Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague-Dawley rats

Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 07/2011; 255(3):261-70. DOI: 10.1016/j.taap.2011.07.009
Source: PubMed

ABSTRACT Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure in the range of 0.02-0.2μg/kgbw/d (25th-95th percentiles). The current study used LC/MS/MS to measure placental transfer and concentrations of aglycone (receptor-active) and conjugated (inactive) BPA in tissues from Sprague-Dawley rats administered deuterated BPA (100μg/kg bw) by oral and IV routes. In adult female rat tissues, the tissue/serum concentration ratios for aglycone BPA ranged from 0.7 in liver to 5 in adipose tissue, reflecting differences in tissue perfusion, composition, and metabolic capacity. Following IV administration to dams, placental transfer was observed for aglycone BPA into fetuses at several gestational days (GD), with fetal/maternal serum ratios of 2.7 at GD 12, 1.2 at GD 16, and 0.4 at GD 20; the corresponding ratios for conjugated BPA were 0.43, 0.65, and 3.7. These ratios were within the ranges observed in adult tissues and were not indicative of preferential accumulation of aglycone BPA or hydrolysis of conjugates in fetal tissue in vivo. Concentrations of aglycone BPA in GD 20 fetal brain were higher than in liver or serum. Oral administration of the same dose did not produce measurable levels of aglycone BPA in fetal tissues. Amniotic fluid consistently contained levels of BPA at or below those in maternal serum. Concentrations of aglycone BPA in tissues of neonatal rats decreased with age in a manner consistent with the corresponding circulating levels. Phase II metabolism of BPA increased with fetal age such that near-term fetus was similar to early post-natal rats. These results show that concentrations of aglycone BPA in fetal tissues are similar to those in other maternal and neonatal tissues and that maternal Phase II metabolism, especially following oral administration, and fetal age are critical in reducing exposures to the fetus.

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Available from: Jeffrey Fisher, Sep 28, 2015
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    • "All the experimental procedures were performed under the national guidelines on the proper care and use of animals in laboratory research and the Institutional Ethics Committee for the use of laboratory animals approved the study. The doses of BPA investigated in this study are much lower than the published " No Observed Adverse Effective Levels " (NOAEL) dose, i.e. 5 mg/kg body weight/day in rodents (Doerge et al., 2011; NTP, 2001). At the same time, one of the dose of BPA used in the present study (50 ␮g/kg bodyweight/day) corresponds to the " Tolerable Daily Intake " (TDI) for humans, as indicated by the U.S Environmental Protection Agency (EPA) and also by the European Food Safety Authority. "
    Dataset: Shikha3
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    • "mg/kg body weight/day in rodents (Doerge et al., 2011; NTP 2001). At the same time, one of the dose of BPA used in the present study (50 µg/kg bodyweight /day) corresponds to the " Tolerable Daily Intake " (TDI) for humans, as indicated by the U.S Environmental Protection Agency (EPA) and also by the European Food Safety Authority. "
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    ABSTRACT: Bisphenol A (BPA) is a well-known plasticizer and xenoestrogen that is responsible for manyacquired reproductive difficulties, especially in men. Despite the prevalence of BPA in society, the mechanism behind reproductive deficits remains elusive. The present study investigates the modeofBPA's action by evaluating its effect on the expression of inducible nitric oxide synthase (iNOS) and steriodogenic acute regulatoryprotein(StAR) in male mice testis.Swiss albino mice were treated with a range BPA concentrations of 0.5, 50 and 100 μg/kg body weight/day intraperitoneally for 60 days. Several markers of oxidative stress and male fertility were investigated. Nitrite levels, malondialdehyde levelsand testicular injury scores were elevated whereas the sperm count, serum testosterone levels and catalase activity were reduced in the BPA groups. Mechanistically, an increase in iNOS expression was observed in the testiswhereas the expression of the StAR was down regulated in the BPA treated mouse.These results suggest that BPA induces oxidative stress by altering the expression ofiNOS, which consequently leads to the down regulation of StAR expressionin the testis of male mouse.
    Environmental Toxicology and Pharmacology 10/2014; 39(1). DOI:10.1016/j.etap.2014.09.014 · 2.08 Impact Factor
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    • "While more than one PBPK model has been developed for BPA (Christensen et al. 2013, Doerge et al. 2011a b, 2012, Fisher et al. 2011, Shin et al. 2010, Taylor et al. 2011, Teeguarden et al. 2013, Vom Saal et al. 2014, Yang et al. 2013), we focus here on the human BPA PBPK models developed by Teeguarden et al. (2005), Fisher et al. (2011), and Yang et al. (2013). The work by Teeguarden and colleagues is of interest because it is a modification and extension of the original E2 PBPK model (Plowchalk and Teeguarden 2002). "
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    ABSTRACT: Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse and non-adverse effects following human exposure to low doses of estrogen active chemicals (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly understood. This review summarizes our current understanding of the pharmacological action with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmacological characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health.
    Critical Reviews in Toxicology 08/2014; 44(8). DOI:10.3109/10408444.2014.930813 · 5.10 Impact Factor
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