposure 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 the 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 with 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 testes 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 μM) increased luteinizing hormone-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 exposure advancing the onset of puberty. High doses of DEHP, which are anti-androgenic, may also be outside the range of real environmental exposure levels.

Original languageEnglish
Pages (from-to)513-520
Number of pages8
JournalJournal of Andrology
Volume28
Issue number4
DOIs
StatePublished - Jul 2007

Keywords

  • Androgen
  • Endocrine disruptor
  • Puberty
  • Steroidogenesis
  • Testis
  • Toxicology

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