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.
    Environment international 10/2015; 83. DOI:10.1016/j.envint.2015.06.005 · 5.56 Impact Factor
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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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    ABSTRACT: Polymer flexibility and elasticity is enhanced by plasticizers. However, plasticizers are often not covalently bound to plastics, and thus can leach from products into the environment. Much research effort has focused on their effects in mammalian species, but data on aquatic species are scarce. In this study, Western clawed frog (Silurana tropicalis) embryos were exposed to 1.3, 12.3, and 128.7mg/L monomethyl phthalate (MMP) until the juvenile stage (11weeks) and to 1.3mg/L MMP until the adult stage (51weeks). MMP decreased survival, hastened metamorphosis, and biased the sex ratio toward males (2M:1F) at the juvenile stage without altering the expression of a subset of thyroid hormone-, sex steroid-, cellular stress- or transcription regulation-related genes in the juvenile frog livers. At the adult stage, exposure to MMP did not have significant adverse health effects, except that females had larger interocular distance and the expression of the heat shock protein 70 was decreased by 60% in the adult liver. In conclusion, this study shows that MMP is unlikely to threaten amphibian populations as only concentrations four orders of magnitude higher than the reported environmental concentrations altered the animal physiology. This is the first complete investigation of the effects of phthalates in a frog species, encompassing the entire life cycle of the organisms. Copyright © 2015. Published by Elsevier Inc.
    General and Comparative Endocrinology 02/2015; 219. DOI:10.1016/j.ygcen.2015.01.019 · 2.47 Impact Factor
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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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    ABSTRACT: Phthalate esters are widely used plasticizers that are present in many daily used products. Although some of their reproductive effects have been reported, pubertal development effects from prenatal exposure to phthalates awaits further investigations. A population based birth cohort was established (N=437 at baseline) with maternal exposure to phthalates assessed in urine collected at the third trimester of pregnancy in 2001 and 2002. Their 133 children with prenatal phthalates exposure were followed up for the outcomes of pubertal development by sequential physical examinations at eight and 11 years old in 2009 and 2012. Urinary concentrations of major phthalate metabolites (i.e., mono-2-ethylhexyl phthalate [MEHP], mono-(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], mono-(2-ethyl-5-oxohexyl) phthalate [MEOHP], mono-butyl phthalate [MBP], mono-benzyl phthalate [MBzP], monomethyl phthalate [MMP], and mono-ethyl phthalate [MEP]) were determined using liquid chromatography linked to tandem mass spectrometry. The reproductive development measurements included bone age (for both genders), testicle size (for boys), uterus size, and ovarian volume (for girls). We reported results of 133 children with complete data by applying generalized estimating equations for the repeated continuous outcomes. After controlling for Tanner stage, we detected a significant association between reduced uterus size and increasing phthalate exposure in the 2(nd) tertile relative to the 1st tertile of creatinine-corrected MEHP (B=-0.40; 95% C.I.: -0.73, -0.07, relative to the 1st tertile) and total DEHP (B=-0.39, 95% C.I.:-0.66, -0.01 for the 2nd tertile and B=0.34, 95% C.I.: -0.67, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend among girls. MBzP was also found negatively associated with bone age/chronological age ratio (B=-0.07, 95% CI: -0.13, -0.01 for the 3rd tertile, relative to the 1st tertile) with a linear trend for girls. We found no evidence of an association between phthalate exposure and ovarian volume or testicle size. This analysis suggests phthalate exposure may affect specific pubertal development characteristics in human beings. Further studies with larger sample sizes and longer follow-up period are warranted. Copyright © 2014. Published by Elsevier Inc.
    Environmental Research 11/2014; 136C:324-330. DOI:10.1016/j.envres.2014.10.026 · 4.37 Impact Factor
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