围生期母鼠双酚A暴露对断乳期雄性子代大鼠脑组织中雌激素受体mRNA表达的影响

目的 研究围生期母鼠双酚A(BPA)暴露对断乳期雄性子代大鼠脑中雌激素受体(ERα和ERβ)mRNA表达的影响,探索BPA影响脑发育的机制.方法 雌雄SD大鼠分笼饲养,按雌:雄为2:1合笼交配.将妊娠大鼠随机分为高、中、低剂量组[BPA的染毒浓度分别为100、20、2 mg/(kg·d)]和1个对照组(食用色拉油)进行灌胃染毒.在出生后第21天,取雄性仔鼠脑组织,提取总RNA.于260、280 nm处测定RNA的浓度及纯度,采用琼脂糖凝胶电泳分析RNA完整性.以核糖体蛋白L19(RPL19)作为内参照,采用RT-PCR方法检测脑组织中ERα和ERβmRNA水平的表达.结果 高、中、低剂量组雄性仔鼠脑组织中ERα、ERβ与RPL19的积分吸光度值之比均高于对照组,差异均有统计学意义(P＜0.05).结论 围生期暴露于BPA可以增加断乳期雄性子代大鼠脑组织中ERα和ERβ mRNA的表达,提示受体表达的改变可能是BPA影响脑发育的机制之一.     

Maternal Arsenic Exposure and Impaired Glucose Tolerance during Pregnancy

Background

Accumulating evidence has shown an increased risk of type 2 diabetes in general populations exposed to arsenic, but little is known about exposures during pregnancy and the association with gestational diabetes (GD).

Objectives

We studied 532 women living proximate to the Tar Creek Superfund Site to investigate whether arsenic exposure is associated with impaired glucose tolerance during pregnancy.

Methods

Blood glucose was measured between 24 and 28 weeks gestation after a 1-hr oral glucose tolerance test (GTT) as part of routine prenatal care. Blood and hair were collected at delivery and analyzed for arsenic using inductively coupled plasma mass spectrometry with dynamic reaction cell.

Results

Arsenic concentrations ranged from 0.2 to 24.1 μg/L (ppb) (mean ± SD, 1.7 ±1.5) and 1.1 to 724.4 ng/g (ppb) (mean ± SD, 27.4 ± 61.6) in blood and hair, respectively. One-hour glucose levels ranged from 40 to 284 mg/dL (mean ± SD, 108.7 ± 29.5); impaired glucose tolerance was observed in 11.9% of women when using standard screening criterion (> 140 mg/dL). Adjusting for age, Native-American race, prepregnancy body mass index, Medicaid use, and marital status, women in the highest quartile of blood arsenic exposure had 2.8 higher odds of impaired GTT than women in the lowest quartile of exposure (95% confidence interval, 1.1–6.9) (p-trend = 0.008).

Conclusions

Among this population of pregnant women, arsenic exposure was associated with increased risk of impaired GTT at 24–28 weeks gestation and therefore may be associated with increased risk of GD.     

In Utero Exposure to Bisphenol A Shifts the Window of Susceptibility for Mammary Carcinogenesis in the Rat

Background

Bisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.

Objective

Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.

Methods

Pregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.

Results

Prenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.

Conclusions

Our study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.     

Polycarbonate Bottle Use and Urinary Bisphenol A Concentrations

Background

Bisphenol A (BPA) is a high-production-volume chemical commonly used in the manufacture of polycarbonate plastic. Low-level concentrations of BPA in animals and possibly in humans may cause endocrine disruption. Whether ingestion of food or beverages from polycarbonate containers increases BPA concentrations in humans has not been studied.

Objectives

We examined the association between use of polycarbonate beverage containers and urinary BPA concentrations in humans.

Methods

We conducted a nonrandomized intervention of 77 Harvard College students to compare urinary BPA concentrations collected after a washout phase of 1 week to those taken after an intervention week during which most cold beverages were consumed from polycarbonate drinking bottles. Paired t-tests were used to assess the difference in urinary BPA concentrations before and after polycarbonate bottle use.

Results

The geometric mean urinary BPA concentration at the end of the washout phase was 1.2 μg/g creatinine, increasing to 2.0 μg/g creatinine after 1 week of polycarbonate bottle use. Urinary BPA concentrations increased by 69% after use of polycarbonate bottles (p < 0.0001). The association was stronger among participants who reported ≥ 90% compliance (77% increase; p < 0.0001) than among those reporting < 90% compliance (55% increase; p = 0.03), but this difference was not statistically significant (p = 0.54).

Conclusions

One week of polycarbonate bottle use increased urinary BPA concentrations by two-thirds. Regular consumption of cold beverages from polycarbonate bottles is associated with a substantial increase in urinary BPA concentrations irrespective of exposure to BPA from other sources.     

孕期暴露双酚A对不同性别仔鼠体重及糖代谢影响的实验研究

目的研究孕期暴露双酚A（BPA）对不同性别仔鼠体重及糖代谢的影响。方法 SD孕鼠从妊娠第6 d至哺乳期结束饮用含1μg/ml双酚A的水,测量仔鼠出生体重及断乳后的体重变化,同时测量断乳后第4周仔鼠空腹血糖、血清胰岛素及脂联素水平。结果与对照组比较,实验组子代雌鼠出生体重、断乳后体重均显著增高（P〈0.05）;空腹血糖和胰岛素水平也显著增高（P〈0.05）。实验组子代雄鼠体重、空腹血糖和胰岛素水平与对照组比较差异无统计学意义（P〉0.05）。实验组仔鼠（雌＋雄）血清脂联素水平明显低于对照组,差异有统计学意义（P〈0.05）。结论发育早期暴露双酚A对仔鼠体重影响具有性别差异;可引起子代雌鼠糖代谢紊乱,出现胰岛素抵抗现象;血清脂联素水平降低是胰岛素抵抗发生的原因之一。     

Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy.Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure.Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure.Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA.Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended.     

围生期双酚A暴露对雄鼠子一代生长和脑发育形态的影响

[目的]研究围生期双酚A暴露对雄性子一代(F1)出生后的生长及脑组织病理形态的影响。[方法]对母鼠从妊娠第11天直至产后断乳双酚A灌胃染毒,高、中、低剂量分别为2、20、100 mg/kg,同时设立对照组。每个剂量组分别在出生后第1、5、10、15、21、30、45天记录子代体重,各时相点取6只F1雄性子代大鼠,采用断头处死法,迅速取脑组织固定包埋进行组织病理学检测。[结果]中、低剂量组雄性子代在出生后(postnatal day,PND)第5、10、15、21、 30、45天体重均高于对照组,统计学上差异有非常显著性(P<0．01)。高剂量组雄性子代PND1、5、10体重均低于对照组, 差异有非常显著性(P<0．01)。组织病理学(HE染色)结果显示PND15、21、30各剂量组脑组织均有不同程度的异常改变, 主要表现为海马CA3区锥体细胞和大脑皮质神经元发生核固缩变性,其中高剂量组和中剂量组较为严重。在PND45各染毒组异常细胞减少,海马和皮质神经细胞总数减少。[结论]围生期暴露于双酚A可以影响F1雄性大鼠子代出生后的生长和引起脑组织的病理形态学改变。     

Temporal variability and predictors of urinary bisphenol A concentrations in men and women

BACKGROUND: Bisphenol A (BPA) is used to manufacture polymeric materials, such as polycarbonate plastics, and is found in a variety of consumer products. Recent data show widespread BPA exposure among the U.S. population. OBJECTIVE: Our goal in the present study was to determine the temporal variability and predictors of BPA exposure. METHODS: We measured urinary concentrations of BPA among male and female patients from the Massachusetts General Hospital Fertility Center. RESULTS: Between 2004 and 2006, 217 urine samples were collected from 82 subjects: 45 women (145 samples) and 37 men (72 samples). Of these, 24 women and men were partners and contributed 42 pairs of samples collected on the same day. Ten women became pregnant during the follow-up period. Among the 217 urine samples, the median BPA concentration was 1.20 microg/L, ranging from below the limit of detection (0.4 microg/L) to 42.6 microg/L. Age, body mass index, and sex were not significant predictors of urinary BPA concentrations. BPA urinary concentrations among pregnant women were 26% higher (-26%, +115%) than those among the same women when not pregnant (p > 0.05). The urinary BPA concentrations of the female and male partner on the same day were correlated (r = 0.36; p = 0.02). The sensitivity of classifying a subject in the highest tertile using a single urine sample was 0.64. CONCLUSION: We found a nonsignificant increase in urinary BPA concentrations in women while pregnant compared with nonpregnant samples from the same women. Samples collected from partners on the same day were correlated, suggesting shared sources of exposure. Finally, a single urine sample showed moderate sensitivity for predicting a subject's tertile categorization.     

Similarity of Bisphenol A Pharmacokinetics in Rhesus Monkeys and Mice: Relevance for Human Exposure

Objective

Daily adult human exposure to bisphenol A (BPA) has been estimated at < 1 μg/kg, with virtually complete first-pass conjugation in the liver in primates but not in mice. We measured unconjugated and conjugated BPA levels in serum from adult female rhesus monkeys and adult female mice after oral administration of BPA and compared findings in mice and monkeys with prior published data in women.

Methods

Eleven adult female rhesus macaques were fed 400 μg/kg deuterated BPA (dBPA) daily for 7 days. Levels of serum dBPA were analyzed by isotope-dilution liquid chromatography–mass spectrometry (0.2 ng/mL limit of quantitation) over 24 hr on day 1 and on day 7. The same dose of BPA was fed to adult female CD-1 mice; other female mice were administered ³H-BPA at doses ranging from 2 to 100,000 μg/kg.

Results

In monkeys, the maximum unconjugated serum dBPA concentration of 4 ng/mL was reached 1 hr after feeding and declined to low levels by 24 hr, with no significant bioaccumulation after seven daily doses. Mice and monkeys cleared unconjugated serum BPA at virtually identical rates. We observed a linear (proportional) relationship between administered dose and serum BPA in mice.

Conclusions

BPA pharmacokinetics in women, female monkeys, and mice is very similar. By comparison with approximately 2 ng/mL unconjugated serum BPA reported in multiple human studies, the average 24-hr unconjugated serum BPA concentration of 0.5 ng/mL in both monkeys and mice after a 400 μg/kg oral dose suggests that total daily human exposure is via multiple routes and is much higher than previously assumed.     

Fetal Growth and Prenatal Exposure to Bisphenol A: The Generation R Study

Background: Prenatal exposure to bisphenol A (BPA) has been associated with adverse birth outcomes, but findings of previous studies have been inconsistent.Objective: We investigated the relation of prenatal BPA exposure with intrauterine growth and evaluated the effect of the number of measurements per subject on observed associations.Methods: This study was embedded in a Dutch population-based prospective cohort study, with urine samples collected during early, mid-, and late pregnancy. The study comprised 219 women, of whom 99 had one measurement, 40 had two measurements, and 80 had three measurements of urinary BPA. Fetal growth characteristics were repeatedly measured by ultrasound during pregnancy and combined with measurements at birth. Linear regression models for repeated measurements of both BPA and fetal growth were used to estimate associations between urinary concentrations of creatinine-based BPA (BPA_CB) and intrauterine growth.Results: The relationship between BPA_CB and fetal growth was sensitive to the number of BPA measurements per woman. Among 80 women with three BPA measurements, women with BPA_CB > 4.22 μg/g crea (creatinine) had lower growth rates for fetal weight and head circumference than did women with BPA_CB < 1.54 μg/g crea, with estimated differences in mean values at birth of –683 g (20.3% of mean) and –3.9 cm (11.5% of mean), respectively. When fewer measurements were available per woman, the exposure–response relationship became progressively attenuated and statistically nonsignificant.Conclusion: Our findings suggest that maternal urinary BPA may impair fetal growth. Because previous studies have shown contradictory findings, further evidence is needed to corroborate these findings in the general population.     

Neonatal Exposure to Bisphenol A and Reproductive and Endocrine Alterations Resembling the Polycystic Ovarian Syndrome in Adult Rats

Background

Bisphenol A (BPA), an endocrine disruptor, is a component of polycarbonate plastics, epoxy resins, and polystyrene. Several studies have reported potent in vivo effects, because BPA behaves as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist.

Objectives

We investigated the effects of neonatal exposure to BPA on the reproductive axis in adult female Sprague-Dawley rats.

Methods

Female rats were injected subcutaneously, daily from postnatal day 1 (PND1) to PND10 with BPA in castor oil at 500 μg/50 μL [BPA500; ~ 10⁻⁴ M, a dose higher than the lowest observed adverse effect level (LOAEL) of 50 mg/kg], 50 μg/50 μL (BPA50), or 5 μg/50 μL (both BPA50 and BPA5 are doses lower than the LOAEL), or castor oil vehicle alone. In adults we studied a) the release of gonadotropin-releasing hormone (GnRH) from hypothalamic explants, b) serum sex hormone levels, and c) ovarian morphology, ovulation, and fertility.

Results

Neonatal exposure to BPA was associated with increased serum testosterone and estradiol levels, reduced progesterone in adulthood, and altered in vitro GnRH secretion. Animals exposed to BPA500 had altered ovarian morphology, showing a large number of cysts. Animals exposed to BPA50 had reduced fertility without changes in the number of oocytes on the morning of estrus, whereas animals exposed to BPA500 showed infertility.

Conclusions

Exposure to high doses of BPA during the period of brain sexual differentiation altered the hypothalamic–pituitary–gonadal axis in female Sprague-Dawley rats. These results have the potential to link neonatal exposure to high doses of BPA in rats with the development of polycystic ovarian syndrome. Studies of doses and routes of administration more consistent with human exposures are needed to determine the relevance of these findings to human health.     

环境雌激素双酚A对小鼠生殖内分泌激素的影响

目的观察双酚A对小鼠体内生殖内分泌激素水平的影响。方法采用放射免疫法分别测定不同剂量双酚A腹腔注射染毒3d及相同剂量双酚A一次染毒后30min、4、12、24、36、48和72h的小鼠血清雌二醇（E：）和睾丸组织睾酮（T）水平。结果不同剂量双酚A染毒3d后,各染毒组T含量明显低于阴性对照组（P〈0．05）,且随着染毒剂量的增加而明显降低;雄性和雌性小鼠血清E2浓度随染毒剂量的增加而逐渐升高,当剂量达到80umol／kg时,明显高于阴性对照组（P〈0．05）。相同剂量双酚A一次染毒后0．5～12h内,小鼠睾丸组织T及血清E2水平迅速下降,之后缓慢上升,72h内可恢复正常水平。结论双酚A对小鼠具有内分泌干扰作用,可引起小鼠组织睾酮水平下降及血清雌二醇水平升高。     

Daily Bisphenol A Excretion and Associations with Sex Hormone Concentrations: Results from the InCHIANTI Adult Population Study

Background

Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited.

Objective

We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations.

Methods

We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography–mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17β-estradiol.

Results

Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42–3.77 ng/mL], and mean excretion was 5.63 μg/day (5th population percentile, 2.1 μg/day; 95th percentile, 16.4 μg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (β = 0.046; 95% CI, 0.015–0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women.

Conclusion

Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.     

Maternal Bisphenol A Exposure Promotes the Development of Experimental Asthma in Mouse Pups

Background

We recently reported that various environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators in vitro.

Objectives

We hypothesized that environmental estrogens would enhance allergic sensitization as well as bronchial inflammation and responsiveness. To test this hypothesis, we exposed fetal and neonatal mice to the common environmental estrogen bisphenol A (BPA) via maternal loading and assessed the pups’ response to allergic sensitization and bronchial challenge.

Methods

Female BALB/c mice received 10 μg/mL BPA in their drinking water from 1 week before impregnation to the end of the study. Neonatal mice were given a single 5 μg intraperitoneal dose of ovalbumin (OVA) with aluminum hydroxide on postnatal day 4 and 3% OVA by nebulization for 10 min on days 13, 14, and 15. Forty-eight hours after the last nebulization, we assessed serum IgE antibodies to OVA by enzyme-linked immunosorbent assay (ELISA) and airway inflammation and hyperresponsiveness by enumerating eosinophils in bronchoalveolar lavage fluid, whole-body barometric plethysmography, and a forced oscillation technique.

Results

Neonates from BPA-exposed mothers responded to this “suboptimal” sensitization with higher serum IgE anti-OVA concentrations compared with those from unexposed mothers (p < 0.05), and eosinophilic inflammation in their airways was significantly greater. Airway responsiveness of the OVA-sensitized neonates from BPA-treated mothers was enhanced compared with those from unexposed mothers (p < 0.05).

Conclusions

Perinatal exposure to BPA enhances allergic sensitization and bronchial inflammation and responsiveness in a susceptible animal model of asthma.     

孕哺期双酚A暴露对雄性仔鼠海马即早基因表达的影响

目的探讨孕哺期双酚A暴露对雄性仔鼠海马即早基因c-fos、c-jun、egr-1和Arc表达的影响。方法低、中、高剂量双酚A组孕鼠分别灌胃染毒2mg／kg、10mg／kg、50mg／kg双酚A,对照组孕鼠用同体积的玉米油灌胃,至哺乳期结束,检测雄性仔鼠的学习记忆能力以及海马c-los、c-jun、egr-1和Arc水平。结果双酚A组雄性仔鼠在水迷宫中的逃离潜伏期明显高于对照组,海马c-los、c-jun和egr-1水平显著低于对照组,具有一定的剂量一反应关系。结论孕哺期双酚A暴露损害雄性仔鼠学习记忆能力的机制可能与海马c-fos、c-jull和egr-1表达降低有关。     

Prenatal and Postnatal Bisphenol A Exposure and Body Mass Index in Childhood in the CHAMACOS Cohort

Background: Bisphenol A (BPA), a widely used endocrine-disrupting chemical, has been associated with increased body weight and fat deposition in rodents.Objectives: We examined whether prenatal and postnatal urinary BPA concentrations were associated with body mass index (BMI), waist circumference, percent body fat, and obesity in 9-year-old children (n = 311) in the CHAMACOS longitudinal cohort study.Methods: BPA was measured in spot urine samples collected from mothers twice during pregnancy and from children at 5 and 9 years of age.Results: Prenatal urinary BPA concentrations were associated with decreased BMI at 9 years of age in girls but not boys. Among girls, being in the highest tertile of prenatal BPA concentrations was associated with decreased BMI z-score (β = –0.47, 95% CI: –0.87, –0.07) and percent body fat (β = –4.36, 95% CI: –8.37, –0.34) and decreased odds of overweight/obesity [odds ratio (OR) = 0.37, 95% CI: 0.16, 0.91] compared with girls in the lowest tertile. These findings were strongest in prepubertal girls. Urinary BPA concentrations at 5 years of age were not associated with any anthropometric parameters at 5 or 9 years, but BPA concentrations at 9 years were positively associated with BMI, waist circumference, fat mass, and overweight/obesity at 9 years in boys and girls.Conclusions: Consistent with other cross-sectional studies, higher urinary BPA concentrations at 9 years of age were associated with increased adiposity at 9 years. However, increasing BPA concentrations in mothers during pregnancy were associated with decreased BMI, body fat, and overweight/obesity among their daughters at 9 years of age.     

Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults

Background: Bisphenol A (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 μg/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans.Objective: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans.Methods: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes.Results: The geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 μg/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0–2.4 ng/mL).Conclusions: Because activation of nuclear-receptor–mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults.     

Three-Generation Study of Male Rats Gestationally Exposed to High Butterfat and Bisphenol A: Impaired Spermatogenesis,Penetrance with Reduced Severity

Gestational high butterfat (HFB) and/or endocrine disruptor exposure was previously found to disrupt spermatogenesis in adulthood. This study addresses the data gap in our knowledge regarding transgenerational transmission of the disruptive interaction between a high-fat diet and endocrine disruptor bisphenol A (BPA). F0 generation Sprague-Dawley rats were fed diets containing butterfat (10 kcal%) and high in butterfat (39 kcal%, HFB) with or without BPA (25 µg/kg body weight/day) during mating and pregnancy. Gestationally exposed F1-generation offspring from different litters were mated to produce F2 offspring, and similarly, F2-generation animals produced F3-generation offspring. One group of F3 male offspring was administered either testosterone plus estradiol-17β (T + E2) or sham via capsule implants from postnatal days 70 to 210. Another group was naturally aged to 18 months. Combination diets of HFB + BPA in F0 dams, but not single exposure to either, disrupted spermatogenesis in F3-generation adult males in both the T + E2-implanted group and the naturally aged group. CYP19A1 localization to the acrosome and estrogen receptor beta (ERbeta) localization to the nucleus were associated with impaired spermatogenesis. Finally, expression of methyl-CpG-binding domain-3 (MBD3) was consistently decreased in the HFB and HFB + BPA exposed F1 and F3 testes, suggesting an epigenetic component to this inheritance. However, the severe atrophy within testes present in F1 males was absent in F3 males. In conclusion, the HFB + BPA group demonstrated transgenerational inheritance of the impaired spermatogenesis phenotype, but severity was reduced in the F3 generation.