Low-dose Bisphenol A Research Articles

Sex-specific influence of maternal exposure to bisphenol A on sodium and fluid balance in response to dipsogenic challenges in rats

The plasticizer bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. Human exposure to BPA occurs almost constantly. BPA is an endocrine disruptor that interferes in estrogen receptor functions. This is important for the developing brain, which is particularly sensitive to the estrogenic effects of BPA. Body fluid balance is maintained by a complex network of systems that regulate sodium and water intakes and electrolyte excretion. The development of these control systems occurs during early life and therefore, may be susceptible to changes in the uterine environment. The aim of this work was to study the effects of two low BPA doses in the dam, during pregnancy and lactation, on adult offspring drinking and sodium and urine excretion after dipsogenic challenge. Dams were exposed to BPA in drinking water to mimic the most likely route of human exposure. The results showed that BPA did not disrupt spontaneous fluid balance, but altered sodium and fluid intakes in the BPA offspring under osmotic challenges. In experiments, both 24h fluid deprivation and sodium depletion modified fluid ingestive response in BPA offspring compared to control offspring. The increased preference for 2.7% NaCl solution in male BPA offspring is similar to female control offspring, altered ingestive behavior appears to be due to feminization of males and “hyperfeminization” of female BPA offspring, as they drink more than female control offspring. Our results indicate that exposure to low doses of BPA in early life may disrupt the development of sex-specific drinking behaviors by altering the steroid programming of the brain, and this disruption affects males and females differently.

Low concentrations of bisphenol A promote the activation of the mitochondrial apoptotic pathway on Beta-TC-6 cells via the generation of intracellular reactive oxygen species and mitochondrial superoxide.

Τhe natural history of type 2 diabetes mellitus is characterized by a progressive loss of pancreatic beta cell function and insulin resistance. Bisphenol A (BPA) is an endocrine-disrupting chemical that is used widely in industry; people are exposed to BPA and its products daily. Studies have delineated that BPA alters the function of pancreatic beta cells. Herein, we examined the effect of low doses of BPA on pancreatic beta cell viability and apoptosis and we tried to elucidate the mechanisms involved in these processes. Beta-TC-6 (ATCC® CRL-11506™) cells were cultured with a medium containing the following dilutions of BPA: 0.002, 0.02, 0.1, 0.2, 2 μΜ up to 72 h. We examined the viability and adenosine triphosphate (ATP) levels of cells. Then, we measured apoptosis, cell cycle, and insulin levels. We quantified the levels of proteins implicated in the mitochondrial pathway of apoptosis; and finally, we quantified the intracellular reactive oxygen species and mitochondrial superoxide. We found that the exposure of Beta-TC-6 cells to BPA results in a decrease in cell viability, ATP levels, and an increase in insulin levels. We found an increase in apoptosis levels and a decrease in cell cycle levels. In addition, we provide evidence of the levels of apoptotic proteins. Finally, we found an increase in the cellular reactive oxygen species and mitochondrial superoxide production. Exposure to low concentrations of BPA triggers the mitochondrial pathway of apoptosis via the generation of intracellular reactive oxygen species and mitochondrial superoxide on Beta-TC-6 cells in a dose-dependent way.

Bisphenol A exposure induces metastatic aggression in low metastatic MCF-7 cells via PGC-1α mediated mitochondrial biogenesis and epithelial-mesenchymal plasticity

AimsThe frequency of estrogen receptor alpha (ERα)-positive breast cancers and their metastatic progression is prevalent in females globally. Aberrant interaction of estrogen-like endocrine-disrupting chemicals (EDCs) is highly implicated in breast carcinogenesis. Studies have shown that single or acute exposures of weak EDCs such as bisphenol A (BPA) may not have a substantial pro-carcinogenic/metastatic effect. However, repeated exposure to EDCs is expected to strongly induce carcinogenic/metastatic progression, which remains to be studied. Main methodsLow metastatic ERα-positive human breast cancer cells (MCF-7) were exposed to nanomolar doses of BPA every 24 h (up to 200 days) to study the effect of repeated exposure on metastatic potential. Following the designated treatment of BPA, markers of epithelial-mesenchymal transition (EMT), migration and invasion, mitochondrial biogenesis, ATP levels, and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) knockdown assays were performed. Key findingsA repeated exposure of low dose BPA induced stable epithelial-mesenchymal plasticity in MCF-7 cells to augment migration and invasion in the ERα-dependent pathway. Repeated exposures of BPA increased the levels of several mesenchymal markers such as N-cadherin, vimentin, cluster of differentiation 44 (CD44), slug, and alpha-smooth muscle actin (α-SMA), whereas reduced the level of E-cadherin drastically. BPA-induced mitochondrial biogenesis favored metastatic aggression by fulfilling bioenergetics demand via PGC-1α/NRF1/ERRα signaling. Knockdown of PGC-1α resulted in suppressing both mitochondrial biogenesis and EMT in BPA exposed MCF-7 cells. SignificanceRepeated exposures of low dose BPA may induce metastatic aggression in ERα-positive breast cancer cells via PGC-1α-mediated mitochondrial biogenesis and epithelial-mesenchymal plasticity.

Basic Exploratory Study of Bisphenol A (BPA) Dietary Administration to Istrian Pramenka Rams and Male Toxicity Investigation.

Bisphenol A (BPA), an endocrine-disrupting chemical and environmental pollutant, has been reported by many researchers to induce male reproductive toxicity in different experimental models. In this study, we investigated whether long-term exposure for two months to 25 µg/kg body weight (low dose) of BPA affects spermatogenesis or sperm quality in young Istrian Pramenka rams exposed via diet. We evaluated body and testicular weights, histopathology of testes and epididymides, and sperm analyses, and compared these parameters between the group of treated rams and the control group of rams. Although there were some differences between the two groups, these differences were not large or statistically significant. The only statistically significant difference was the lower epithelial height of seminiferous tubules in treated rams, compared to control rams. In addition to assessing toxicity, BPA concentrations in the blood plasma of treated rams were determined after the first administration, and the toxicokinetic parameters of total BPA were calculated. In this study, no major signs of altered reproduction in rams were detected.

Impact of chronic exposure of rats to bisphenol A from perinatal period to adulthood on intraprostatic levels of 5α-reductase isozymes, aromatase, and genes implicated in prostate cancer development

The synergetic effect of estrogens and androgens is known to play a crucial role in the physiopathology of the prostate gland. Bisphenol A (BPA) is an endocrine disrupting compound that can interfere with endocrine hormone functioning and thereby influence prostate development. The objective of this study was to examine the impact on prostate expression of aromatase, 5α-R isozymes, and prostate cancer-related genes of exposure to low doses of BPA from perinatal period to adulthood. Vehicle or BPA (2.5 μg/kg b.w./day) was administered to gestating Wistar rats from gestational day 12 (GD12) to parturition and then to their male pups from postnatal day 1 (PND1) until euthanization on PND90. Their prostate glands were examined by qRT-PCR, Western blot, PCR array, and morphological study. mRNA and protein levels of 5α-R2 were significantly reduced and mRNA and protein levels of aromatase were significantly increased in BPA-treated animals, which also showed modifications of 8 out of the 84 key genes implicated in the development of prostate cancer. Because BPA interferes with genes involved in intraprostatic androgen and estrogen production and others implicated in prostate cancer, research is warranted into the prostate disease risk associated with chronic low-dose BPA exposure throughout life.

Effects of mammalian target of rapamycin and aryl hydrocarbon receptor‐mediating autophagy signaling on the balance of Th17/Treg cells during perinatal bisphenol A exposure in female offspring mice

Bisphenol A (BPA)'s immunotoxic properties have received increasing interest, which can lead to immune dysfunction and related disease development. However, the mechanism is not completely clear. A growing body of evidence suggests that autophagy has important roles in innate immunity, inflammatory response, and adaptive immunity. This study aimed to investigate the possible mechanisms of mammalian target of rapamycin (mTOR), aryl hydrocarbon receptor (AhR), and autophagy in Treg/Th17 imbalance induced by perinatal BPA exposure. Our results showed that the number of Th17 cells in the spleen of offspring female mice significantly increased, while the number of Treg cells decreased significantly, which was consistent with the expression levels of up-regulation of RORγt protein and a down-regulation Foxp3 protein. The levels of mTOR, p-mTOR, P62, and AhR protein expression increased, and LC3 protein decreased in spleen. However, in the thymus, we found that RORγt and Foxp3 proteins changed most significantly in the low-dose BPA group, and the same as p-mTOR and P62 protein levels. We conjectured that the potential mechanism of the imbalance of Th17/Treg upon perinatal exposure to BPA was probably associated with autophagy dysfunction. Proper autophagy plays an important role in maintaining the homeostasis of the thymic and spleen immune system.

Bisphenol A exposure triggers the malignant transformation of prostatic hyperplasia in beagle dogs via cfa-miR-204/KRAS axis

The prostatic toxicity of bisphenol A (BPA) exposure is mainly associated with hormonal disturbances, thus interfering with multiple signal pathways and increasing the susceptibility to prostatic lesions. This study concentrates predominantly on the potential effect and mechanisms of low-dose BPA exposure on prostates in adult beagle dogs. The dogs were orally given BPA (2, 6, 18 μg/kg/day) and vehicle for 8 weeks, followed by blood collection and dissection. The ascended organ coefficient and volume of prostates, thickened epithelium, as well as histopathological observation have manifested that BPA exposure could trigger the aberrant prostatic hyperplasia in beagle dogs. Hormone level detection revealed that the ratios of estradiol (E2) to testosterone (T) (E2/T) and prolactin (PRL) to T (PRL/T) were up-regulated in the serum from BPA group. Based on microRNA (miRNA) microarray screening and functional enrichment analysis, BPA might facilitate the progression of prostate tumorigenesis in beagle dogs via cfa-miR-204 and its downstream target KRAS oncogene. Subsequently, the overexpression of KRAS, CDKN1A, MAPK1, VEGFA, BCL2 and PTGS2 was validated. These findings provide a series of underlying targets for preventing the initiation and metastasis of BPA-induced prostatic hyperplasia and tumorigenesis, while the regulatory relationship headed with KRAS requires further investigation.

Analysis of Indirect Biomarkers of Effect after Exposure to Low Doses of Bisphenol A in a Study of Successive Generations of Mice.

Simple SummaryLiving beings are constantly and inadvertently exposed to a series of environmental and food pollutants, triggering effects on health that are transmitted over generations. Bisphenol A is a compound produced in large amounts world-wide and used in the manufacture of plastic containers and other utensils for daily use. It is an environmental and food pollutant with a demonstrated capacity to produce effects on the health of organisms exposed to it. The objective of our study was to identify possible indirect biomarkers of effect by means of the analysis of the blood biochemistry, and of certain reproductive parameters of animals exposed to Bisphenol A in doses considered to be safe over different generations. Our results did not show any modifications in the reproduction parameters evaluated, such as the duration of the estrous cycle, the size of the litters, or the percentage of the young alive at weaning time. However, they showed that there were alterations in biochemical parameters like glucose, total proteins, and albumin, which could therefore, be regarded as indirect indicators of an early effect of alterations in health caused by this compound.Bisphenol A (BPA) is considered as being an emerging pollutant, to which both animal and human populations are continuously and inadvertently exposed. The identification of indirect biomarkers of effect could be a key factor in determining early adverse outcomes from exposure to low doses of BPA. Thus, this study on mice aims to evaluate and identify indirect biomarkers of effect through the analysis of their blood biochemistry, and of certain reproduction parameters after exposure to different BPA concentrations (0.5, 2, 4, 50, and 100 µg/kg BW/day) in drinking water over generations. Our results showed that there were no modifications in the reproductive parameters evaluated, like estrous cycle duration, litter size, or the percentage of the young alive at reaching the weaning stage, at the exposure levels evaluated. However, there were modifications in the biochemical parameters, e.g., alterations in the glucose levels, that increased significantly (p < 0.05) in the breeders at the higher exposure doses (50 and 100 µg/kg BW/day in F1; 50 µg/kg BW/day in F2 and 100 µg/kg BW/day in F3), that would suggest that the BPA could induce hyperglycemia and its complications in adult animals, probably due to some damage in the pancreas cells; albumin, that increased in the breeders exposed to the highest dose in F1 and F3, inferring possible hepatic alterations. Further, total proteins showed a diminution in their values in F1 and F2, except the group exposed to 100 µg/kg BW/day, whereas in F3 the values of this parameter increased with respect to the control group, this aspect likely being related to a possible hepatic and renal alteration. Based on these results, glucose, albumin, and total proteins could initially be considered as early indicators of indirect effect after prolonged exposure to low BPA doses over generations.

Multi- and transgenerational biochemical effects of low-dose exposure to bisphenol A and 4-nonylphenol on testicular interstitial (Leydig) cells.

Bisphenol A (BPA) and 4-nonylphenol (NP) are well-known endocrine-disrupting chemicals (EDCs) that have been proven to affect Leydig cell (LC) functions and testosterone production, but whether BPA and NP have multi- and transgenerational biochemical effects on Leydig cells (LCs) is unknown. Fourier transform infrared (FTIR) spectroscopy is a powerful analytical technique that enables label-free and non-destructive analysis of the tissue specimen. Herein we employed FTIR coupled with chemometrics analysis to identify biomolecular changes in testicular interstitial (Leydig) cells of rats after chronic exposure to low doses of BPA and NP. Cluster segregations between exposed and control groups were observed based on the fingerprint region of 1800-900 cm-1 in all generations. The main biochemical alterations for segregation were amide I, amide II and nucleic acids. BPA and NP single and co-exposure induced significant differences in the ratio of amide I to amide II compared to the corresponding control group in all generations. BPA exposure resulted in remarkable changes of cellular gene transcription and DNA oxidative damage across all generations. Direct exposure to BPA, NP, and BPA&NP of F0 and F1 generations could significantly decrease lipid accumulation in LCs in the F2 and F3 generations. The overall findings revealed that single or co-exposure to BPA and NP at environmental concentrations affects the biochemical structures and properties of LCs.

Bisphenol A reveals its obesogenic effects through disrupting glucose tolerance, oxidant-antioxidant balance, and modulating inflammatory cytokines and fibroblast growth factor in zebrafish.

Obesogens affect lipid metabolism, and genetic or epigenetic factors may also contribute to the progression of obesity. Endocrine-disrupting chemicals (EDCs) are the most striking among obesogens. Bisphenol A (BPA) is an estrogenic EDC used in food containers, adhesives, dye powders, and dental fillers. We aimed to elucidate molecular mechanisms of BPA's obesogenic effects focusing on obesogenic pathways in the liver including fibroblast growth factor (FGF) and Dnmt3a which is its epigenetic regulator, oxidant-antioxidant status, and inflammatory cytokines. Zebrafish were divided into three groups as control, low-dose BPA (1μm BPA), and high-dose BPA groups (10μm BPA). At the end of 30days, oral glucose tolerance test (OGTT) was performed, fasting blood glucose levels were measured, and hepatopancreas tissues were taken. Malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione S-transferase (GST), and nitric oxide (NO) activities were examined in the hepatopancreas. Inflammatory cytokines, lepa, fgf21, and dnmt3a expressions were determined by RT-PCR. BPA exposure increased the body weights, il1ß, tnfα, il6, lepa, fgf21, and dnmt3a expressions, impaired glucose tolerance, and oxidant-antioxidant status in a dose-dependent manner. Hepatocyte degeneration, lipid vacuolization, and vasocongestion were observed in both BPA-exposed groups. Our study suggests impaired glucose tolerance, oxidant-antioxidant balance, increased inflammatory response, fgf21 expression, and dnmt3a expressions as the possible mechanisms for the BPA-induced obesity model in zebrafish.

Roles of ERRα and TGF-β signaling in stemness enhancement induced by 1 µM bisphenol A exposure via human neural stem cells.

Bisphenol A (BPA) is a common industrial chemical widely used to produce various plastics and is known to impair neural stem cells (NSCs). However, the effects of low-dose BPA exposure on the stemness maintenance and differentiation fate of NSCs remain unclear in the infant brain. The present study demonstrated that 1 µM BPA promoted human NSC proliferation and stemness, without significantly increasing apoptosis. The Chip-seq experiments demonstrated that both the cell cycle and the TGF-β signaling pathway were accelerated after treatment with 1 µM BPA. Subsequently, estrogen-related receptor α (ERRα) gene knockout cell lines were constructed using CRISPR/Cas9. Further western blotting and chromatin immunoprecipitation-PCR experiments demonstrated that BPA maintained cell stemness by binding to an EERα receptor and activating the TGF-β1 signaling pathway, including the downstream factors Aurora kinases B and Id2. In conclusion, the stemness of NSCs could be maintained by BPA at 1 µM through the activation of the ERRα and TGF-β1 signaling pathways and could restrain the differentiation of NSCs into neurons. The present research further clarified the mechanism of BPA toxicity on NSCs from the novel perspective of ERRα and TGF-β1 signaling pathways regulated by BPA and provided insights into potential novel methods of prevention and therapy for neurogenic diseases.

BPA-induced prostatic hyperplasia in vitro is correlated with the unbalanced gene expression of AR and ER in the epithelium and stroma

As a typical environmental endocrine disruptor (EED), bisphenol A (BPA) can induce pathological hyperplasia of the prostatic epithelium and stroma. This study concentrates mainly on the effect and underlying mechanisms of BPA on prostatic hyperplasia, which is based on the culture of primary human prostate epithelial cells (HPEpiC) and human prostate fibroblasts (HPrF). In an effect to screen the optimal pro-survival BPA levels, HPEpiC and HPrF were, respectively, exposed to concentration gradients of BPA (10-12M-10-4M) solution diluted with two corresponding medium and incubated for 72h at 37°C. CCK-8 assay showed that 10-9 M-10-5M BPA could facilitate the proliferation of HPEpiC, while similar proliferative effect of HPrF only needed 10-11 M-10-7M BPA. HPrF were more sensitive to BPA than HPEpiC. The qualification of PCNA gene expression measured using quantitative real-time polymerase chain reaction (qRT-PCR) also mirrored the BPA-induced cell proliferation. Additionally, our results considered that androgen receptor (AR), estrogen receptor (ERα, ERβ), and NFKB1 gene expressions exhibited up-regulation in HPEpiC treated with 10-9M BPA for 72h. However, in HPrF, the identical BPA treatment could activate ERα, ERβ, and NFKB1 gene expressions and down-regulated the expression of AR levels. It is further confirmed that low-dose BPA can indeed promote the proliferation of human prostate cells in vitro, and the mechanisms of BPA for prostatic epithelial and stromal hyperplasia may not be consistent.

Proteomic profile of the effects of low-dose bisphenol A on zebrafish ovaries

Human exposure to bisphenol-A (BPA) is largely unavoidable because BPA is an environmental contaminant found in soil, water, food and indoor dust. The safety of authorized BPA amounts in consumer products is under question because new studies have reported adverse effects of BPA at doses far below that previously established by the NOAEL (50 μg/kg per day). To protect public health, the consequences of low-dose BPA exposure in different organs and organismal functions must be further studied to generate relevant data. This study attempted to investigate the effects and potential molecular mechanisms of short-term exposure to 1 μg/L BPA on zebrafish ovarian follicular development. We observed only minor changes at the histopathological level with a small (3 %) increase in follicular atresia. However, a shotgun proteomics approach indicated deep alterations in BPA-exposed ovarian cells, including induction of the oxidative stress response, metabolic shifts and degradome perturbations, which could drive oocytes towards premature maturation. Based on these results, it could be suggested that inadvertent exposure to small concentrations of BPA on a continuous basis causes alteration in biological processes that are essential for healthy reproduction.

Chronic exposure to low doses of bisphenol A alters hydromineral responses in rats

Bisphenol A (BPA) is a chemical commonly used in the industrial sectors, hence humans are exposed to the compound repetitively. BPA is an endocrine disruptor and has been anticipated to interfere on chemical estrogen receptor functions and other nuclear hormone receptors. Estrogens are steroid hormones that, in addition to their neuroendocrine roles, affect water and salt intakes in numerous species, including humans and rodents. Changes in the hydrosaline balance produce compensatory behavioral and physiological responses, which serve to preserve or restore osmolarity and blood volume to optimal levels, thus preventing cardiovascular disease. The aim of the present work was to determine for first time the effect of long-term and low-dose BPA treatment on thirst and sodium appetite. Wistar rats were exposed to BPA via drinking water to mimic the most likely route of human exposure, and different dipsogenic and natriorexigenic stimuli were assessed. The BPA-treated rats tend to drink less water that control rats following 24-h fluid restriction, but there was no statistically significant decrease. Perhaps the BPA dose does not have enough estrogenic potency to affect water intake. In the extracellular fluid depletion test, the control rats significantly increased 2.7% NaCl solution intake on repeated testing, showing sodium appetite sensitization, i.e. the capacity to enhance sodium intake produced by stimulus repetition; whereas BPA-treated rats did not. In this study, fluid and electrolyte balance in BPA-treated rats is generally adequate but impaired in osmotic challenges, for example by sodium depletion. Thus, neuroendocrine systems involved in maintaining body fluid and electrolyte homeostasis were altered in BPA-treated rats.

Altered Testicular Histomorphometric and Antioxidant Levels Following In vivo Bisphenol-A Administration

Background: Bisphenol-A (BPA) is a pervasive environmental toxin that is used in the production processes of many consumables and equipment that are in daily application. The aim of this study was to determine the effects of BPA on the structural and functional integrity of the reproductive system in male Wistar rats and its interaction with melatonin. Methods: Adult female rats in pro-estrus phases were mated with adult male rats and the conception determined. The male pups were divided into two groups of A and B. These groups were further subdivided into six subgroups each. They were administered varying low doses of BPA (25 or 50mg/kg) and melatonin (10mg/kg) at neonatal and adolescent ages. The testes, epididymis and blood samples were collected for histological, semen and biochemical investigations, respectively. Results: The results show that BPA caused histological alterations, reduced quality and quantity of sperm cells, and induced oxidative stress at birth and adolescence. Conclusion: Bisphenol A exposure, even at low dose, is toxic to the male reproductive system, and melatonin administration did not significantly improve the alterations caused by the BPA.

Investigation of the Impact of Dental Care via Composite Resin Restoration among Children with Attention Deficit Hyperactivity Disorder: A Registry-Based Nested Case–Control Study

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric conditions. Many studies have shown that exposure to low-dose bisphenol-A (BPA) can contribute to ADHD. The relationship between ADHD and composite resin is still unclear. We designed a nested case–control study to investigate the relationship between ADHD and composite resin restorations among children from the Taiwan’s National Health Insurance Research Database. We included 85,503 people whose birth years were between 1998 and 2005 and who received resin restoration from January 2000 to December 2008. A 1:2 matched control sample without ADHD was randomly selected from the database by propensity score matching based on birth year and sex. We identified 4984 individuals as ADHD patients. The average diagnostic age of ADHD was 7.45 years old. The patients who received composite resin restorations had higher risk of ADHD than those who had never received them (aOR (adjusted odds ratio) = 1.25; 95% CI (confidence interval) = 1.13–1.38). Males had a higher risk of ADHD (aOR = 1.29; 95% CI = 1.14–1.43). Taken together, this nested case–control study demonstrated a positive association between ADHD and dental care via composite resin restoration in Taiwanese children. Prospective clinical studies of the relationship between ADHD and composite resin are warranted.

Prenatal Exposure to BPA: The Effects on Hepatic Lipid Metabolism in Male and Female Rat Fetuses.

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.

Combined effect of fulvestrant and low dose BPA: comparative implications on EMT, apoptosis, and TGF-β1 signaling in HepG2 cells

Bisphenol A (BPA) is an endocrine-disrupting chemical utilized in the manufacture of food packaging, dental materials, medical devices, children's toys, and baby products. Numerous studies have indicated the role of BPA in the etiology of many diseases such as diabetes, cardiovascular diseases, obesity, cancer, and chemotherapeutic resistance. However, the effects of BPA- chemotherapeutic combination remain to be investigated in different cell lines. Here, we demonstrate that low dose BPA and fulvestrant (estrogen receptor antagonist) combination synergistically decrease proliferation, promote cell migration and mesenchymal transition, switching from E-cadherin to N-cadherin expression Hepg2 cells. Moreover, we determined that low dose BPA may evoke susceptibility to apoptosis in HepG2 cells. The mechanism underlying these effects has been identified as increased TGF-β1 signaling. Our results provide an experimental basis for evaluating the potential health risks of low-dose BPA for fulvestrant therapy in hepatocytes.

Low-dose bisphenol A impairs the function of mouse decidual stromal cells by activating LUMAN-mediated unfolded protein response

The nonsteroidal estrogenic compound bisphenol A (BPA) is widely present in several industrial and medical products including plastic food containers and sealants in dentistry. There are growing concerns on the toxic effects of this compounds since BPA is known to have reproductive toxicity. This study evaluated the effects of low-dose BPA exposure on decidual stromal cells (DSCs) of mice. The results showed that although 10 nM of BPA have no significant effect on the cell viability, it alters the expression of decidualization-related genes including Prl8a2, Prl3c1, Ptgs2, and Mmp2. Moreover, we found that low-dose BPA exposure induces UPR response in DSCs. However, the expression of the three major UPR receptors (Perk, Ire 1, and Xbp1) did not change significantly. Interestingly, the expression of Luman, a novel receptor of UPR, was significantly upregulated in a dose-dependent manner. Lentivirus containing shLuman sequence was used to generate stable Luman silencing DSCs. It's showed that Luman knockdown could affect the expression of decidualization-related genes in decidual cells after BPA treatment. In summary, these results suggest that Luman plays a key role in low dose BPA-induced decidual toxicity of DSCs in mouse.

Changes Caused by Low Doses of Bisphenol A (BPA) in the Neuro-Chemistry of Nerves Located in the Porcine Heart.

Simple SummaryBisphenol A (BPA) is a substance commonly used in the plastics industry, which is a part of many everyday items. It may leach from plastics and penetrate food, water, soil and air. It is known that BPA negatively affects living organisms. It impairs the functions of the intestine, neurons, reproductive organs, endocrine glands and immune cells. Previous studies have also reported that BPA negatively influences the cardiovascular system, leading to heart arrhythmia, intensification of atherosclerosis, blood hypertension and increased risk of a heart attack. However, many aspects of the influence of BPA on the heart are still poorly understood. One of these aspects is the BPA impact on heart innervation. Therefore, this article aimed to investigate the influence of low doses of BPA on the number of nerves containing selected active substances taking part in neuronal stimuli conduction located in the porcine heart apex. The results indicate that even relatively low doses of BPA are not neutral to the cardiovascular system, because they affect the neurochemical characterization of nerves in the heart. These changes may underlie the negative effects of BPA on the heart.Bisphenol A (BPA) contained in plastics used in the production of various everyday objects may leach from these items and contaminate food, water and air. As an endocrine disruptor, BPA negatively affects many internal organs and systems. Exposure to BPA also contributes to heart and cardiovascular system dysfunction, but many aspects connected with this activity remain unknown. Therefore, this study aimed to investigate the impact of BPA in a dose of 0.05 mg/kg body weight/day (in many countries such a dose is regarded as a tolerable daily intake–TDI dose of BPA–completely safe for living organisms) on the neurochemical characterization of nerves located in the heart wall using the immunofluorescence technique. The obtained results indicate that BPA (even in such a relatively low dose) increases the number of nerves immunoreactive to neuropeptide Y, substance P and tyrosine hydroxylase (used here as a marker of sympathetic innervation). However, BPA did not change the number of nerves immunoreactive to vesicular acetylcholine transporter (used here as a marker of cholinergic structures). These observations suggest that changes in the heart innervation may be at the root of BPA-induced circulatory disturbances, as well as arrhythmogenic and/or proinflammatory effects of this endocrine disruptor. Moreover, changes in the neurochemical characterization of nerves in the heart wall may be the first sign of exposure to BPA.