Bisphenol A and human health: A review of the literature

Intrauterine exposure to thiopurines

Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization

One of the more notable public health debates in recent times relates to the purported association between the ubiquitous environmental chemical bisphenol-A (BPA) and a host of chronic diseases. The past 5 years have seen a rapid increase in the evidence linking BPA to obesity, diabetes, and cardiovascular disease in human, population-based epidemiological studies. However, 2 recent reports (1, 2) in the JCEM, while both showing modest associations between BPA (measured in urine) and chronic disease, have achieved little in definitively addressing the controversy. Shankar and Teppala (1), using National Health and Nutritional Examination Survey (NHANES) data, showed a positive association between BPA levels and diabetes, and Wang et al (2) report associations between urinary BPA and obesity and insulin resistance in a cohort of adults aged 40 years or older in China. However, the interpretation of these findings is limited by many caveats that relate to BPA metabolism and its analysis, both in the testing methods currently available and with respect to appropriate adjustment for confounders. There is little doubt that most in vitro and animal data support a relationship existing between BPA and adverse physiological effects in humans. In vitro studies by Hugo et al (3) using BPA at environmentally relevant levels have shown that BPA inhibits adiponectin, a key adipokine that increases insulin sensitivity and decreases tissue inflammation. This study provides direct evidence of the health effects of BPA in human tissue. In addition, AlonsoMagdalena et al (4) showed that mice exposed long term to BPA developed hyperinsulinemia, insulin resistance, and glucose intolerance. Skeptics argue that the animal models are too dissimilar to humans to extrapolate the findings with any confidence, not to mention any certainty. But evidence in this regard is becoming more robust: recent reports demonstrate that BPA metabolism toxicokinetics are very similar in humans, monkeys, and mice and suggest also that human exposure is greater than previously estimated (5). These studies achieved plasma levels in monkeys equivalent to those found on many human biomonitoring studies of .3–4.0 ng/mL. The amount of BPA needed to achieve the serum concentrations in monkeys far exceeded the 2007 U.S. Food and Drug Administration human exposure estimate of .16 g/ kg/d as well as the U.S. Environmental Protection Agency’s daily intake dose of 50 g/kg (5), an indication that human exposure is probably underestimated. It is important to note, however, that exposure to BPA is ubiquitous and apart from food and beverage containers, BPA has been detected in dust and air particles, dental sealants, thermal papers, and even water (6). If we look critically at the human data, there are aspects that warrant mention. Much of the data that have shown a positive relationship between BPA and adverse effects in humans have come from one population, the NHANES cohort, across the years 2003–2008. Four of the publications from population-based samples (1, 7–9) have come from this population. Although associations have also been reported in the UK EPIC cohort (10) and two further publications from the same large cross-sectional study in Shanghai, China (2, 11) (with conflicting results), it is important that we gather data from many different countries. This is because median urinary BPA levels and BPA exposure routes may vary widely over these populations and, secondly, using the same set of samples with different outcomes does not necessarily add clarity to literature. We

For the past two decades, growing research has been pointing to multiple repercussions of bisphenol A (BPA) exposure to human health. BPA is a synthetic oestrogen which primarily targets the endocrine system; however, the compound also disturbs other systemic organ functions, in which the magnitude of impacts in those other systems is as comparable to those in the endocrine system. To date, the discoveries on the association between BPA and health outcomes mainly came from animal and in vitro studies, with limited human studies which emphasised on children's health. In this comprehensive review, we summarised studies on human, in vivo and in vitro models to understand the consequences of pre-, post- and perinatal BPA exposure on the perinatal, children and adult health, encompassing cardiovascular, neurodevelopmental, endocrine and reproductive effects.Conclusion: Evidence from in vitro and animal studies may provide further support and better understanding on the correlation between environmental BPA exposure and its detrimental effects in humans and child development, despite the difficulties to draw direct causal relations of BPA effects on the pathophysiology of the diseases/syndromes in children, due to differences in body system complexity between children and adults, as well as between animal and in vitro models and humans. What is known: • Very limited reviews are available on how BPA adversely affects children's health. • Previous papers mainly covered two systems in children. What is new: • Comprehensive review on the detrimental effects of BPA on children health outcomes, including expectations on adult health outcomes following perinatal BPA exposure, as well as covering a small part of BPA alternatives. • Essentially, BPA exposure during pregnancy has huge impacts on the foetus in which it may cause changes in foetal epigenetic programming, resulting in disease onsets during childhood as well as adulthood.

Relationship between bisphenol A exposure and attention-deficit/ hyperactivity disorder: A case-control study for primary school children in Guangzhou, China.

Getting Big on BPA: Role for BPA in Obesity?

Chapter 41 - Toxicity and Risk Assessment of Bisphenol A

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A common industrial chemical known as bisphenol A (BPA) has been linked to endocrine disruption and can interfere with hormonal signaling pathways in humans and animals. This comprehensive review aims to explore the detrimental consequences of BPA on reproductive organ performance and apoptosis induction, shedding light on the emerging body of evidence from laboratory animal studies. Historically, most studies investigating the connection between BPA and reproductive tissue function have mainly leaned on laboratory animal models. These studies have provided crucial insights into the harmful effects of BPA on several facets of reproduction. This review consolidates an increasing literature that correlates exposure to BPA in the environment with a negative impact on human health. It also integrates findings from laboratory studies conducted on diverse species, collectively bolstering the mounting evidence that environmental BPA exposure can be detrimental to both humans and animals, particularly to reproductive health. Furthermore, this article explores the fundamental processes by which BPA triggers cell death and apoptosis in testicular cells. By elucidating these mechanisms, this review aids a deeper understanding of the complex interactions between BPA and reproductive tissues.

Bisphenol A (BPA), 2,2-bis(4-hydroxyphenyl) propane, is one of the most utilized industrial chemicals worldwide, with the ability to interfere with/or mimic estrogenic hormones with associated biological responses. Environmental human exposure to this endocrine disruptor, mostly through oral intake, is considered a generalized phenomenon, particularly in developed countries. However, in the context of occupational exposure, non-dietary exposure sources (e.g., air and contact) cannot be underestimated. Here, we performed a review of the literature on BPA occupational exposure and associated health effects. Relevantly, the authors only identified 19 studies from 2009 to 2017 that demonstrate that occupationally exposed individuals have significantly higher detected BPA levels than environmentally exposed populations and that the detection rate of serum BPA increases in relation to the time of exposure. However, only 12 studies performed in China have correlated potential health effects with detected BPA levels, and shown that BPA-exposed male workers are at greater risk of male sexual dysfunction across all domains of sexual function; also, endocrine disruption, alterations to epigenetic marks (DNA methylation) and epidemiological evidence have shown significant effects on the offspring of parents exposed to BPA during pregnancy. This overview raises awareness of the dramatic and consistent increase in the production and exposure of BPA and creates urgency to assess the actual exposure of workers to this xenoestrogen and to evaluate potential associated adverse health effects.

Bisphenol A (BPA) and triclosan (TCS) are both endocrine-disrupting chemicals (EDCs), and pregnant women are usually exposed to them through daily consumption. This study aimed to explore the relationship between prenatal BPA and TCS exposure and allergic diseases in childhood by systematic review and meta-analysis. We searched the topic of prenatal BPA and TCS exposure and allergic diseases in childhood published before March 22, 2021, in four databases, including PubMed, Web of Science, Embase, and Cochrane. Statistical analysis was completed using Stata software (version 16.0). Seven papers on BPA and four papers on TCS were included in this meta-analysis. The association between prenatal exposure to BPA and total allergic diseases in childhood showed a pooled effect estimate of 1.13 (95% CI, 1.04, 1.23), with I2 = 0.0% (P = 0.615). The effect estimates between BPA exposure and each allergic disease were 1.18 (95% CI, 1.02, 1.36) for wheezing, 1.23 (95% CI, 1.01, 1.50) for asthma, 1.03 (95% CI, 0.89, 1.18) for eczema/rashes or hives, and 1.19 (95% CI, 0.91, 1.56) for aeroallergies. Prenatal exposure to TCS had no association with the four types of allergic disease in childhood. BPA exposure during the prenatal period was positively associated with allergic disease in childhood. Strengthening prenatal EDC exposure control is necessary for child health.

The effect of environmental Bisphenol A exposure on breast cancer associated with obesity

Bisphenol A exposure and risk of thyroid nodules in Chinese women: A case-control study

Key assumptions about bisphenol A (BPA) exposure and bioavailability may be off base, according to a new report in EHP that questions the traditional interpretation of biomonitoring data underlying current risk assessments of the chemical.1 Laboratory research suggests that BPA, a widely used chemical for polycarbonate plastics and other products, is an endocrine disruptor with potential adverse health effects involving reproduction, metabolism, and cancer.2,3 Median daily intake of the chemical through the diet is estimated to be 0.01–0.12 µg/kg body weight, based on urinary concentrations of BPA metabolites.4 These metabolites, particularly BPA glucuronide (BPAG), are not biologically active like the parent compound. Nearly all ingested BPA has been thought to be absorbed in the small intestine and rapidly converted to BPAG in the liver prior to bodywide distribution.5,6 Given the estimated daily intake and assumption of rapid conversion, the European Food Safety Authority set a tolerable daily intake of BPA at 0.05 mg/kg.1 However, the current study indicates that BPA can be completely absorbed directly into the bloodstream from the mouth, thus bypassing early rapid metabolism and remaining biologically active for an extended period of time. “Most previous studies have relied on the gavage method, where BPA is distributed directly into the gut,” says Laura Vandenberg, a postdoctoral fellow at the Tufts University Center for Regenerative and Developmental Biology, who was not involved in the study. “This isn’t how food actually enters our bodies. We chew it, move it around in our mouths, and it interacts with numerous surfaces—our tongue, cheeks, etc.—before it enters the stomach.” Gavage studies suggest there should not be detectable levels of unmetabolized BPA in the blood after exposure, yet dozens of other studies report otherwise, she says. The researchers compared the bioavailability of BPA given sublingually (under the tongue) versus intravenously or by gavage. In one experiment 6 dogs received a dose of 5 mg/kg first intravenously, then a week later sublingually either all at once or one drop at a time. In another experiment, conducted in three parts, the same dogs received a dose of 0.05 mg/kg first intravenously, then sublingually, and finally a 20-mg/kg dose delivered by gavage. After each administration, blood samples were collected to measure BPA and BPAG and calculate various parameters such as maximum concentration, time to maximum concentration, and mean residence time.1 BPA was readily absorbed from both the mouth and the gut, but bioavailability throughout the body differed significantly depending on the absorption site. Over the 2 hours following dosing, 5 mg/g and 0.05 mg/kg sublingual BPA yielded ratios of biologically inactive BPAG to biologically active BPA of 1:1–13:1 and 1:1–6:1, respectively, compared with 237:1–634:1 for the dose placed directly in the stomach.1 If confirmed, new findings on sublingual BPA dosing could have important implications for human exposures to BPA. “The sublingual route is a rather well-known route of absorption for those who are involved in the development of drugs but not for those working with contaminants in general and BPA in particular,” says study coauthor Pierre-Louis Toutain, a professor of physiology and therapeutics at the National Veterinary School of Toulouse, France. He says dogs were chosen as the study animals because their oral tissue closely resembles that of humans. The sublingual dosing used in the study may present different conditions from the exposure that occurs while eating or drinking. It also does not reflect potential nonfood exposures from sources such as dust, cigarette filters, thermal papers, and dental sealants that previous research has suggested occur.7 However, “the authors have shown very clearly that when BPA comes into contact with the mucosa under the tongue, it can be rapidly absorbed into the bloodstream. When this happens, it enters the bloodstream without being metabolized,” says Vandenberg. Additionally, this study may explain previous biomonitoring reports of plasma BPA levels deemed impossible or incorrect based on assumptions about gut-only absorption. This is important because plasma levels found in biomonitoring studies are similar to those found to cause adverse health effects in animal studies.7 Urinary BPAG serves as an index of external BPA exposure in biomonitoring studies, but it tells us nothing about the route of absorption, says Toutain. Given the researchers’ findings, he says it would be unacceptable to assume that only a negligible fraction of BPAG circulated as active BPA before it was converted to the inactive form measured in urine. He says, “It is clear that our data suggesting that BPA bioavailability can be high should raise some questions and possibly lead some agencies to reconsider their risk analysis on BPA.”

Prenatal bisphenol A (BPA) exposure has been shown to alter the development of reproductive organs in animal models,1 although the impacts on development of other organ systems remain largely unknown. Researchers at the University of California, Davis, now report in EHP that BPA exposure late in gestation alters airway cell development in rhesus macaques.2 Previous studies have associated BPA exposure with an experimental model of asthma in mice.3 Epidemiological studies have found evidence of an association between prenatal BPA exposure and wheeze in young children,4 and between postnatal exposure and childhood asthma.5 “This study sheds light on the possible mechanisms by which BPA may affect lung health,” says Kathleen Donohue, an assistant professor of medicine at Columbia University. Donohue was not involved in the current study. BPA exposure is widespread. One report from the National Health and Nutrition Examination Survey found that more than 90% of urine samples collected from U.S. males and females over age 6 years contained detectable levels of the chemical.6 For the current study, pregnant rhesus macaques received BPA via subcutaneous implant for 50 days during gestational days 50–100 or 100–150 (roughly comparable to the second and third trimesters, respectively, in humans). Control macaques received a corn oil implant or ate corn oil–treated fruit. Treatment groups included at least 6 animals, with histopathologic analyses conducted on smaller subgroups. “Our goal was to model constant serum levels of BPA that have been measured in humans,” says first author Laura Van Winkle, a toxicologist at the university. “Lung development patterns and cellular abundance in the airways of these animals match humans much more closely than rodent models.” At the end of each group’s exposure period the researchers collected fetal airway tissue samples. They used only female fetuses, as the study originated from a project designed to examine the effects of BPA on female reproductive development. They found that BPA exposure in late pregnancy was associated with increased expression of secretory proteins in fetal tissue. The cells that produce these proteins mature late in gestation; the proteins themselves—Clara cell secretory protein (CCSP) and the mucins MUC5AC and MUC5B—are key components of airway mucous secretions.2 Expression of the Muc5B gene was approximately six times higher at 150 days’ gestation in fetuses whose mothers were exposed to BPA late in pregnancy compared with those whose mothers received no BPA exposure. Expression of the Muc5AC gene also was increased. Histological staining of the lung tissue indicated there were more mucous cells in the airway epithelium of exposed fetuses and suggested an increase in the amount of mucous production (however, the researchers did not have a large enough sample size to run statistical analyses).2 Late-pregnancy exposure to BPA (B) was associated with a higher number of mucous cells in the airway epithelium of exposed fetuses, compared with exposure in mid-pregnancy (D) and controls (A and C). There were no significant changes in protein expression after exposure during mid-pregnancy, suggesting that late pregnancy may be a critical period in which BPA exposure may alter airway cell development. This critical window may also apply to human exposures to BPA in the third trimester of pregnancy due to similarities in the timing of cellular development and airway structure between rhesus macaques and humans.2 “Taken together with earlier studies in humans, this study in monkeys is important because it is another link in the chain of evidence [potentially] connecting BPA exposure to lung disease,” says Donohue. An increase in mucous cell abundance is one of the hallmarks of asthma, the authors report. However, they say, the clinical relevance of this particular study remains to be seen. The researchers examined only fetal airway tissue samples, and it is unknown whether an increase in mucous cell abundance would have resulted in airway disease after birth. The potential effects of environmental estrogens such as BPA on lung development also are not well known, says Van Winkle. Although estrogen is known to increase the expression of MUC5B in cultured airway epithelium cells from humans,7 and lung tissue does have estrogen receptors,8 it’s not clear how this affects the development of secretory proteins. Recent experimental studies have suggested that BPA may also disrupt fetal development through epigenetic and nonestrogenic pathways.9,10 Van Winkle suspects a combination of hormonal and nonhormonal effects may be at play. “A third possibility is that BPA affects something else entirely in the body that in turn alters lung development,” she says.