Bisphenol A Exposure Induces Sensory Processing Deficits in Larval Zebrafish during Neurodevelopment

Bisphenol A modulates expression of sex differentiation genes in the self-fertilizing fish, Kryptolebias marmoratus

Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.

In animal models, estrogens can drive carcinogenesis of the prostate and have long been suspected of playing a role in human prostate cancer. Scientists have hypothesized that prenatal exposure to estrogen-like compounds, including monomeric bisphenol A (BPA), may account for recent increases in rates of prostate cancer. Now a rat study by Gail Prins of the University of Illinois at Chicago Department of Urology, Shuk-Mei Ho of the University of Cincinnati Department of Environmental Health, and their colleagues provides the first evidence of a direct link between low-dose BPA exposure during development and later prostate cancer. BPA initially was synthesized for use in also is used as a cross-linking compound in the manufacture of polycarbonate plastics and epoxy resins. It leaches from food and beverage containers and from dental sealants, although the latter currently are not thought to be a major source of exposure. Today, this hormonally active chemical is widespread in the environment, with detectable serum levels present in approximately 90% of humans in the United States and other industrialized countries, by Prins’s estimate. BPA concentrations measured in placental and fetal tissues may be fivefold higher than maternal serum levels, with higher levels found in male fetuses compared to females, according to Prins. BPA has been in use for about 50 years in the industrialized world. Some investigators have proposed that widespread ingestion of monomeric BPA from polycarbonate food and drink containers might partially explain recent increases in prostate cancer rates. According to the American Cancer Society, rates have been on the rise since 1975. With the 1987 introduction of prostate-specific antigen testing, the newly enhanced ability to diagnose the disease caused incidence to spike to 240 age-adjusted cases per 100,000 men by 1992. After this “catch-up” period, rates dropped for three years, but are now back on the rise. In the study, described in the 1 June 2006 issue of Cancer Research, groups of newborn rats were given high or low doses of estradiol or an environmentally relevant dose of BPA. The findings provide a molecular underpinning for potential long-term effects by showing changes in methyl groups on DNA that are responsible for turning genes on or off. For example, one key prostate gene that normally fuels cell growth during development stayed turned on in the prostates of male rats exposed to BPA or elevated estradiol from birth, says Prins. Such epigenetic alterations may leave a permanent impression on genes, possibly sensitizing the animal to developing diseases later in life. One must exercise caution, however, in extrapolating the current rat findings to humans. How might one conduct an analogous program of research on men? The researchers consider such a program virtually impossible because 50 years or more typically would be required for results of early exposure to BPA to show up as prostate cancer. Indeed, Rebecca Sokol, a professor of medicine at the University of Southern California, cautions against extrapolating human effects from rat studies. She does, however, note that unlike strong carcinogens that damage DNA profoundly, BPA appears to cause subtle changes that may pass from one generation to the next. She asks whether something is happening to alter genes seemingly without changing the genetic code itself. Says Prins, “Our evidence shows that in an animal model, some genes are altered by the addition or removal of methyl groups on the DNA, which changes the ability of those genes to be transcribed and translated to proteins. It is possible that these effects may pass through generations as has been shown recently for sperm cells.” However, she adds, that analysis awaits future studies.

Paraoxonase 1 (PON1) is an antioxidant enzyme linked to metabolic disorders by genome-wide association studies in humans. Exposure to metabolic disrupting chemicals (MDCs) such as bisphenol A (BPA), together with genetic and dietary factors, can increase the risk of metabolic disorders. The objective of this study was to investigate how PON1 responds to the metabolic changes and oxidative stress caused by a western diet, and whether exposure to BPA alters the metabolic and PON1 responses. Zebrafish larvae at 14 days post fertilization were fed a custom-made western diet with and without aquatic exposure to two concentrations of BPA for 5 days. A combination of western diet and 150 μg/L BPA exposure resulted in a stepwise increase in weight, length and oxidative stress, suggesting that BPA amplifies the western diet-induced metabolic shift. PON1 arylesterase activity was increased in all western diet and BPA exposure groups and PON1 lactonase activity was increased when western diet was combined with exposure to 1800 μg/L BPA. Both PON1 activities were positively correlated to oxidative stress. Based on our observations we hypothesize that a western diet caused a shift towards fatty acid-based metabolism, which was increased by BPA exposure. This shift resulted in increased oxidative stress, which in turn was associated with a PON1 activity increase as an antioxidant response. This is the first exploration of PON1 responses to metabolic challenges in zebrafish, and the first study of PON1 in the context of MDC exposure in vertebrates.

Comparison of daily bisphenol A intake based on dietary and urinary levels in breastfeeding women

Bisphenol A exposure disrupts the circadian clock system and impairs glycolipid metabolic function in mice liver.

The number of neurotoxic pollutants is increasing, but their mechanism of action is unclear. Here, zebrafish were exposed to 0, 1, 10, and 100 μg/L bisphenol S (BPS) for different durations beginning at 2 h postfertilization (hpf) to explore the neurotoxic mechanisms of BPS. Zebrafish larvae exposed to BPS displayed abnormal neurobehaviors. At 48 and 120 hpf, BPS inhibited yolk lipid consumption and reduced the lipid distribution in the zebrafish brain. Moreover, BPS downregulated the mRNA levels of genes involved in fatty acid elongation in the endoplasmic reticulum (ER) and activated ER stress pathways at 48 and 120 hpf, and KEGG analysis after RNA-seq showed that the protein processing pathway in the ER was significantly enriched after BPS exposure. Exposure to ER toxicants (thapsigargin and tunicamycin), two positive controls, induced neurotoxic effects on zebrafish embryos and larvae similar to those of BPS exposure. These data suggested that BPS and ER toxicants disturbed ER function and reduced brain lipid levels. Continued exposure to BPS into adulthood not only inhibited brain fatty acid elongation and ER function but also caused abnormal swelling of the ER in zebrafish. Our data provide new insights into the neurotoxic mechanism of BPS.

It has been speculated that the increasing incidence of breast cancer might be linked to the increased exposure to environmental synthetic estrogens, such as bisphenol A (BPA), which is a most pervasive chemical in modern life as a component of polycarbonate plastics and epoxy resins used widely for food and beverage containers and dental sealants. Perinatal exposure to low, environmentally relevant doses of BPA in rodents resulted in the induction of pre-neoplastic ductal hyperplasia, carcinoma in situ, and increased susceptibility to tumorigenesis. However, the underlying mechanism for these observations is unclear. The murine mammary stem cells (MaSCs) are present in fetal mammary rudiments and could be the putative targets for BPA-induced tumorigenesis. More recently, MaSCs of different lineages have been matched with different subtypes of breast cancer by their specific gene-expression signatures. We thus hypothesize that mammary gland exposed to BPA at a susceptible window may lead to its susceptibility to tumorigenesis through a MaSC and/or stem cell niche mediated mechanism. To test this hypothesis, we exposed 21-day old Balb/C mice to BPA by gavage at 25 µg/kg/day during puberty for 3 weeks, and then isolated primary mammary cells at different time points (6-week, 2 and 4-month) for MaSC quantification using an in vitro mammosphere formation and 3D-ECM sphere differentiation assay as well as the in vivo cleared mammary fat pad regeneration assay. Our findings indicate that low dose BPA exposure at puberty can accelerate puberty onset, increase lateral branches and hyperplasia in adult mammary glands. Further, a single oral dose of DMBA at 30 mg/kg administrated at 2-month old resulted in a 2.4-fold increase in hyperplasia of mammary glands harvested at 4-month old when compared with BPA treated group without DMBA. Most significantly, puberty BPA exposure increased luminal MaSCs during gland development and this resulted in an increase of luminal cells in adult glands. In addition, puberty BPA exposure also altered basal MaSCs in such a way that regenerated glands from these basal MaSCs yielded higher preneoplastic lesion than control basal MaSCs, indicating puberty BPA exposure render basal MaSCs more susceptible to transformation. We also found significant increase of gene expression in steroid hormonal receptors (e.g. ERs and PR) in the stromal compartment (or stem cell niche), which suggest that the changes we observed above for the luminal and basal MaSCs may be caused indirectly through altered stromal environment upon BPA exposure during early life stage. Future studies are necessary to differentiate the effect of BPA exposure on MaSCs or the MaSC niche. In conclusion, our study showed that BPA-induced morphogenesis changes in mammary gland had a stem cell origin. More importantly, our findings suggest that BPA-induced susceptibility of mammary glands to tumorigenesis may also have a stem cell origin. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-06.

Background: Bisphenol A (BPA), a xenoestrogenic monomer, is one of the most common industrial chemicals used in epoxy coatings for canned food and other consumer items. There is only limited information regarding the potential health risks from BPA exposure in children and adolescents from Asian countries. Objective: To detect and determine urinary BPA concentrations, and identify possible association between urinary BPA levels, demographic characteristics, and BPA exposure risks in Thai children and adolescents. Methods: A cross-sectional study was conducted in 376 children and adolescents aged 3−18 years from kindergarten, elementary, and middle schools in Bangkok, Thailand. Urinary concentrations of total BPA were determined by liquid chromatography tandem mass spectrometry (LC−MSMS). Anthropometric data and questionnaires regarding BPA exposure risks were collected. Results: BPA was detected in 283 of 376 urine samples (75.3%) with a median adjusted BPA 0.53 μg/g creatinine (range 0.04−1.12). Thirty-one participants (9%) were overweight and 39 (11%) were obese. The BPA detection rate was significantly higher in obese children (OR 3.42, 95% confidence interval (CI) 1.18−9.95, P = 0.02) compared with children of normal weight. BPA was detected more often in younger children (3–6 years) when compared with children (6−10 years) and adolescents (10−18 years). There were no significant association between BPA levels and other demographic data or BPA exposure risks. Conclusions: BPA exposure in Thai children and adolescents may be lower than exposure in children from the United States, some European nations, and other Asian countries. Obese and younger children were significantly associated with BPA detection.

Bisphenol A and bisphenol S exposures during pregnancy and gestational age – A longitudinal study in China

Bisphenol A exposure enhances proliferation and tumorigenesis of papillary thyroid carcinoma through ROS generation and activation of NOX4 signaling pathways.

MicroRNA expression in response to bisphenol A is associated with high blood pressure

The ER-α and β ligand bisphenol A (BPA) is used in the production of polycarbonate plastic and epoxy resins. BPA presents a potential environmental challenge to both human and wildlife immunity due to its widespread use and its resulting presence in surface water and wastewater runoff. We observed that BPA exposure downregulates the expression of a neutrophil-recruiting chemokine in both mice (cxcl1) and zebrafish (cxcl8) and that BPA exposure decreases neutrophil recruitment to a tail injury in zebrafish. Neutrophils are essential for the removal of damaged tissue and invading microbes, thus facilitating tissue regeneration of the tail fin. To investigate BPA’s effects on larval zebrafish tail regeneration, we induced a tail injury at day 3 post fertilization (dpf) and found that fish exposed to 100 ng/ml BPA regenerate a smaller tail fin area at 3 dpi (p-value < 0.01). We hypothesized that neutrophil recruitment could be tied to regeneration by altering the expression of inflammation- and regeneration-related genes. 3 dpf embryos exposed to BPA show modulated levels of background wnt10a and il-10 expression compared to controls. BPA exposure reduces the 3 hour post-injury inflammatory response by decreasing both il-1 and il-6 expression. By modifying the cytokine environment both prior to and following infection and injury, BPA impacts both the inflammatory response and tissue regeneration. Multiple cytokine and chemokine genes are regulated by the transcription factor NF-kB and Wnt plays a key role in tissue regeneration; these two proteins also cross regulate one another. The impact of BPA on wnt10a and nfkb expression following tissue injury and LPS exposure will be discussed. Supported by Carleton College.


 The utility of dental materials to posing oral diseases have impact in the risk of Bisphenol A (BPA) exposure which can be harmful to human organs. BPA used in dentistry is related to the production of polycarbonate plastics and epoxy resins. For instance, composite filling materials and dental sealant are containing BPA that can promote risk to endocrine-disrupting, estrogenic effect, and renal exposure. The current study is reviewing the BPA exposures of dental materials and it impact risk to the systemic health. This systematic review critically evaluates, and the information gathered form several literatures. The source of these articles was Pub Med and Web of Science, search done with the following terms: BPA of dental materials, BPA exposure, BPA and health risks, BPA, and oral health. BPA exposure found in oral mucosa and saliva after the application of BPA-containing dental materials. BPA derivatives used in dental products have not been evaluated for the endocrine disruptor, estrogenicity. BPA exposures can be absorbed through the oral mucosa and may lead to internal exposures the absorption of BPA from the gastrointestinal tract. Manufacturers should be required to report complete information on the chemical composition of dental materials and strict precaution application techniques must be considered by the practitioner.

Back to table of contents Previous article Next article Professional NewsFull AccessConcerns Grow Over Chemical’s Effects on Developing BrainsLeslie SinclairLeslie SinclairSearch for more papers by this authorPublished Online:2 Dec 2011https://doi.org/10.1176/pn.46.23.psychnews_46_23_6-bAbstractThe news about bisphenol A (BPA), the estrogenic industrial chemical present in many hard-plastic bottles and metal-based food and beverage cans since the 1960s, just keeps getting worse.In January 2010, the Food and Drug Administration announced that it shares the perspective of the National Toxicology Program that recent studies provide reason for concern about the potential effects of BPA on the brain, behavior, and prostate gland of fetuses, infants, and children. The agency said it would support “reasonable steps to reduce human exposure to BPA, including actions by industry and recommendations to consumers on food preparation” while pursuing further studies of BPA’s effects.The use of bisphenol A in the manufacture of baby bottles has been banned in many jurisdictions, and new research suggests gestational exposure may be of concern.Credit: gosphotodesign/ShutterstockSince then, the use of BPA in baby bottles and children’s cups has been banned in several states, and further measures are under consideration throughout the United States. Canada became the first country to ban BPA use in baby bottles.But what about other sources of exposure to the chemical for fetuses, infants, and children? In the November Pediatrics, researchers from the Harvard School of Public Health published the most recent update of an ongoing study, funded by the National Institutes of Health, of the effects of early-life BPA exposure on behavior and executive function in children.Joe Braun, Ph.D., a research fellow in the Department of Environmental Health at the Harvard School of Public Health, and his colleagues have been prospectively following a group of mothers and their children who were participating in the Health Outcomes and Measures of the Environment Study in the Cincinnati, Ohio, metropolitan area. The study was designed to assess low-level environmental toxicant exposures.BPA exposure was assessed in the group using urine samples taken from the mothers during gestation and from the children at ages 1, 2, and 3. The children’s behavior was assessed at age 3 using the Behavioral Assessment System for Children 2 (BASC-2) Parent Rating Scale for pre-schoolers. Children’s executive functions were assessed by using the Behavior Rating Inventory of Executive Function-Pre-school (BRIEF-P).“Gestational urinary BPA concentrations were associated with some neurobehavioral measures at 3 years of age in this cohort,” reported Braun and colleagues. “In particular, gestational BPA exposure was associated with higher scores for measures of anxiety, hyperactivity, emotional control, and behavioral inhibition.”Different responses to gestational BPA exposure were especially pronounced for hyperactivity; girls exhibited increases in hyperactivity, and boys exhibited decreases. Braun and his colleagues described their findings as “consistent with numerous studies demonstrating altered neurobehavior among BPA-exposed animals.”But they expressed reservations about their findings, citing their modest sample size as one limitation. “The clinical relevance of these findings is unclear at this point,” they said. Despite this uncertainty, they offered clinical guidance, telling clinicians to advise concerned patients to reduce their exposure, but cautioning that is it difficult to avoid all sources of exposure, and the health consequences of BPA exposure are not fully understood.The American Chemistry Council (ACC), which represents companies involved in the chemical industry, has been quick to respond to the work of Braun and colleagues: “For parents, the most important information from this report is that the authors themselves question its relevance,” said Steven Hentges, Ph.D., of the ACC’s Polycarbonate/BPA Global Group. “The study … has significant shortcomings in study design, and the conclusions are of unknown relevance to public health.”Hentges cited recent research that he said was funded by the U.S. Environmental Protection Agency and conducted by scientists at the government’s Pacific Northwest National Laboratory that indicates “it is very unlikely BPA could cause health effects at any realistic exposure level, because of the way it is processed in the body.”Braun and his colleagues noted that there is considerable debate regarding the toxicity of low-level BPA exposure and that as a result their findings warrant additional research.An abstract of “Impact of Early-Life Bisphenol A Exposure on Behavior and Executive Function in Children” is posted at <www.ncbi.nlm.nih.gov/pubmed/22025598>. ISSUES NewArchived