Pubertal Administration of DEHP Delays Puberty, Suppresses Testosterone Production, and Inhibits Reproductive Tract Development in Male Sprague-Dawley and Long-Evans Rats

Division of Neuroscience, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.
Toxicological Sciences (Impact Factor: 3.85). 07/2009; 111(1):163-78. DOI: 10.1093/toxsci/kfp129
Source: PubMed


Although is clear that exposure to high dosage levels of some phthalates delays the onset of puberty in the male rat, it has been hypothesized that low levels of di(2-ethylhexyl) phthalate (DEHP) accelerate puberty by enhancing testicular androgen synthesis. The current study was designed to determine if the dose response to DEHP was nonmonotonic, as hypothesized. Pubertal administration of DEHP delayed the onset of puberty and reduced androgen-dependent tissue weights in both Long-Evans (LE) and Sprague-Dawley (SD) male rats 300 and 900 mg DEHP/kg/day. These effects were generally of greater magnitude in LE than SD rats. By contrast, alterations in testis histopathology (300 and 900 mg/kg/day) were more severe in SD than in LE rats. Taken together, these results suggest that DEHP may be acting on the pubertal male rat testis via two modes of action; one via the Leydig cells and the other via the Sertoli cells. Treatment with DEHP generally reduced serum testosterone and increased serum luteinizing hormone (LH) levels, demonstrating that the reduction in testosterone was due to the effect of DEHP on the testis and not via an inhibition of LH from hypothalamic-pituitary axis. Testosterone production ex vivo (with and without human chorionic gonadotropin stimulation) was consistently reduced in males at the time of puberty and shortly thereafter. DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at 10 or 100 mg/kg/day in either LE or SD rats, as some have hypothesized. Taken together, these results do not provide any evidence of a nonmonotonic dose response to DEHP during puberty.

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    • "Such perturbation may be of pathological significance in connection with disorders of the hormonal stress response (Supornsilchai et al., 2007). While others argued that DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at low dose in rats (Noriega et al., 2009). In humans, the process of puberty occurrence is primarily regulated by the endocrine system through chemical messengers , specifically the sexual hormones. "
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    ABSTRACT: Phthalates may interfere with the timing of pubertal development in adolescence and existing studies have shown inconsistent results. This study aims to assess the associations of pubertal onset and progression with urinary concentrations of phthalate metabolites in school-aged boys and girls. Using isotope-dilution liquid chromatography tandem mass spectrometry, we analyzed 6 phthalate metabolites in urine samples of 430 children (222 boys and 208 girls) aged 9.7±2.2years (age range 6.1 to 13.8years) at baseline and 18months of follow-up. The associations of exposures to phthalates with pubertal development such as the testis, breast and pubic hair were evaluated using ordered logistic regression models, adjusting for baseline development stage, current chronological age, current body fat composition, and parental education. Urinary mono-n-butyl phthalate (MnBP) was associated with a 39% increase in the odds of presenting lower pubic hair development stages in boys, and mono (2-ethylhexyl) phthalate (MEHP) (p<0.10), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were associated with 54%-65% increase in the odds of presenting higher breast development stages in girls (p<0.05), while MEHHP and MEOHP were also associated with a 70% increase in the odds of menarche onset (p<0.05). After adjusting for potential confounding variables, the associations of girls' pubertal onset with MnBP, MMP, MEP and MEHP were significant. The odds of girls' breast onset were 4 to 10 times higher in high MnBP, MMP, MEP or MEHP exposure group than in low exposure group. Our findings suggest subtle effects of phthalate metabolites associated with pubertal onset and progression. MnBP exposure may be associated with delayed pubic hair development in boys, while MnBP, MMP, MEP, and MEHP exposures may be associated with breast onset, and MEHP metabolites associated with speedup in breast development progression and earlier menarche onset in girls. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Oct 2015 · Environment international
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    • "Phthalates have been shown to affect later life events such as reproduction in mammalian species (Frederiksen et al., 2012; Giribabu et al., 2014; Higuchi et al., 2003; Noriega et al., 2009; Tyl et al., 2004; Yamasaki et al., 2009). However, there is a critical lack of data on the chronic effects of phthalates in amphibians. "
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    Full-text · Article · Feb 2015 · General and Comparative Endocrinology
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    • "Although most evidence was built on animal models, the adverse affects for phthalates on reproductive physiology and endocrine function has been suggested, but not yet conclusive (Kay et al., 2013; Martinez-Arguelles et al., 2013; Moyer and Hixon, 2012). In research focusing on the male reproductive system, investigators have observed some germ cell decrease, cryptorchidism , lower testosterone concentration, and malformations of the epididymis, vas deferens, seminal vesicles, and prostate gland in rats (Martino-Andrade and Chahoud, 2010; Noriega et al., 2009; Parks et al., 2000; Veeramachaneni and Klinefelter, 2014). For females , it has been suggested that phthalate exposures may modulate circulating hormone concentrations and cellular differentiation of estrogen sensitive tissues and disturb the reproductive system development, resulting in delayed puberty, adverse effects on ovarian function, steroidogenesis, structure of reproductive organs, oocyte development, ovulation, fertility, and progression of pregnancy in animal models (mostly rats) (Kay et al., 2013). "
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