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CHRONIC EXPOSURE TO DI(2-ETHYLHEXYL) PHTHALATE (DEHP) DELAYS PUBERTY AND REDUCES ANDROGEN-DEPENDENT TISSUE WEIGHTS IN THE MALE RAT
Citation:
Gray Jr., L E., J. R. FURR, C. R. LAMBRIGHT, AND J. S. OSTBY. CHRONIC EXPOSURE TO DI(2-ETHYLHEXYL) PHTHALATE (DEHP) DELAYS PUBERTY AND REDUCES ANDROGEN-DEPENDENT TISSUE WEIGHTS IN THE MALE RAT. Presented at Society for the Study of Reproduction, Vancouver, British Columbia, Canada, August 1-4, 2004.
Description:
DEHP, dibutyl (DBP)-, and benzyl butyl (BBP)- phthalate are plasticizers that cause adverse developmental reproductive effects in laboratory animals. They alter sexual differentiation in the rat by reducing fetal Leydig cell testosterone synthesis and insl3 mRNA levels, which in turn, result in abnormalities of the testis, ubernaculum, epididymis and other androgen-dependent tissues. When exposure includes the pubertal stage of life, DBP and BBP delay puberty and reduce androgen-dependent tissue weights. Although it was reported as early as 1986 that chronic DEHP treatment reduces testosterone levels and androgen-dependent organ weights, a recent report claimed that chronic DEHP-treatment actually elevated testosterone and estradiol levels in male rats and the authors proposed that DEHP would accelerate male puberty. However, since the age at puberty has never been measured in male rats exposed chronically to DEHP, one of the objectives of this study was to determine if chronic administration of DEHP would delay puberty as do DBP and BBP, or if DEHP treatment would accelerate puberty, as the model suggested. In the current study, pregnant SD rats were dosed by gavage with DEHP from gestational day 8 to day 17 of lactation with 0, 11, 33, 100 or 300 mg/kg/d. Dosing was continued in 2-3 males/litter from day 18 until necropsy at 63-65 days of age. DEHP treatment delayed puberty at 100 and 300 mg/kg/d and these treated males were heavier when preputial separation occurred. In addition, all five androgen-dependent organ weights were reduced in the 300 mg/kg/d dose group (p<0.001). Serum testosterone and estradiol levels were slightly, but not significantly, reduced in DEHP treated male rats. Liver weights were increased and adrenal weights were decreased in all DEHP dose groups. In addition to this study, Noriega et al. (2004) found that subchronic DEHP administration after weaning also delays puberty and reduces sex accessory gland sizes in an "antiandrogenic" manner. In summary, chronic DEHP, DBP and BBP exposures alter the androgen-signaling pathway in developing animals in an "antiandrogenic" fashion. It is likely that they all act via a common mode of action that involves altered Leydig cell maturation and reduced hormone synthesis.