Background Bisphenol A Research Articles

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

BackgroundBisphenol 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.ObjectivesWe investigated the effects of neonatal exposure to BPA on the reproductive axis in adult female Sprague-Dawley rats.MethodsFemale 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.ResultsNeonatal 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.ConclusionsExposure 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.

Association of Urinary Bisphenol A Concentration with Heart Disease: Evidence from NHANES 2003/06

BackgroundBisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years.Methodology and FindingsA cross-sectional analysis of NHANES: subjects were n = 1455 (2003/04) and n = 1493 (2005/06) adults aged 18–74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value = 0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA = 1.33, 95%CI: 1.01 to 1.75, p = 0.043) and in pooled data (OR = 1.42, CI: 1.17 to 1.72, p = 0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR = 1.24, CI: 1.10 to 1.40, p = 0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant.ConclusionsHigher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.

Peroxisome Proliferator–Activated Receptor-γ Mediates Bisphenol A Inhibition of FSH-Stimulated IGF-1, Aromatase, and Estradiol in Human Granulosa Cells

BackgroundBisphenol A (BPA), a chemical used as a plasticizer, is a potent endocrine disruptor that, even in low concentrations, disturbs normal development and functions of reproductive organs in different species.ObjectivesWe investigated whether BPA affects human ovarian granulosa cell function.MethodsWe treated KGN granulosa cells and granulosa cells from subjects undergoing in vitro fertilization (IVF) with follicle-stimulating hormone (FSH), BPA, or BPA plus FSH in a dose- and time-dependent manner. We then evaluated expression of insulin-like growth factor 1 (IGF-1), aromatase, and transcription factors known to mediate aromatase induction by FSH [including steroidogenic factor-1 (SF-1), GATA4, cAMP response element binding protein-1 (CREB-1), and peroxisome proliferator–activated receptor-γ (PPARγ)], as well as 17β-estradiol (E2) secretion. KGN cells were transfected with a PPARγ-containing vector, followed by assessment of aromatase and IGF-I expression.ResultsBPA reduced FSH-induced IGF-1 and aromatase expression and E2 secretion in a dose-dependent fashion. Similar effects on aromatase were observed in IVF granulosa cells. SF-1 and GATA4, but not CREB-1, were reduced after BPA treatment, although PPARγ, an inhibitor of aromatase, was significantly up-regulated by BPA in a dose-dependent manner, with simultaneous decrease of aromatase. Overexpression of PPARγ in KGN cells reduced FSH-stimulated aromatase and IGF-1 mRNAs, with increasing concentrations of the transfected expression vector, mimicking BPA action. Also, BPA reduced granulosa cell DNA synthesis without changing DNA fragmentation, suggesting that BPA does not induce apoptosis.ConclusionsOverall, the data demonstrate that BPA induces PPARγ, which mediates down-regulation of FSH-stimulated IGF-1, SF-1, GATA4, aromatase, and E2 in human granulosa cells. These observations support a potential role of altered steroidogenesis and proliferation within the ovarian follicular compartment due to this endocrine disruptor.

Does rapid metabolism ensure negligible risk from bisphenol A?

BackgroundBisphenol A (BPA) risks are being evaluated by many regulatory bodies because exposure is widespread and the potential exists for toxicity at low doses.ObjectiveWe evaluated evidence that BPA is cleared more rapidly in humans than in rats in relation to BPA risk assessment.DiscussionThe European Food Safety Authority (EFSA) relied on pharmacokinetic evidence to conclude that rodent toxicity data are not directly relevant to human risk assessment. Further, the EFSA argues that rapid metabolism will result in negligible exposure during the perinatal period because of BPA glucuronidation in pregnant women or sulfation in newborns. These arguments fail to consider the deconjugation of BPA glucuronide in utero by β-glucuronidase, an enzyme that is present in high concentrations in placenta and various other tissues. Further, arylsulfatase C, which reactivates endogenous sulfated estrogens, develops early in life and so may deconjugate BPA sulfate in newborns. Biomonitoring studies and laboratory experiments document free BPA in rat and human maternal, placental, and fetal tissues, indicating that human BPA exposure is not negligible. The pattern of these detections is consistent with deconjugation in the placenta, resulting in fetal exposure. The tolerable daily intake set by the EFSA (0.05 mg/kg/day) is well above effect levels reported in some animal studies.ConclusionThis potential risk should not be dismissed on the basis of an uncertain pharmacokinetic argument. Rather, risk assessors need to decipher the BPA dose response and apply it to humans with comprehensive pharmacokinetic models that account for metabolite deconjugation.

Polycarbonate bottle use and urinary bisphenol A concentrations.

BackgroundBisphenol 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.ObjectivesWe examined the association between use of polycarbonate beverage containers and urinary BPA concentrations in humans.MethodsWe 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.ResultsThe 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).ConclusionsOne 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.

Bisphenol A levels in blood and urine in a Chinese population and the personal factors affecting the levels

The objective of the study was to describe the background bisphenol A (BPA) levels in urine and serum of a Chinese population without occupational exposure and to examine the personal characteristics influencing these levels. Workers from 10 factories and their family members were recruited and their peripheral blood and spot urine samples were collected. The conjugated and free BPA of the samples was assayed with high-performance liquid chromatography. The exposure levels were checked with 2-independent-samples test, and the potential personal factors influencing exposure levels were analyzed using nonlinear correlation. Of the total of 952 subjects participating in the study, urine and blood samples were taken from 97% and 93% of them, respectively. The detectable rates were 50% for urine samples and 17% for serum samples, given the detection limit of 0.31 microg/L for urine and 0.39 microg/L for serum. The arithmetic mean (AM) and geometric mean (GM) of non-creatinine-adjusted urinary BPA level were 10.45 and 0.87 microg/L, which became 24.93 and 0.38 microg/g Cr after the creatinine level was adjusted; serum BPA levels were 2.84 microg/L (AM) and 0.18 microg/L (GM). Males and those with smoking habit had higher biological burden of BPA. The results indicated that half of the study subjects had detectable BPA in their urine samples. BPA levels were influenced by gender and smoking status. The sources of non-occupational BPA exposures should be explored.

Neonatal Exposure to Bisphenol A Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats

BackgroundBisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins, and polystyrene and is found in many products. Several reports have revealed potent in vivo effects, because BPA acts as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist.ObjectivesWe analyzed the effects of neonatal exposure to BPA on the reproductive axis of female Sprague-Dawley rats.MethodsFemale rats were injected subcutaneusly, daily, from postnatal day 1 (PND1) to PND10 with BPA [500 μg/50 μL (high) or 50 μg/50 μL (low)] in castor oil or with castor oil vehicle alone. We studied body weight and age at vaginal opening, estrous cycles, and pituitary hormone release in vivo and in vitro, as well as gonadotropin-releasing hormone (GnRH) pulsatility at PND13 and in adults. We also analyzed two GnRH-activated signaling pathways in the adults: inositol-triphosphate (IP3), and extracellular signal-regulated kinase1/2 (ERK1/2).ResultsExposure to BPA altered pituitary function in infantile rats, lowering basal and GnRH-induced luteinizing hormone (LH) and increasing GnRH pulsatility. BPA dose-dependently accelerated puberty onset and altered estrous cyclicity, with the high dose causing permanent estrus. In adults treated neonatally with BPA, GnRH-induced LH secretion in vivo was decreased and GnRH pulsatility remained disrupted. In vitro, pituitary cells from animals treated with BPA showed lower basal LH and dose-dependently affected GnRH-induced IP3 formation; the high dose also impaired GnRH-induced LH secretion. Both doses altered ERK1/2 activation.ConclusionsNeonatal exposure to BPA altered reproductive parameters and hypothalamic–pituitary function in female rats. To our knowledge, these results demonstrate for the first time that neonatal in vivo BPA permanently affects GnRH pulsatility and pituitary GnRH signaling.

Oral exposure to bisphenol a increases dimethylbenzanthracene-induced mammary cancer in rats.

BackgroundBisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.ObjectivesBased on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer.MethodsWe exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age.ResultsThe combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age.ConclusionsThe data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.

Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women

BackgroundBisphenol 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.ObjectiveOur goal in the present study was to determine the temporal variability and predictors of BPA exposure.MethodsWe measured urinary concentrations of BPA among male and female patients from the Massachusetts General Hospital Fertility Center.ResultsBetween 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 μg/L, ranging from below the limit of detection (0.4 μg/L) to 42.6 μg/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.ConclusionWe 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.

Exposure to bisphenol A from bis-glycidyl dimethacrylate–based dental sealants

Bisphenol A (BPA) is a common component of composites and dental sealants. The potential exists for human exposure after sealant placement. The authors prospectively enrolled 15 men in an exposure assessment study; 14 completed the study. After placement of clinically appropriate amounts of one of two sealants, the authors measured BPA in saliva and urine samples collected at prescribed intervals after the sealants were placed. They used selective and sensitive isotope-dilution mass-spectrometry-based methods for BPA measurements, thus providing the most reliable results. Helioseal F (Ivoclar Vivadent, Amherst, N.Y.) leached negligible amounts of BPA. Urinary and salivary BPA levels in subjects who received these sealants were similar to baseline levels. Delton Light Cure (LC) Opaque pit-and-fissure sealant (Dentsply/Ash, York, Pa.) leached more BPA, resulting in low-level BPA exposures similar to those used in laboratory animal testing. BPA exposure after Delton LC sealant placement was significantly higher than exposure after placement of Helioseal F. Patients treated with Delton LC had significantly higher doses of BPA (110 microg) than did those treated with Helioseal F (5.5 microg) (P < .0001). Placement of clinically relevant amounts of Delton LC sealant resulted in low-level BPA exposure; however, exposure was negligible after placement of Helioseal F. Saliva collection after sealant placement likely reduced systemic absorption of BPA from dental sealants. Sealants should remain a useful part of routine preventive dental practice, especially those that leach negligible amounts of BPA. Dental sealants may be a point source for low-level BPA exposure at levels that show health effects in rodents. Further research is required to determine whether human exposure to BPA at these levels causes adverse effects.