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Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11310

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Dr. Cinzia La Rocca

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Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Interests: chemical health effects; plasticizers; biomarkers; endocrine disrupting chemicals; contaminants; human biomonitoring; exposure and health
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Dear Colleagues,

Bisphenol A (BPA) is a plasticizer widely used in the manufacturing of polycarbonate plastics and epoxy resins for food contact materials and non-food applications. Human exposure to BPA can be associated with reproductive impairment, neurodevelopmental problems, immunological disorders, and metabolic syndrome. As an endocrine-disrupting chemical, BPA acts mainly through steroid receptors as well as by thyroid and peroxisome receptors, but also by altering hormone synthesis and exerting epigenetic effects. To reduce health risks, the use and production of BPA have been restricted; however, BPA has been replaced by several bisphenol analogues, such as BPF and BPS, with toxicological effects comparable to BPA, and recently detected in the environment, in food, and even in humans.

The main aim of the present Special Issue is to advance the knowledge on toxicological effects and mechanisms of action of BPA and its analogues by in vitro, in vivo, and human studies to contribute to human health risk assessment.

Dr. Cinzia La Rocca
Guest Editor

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Keywords

bisphenol A
bisphenol analogues
toxicity
mechanism of action
risk assessment

Published Papers (6 papers)

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Editorial

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2 pages, 163 KiB

Open AccessEditorial

Special Issue “Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health”

by Lucia Coppola and Cinzia La Rocca

Int. J. Mol. Sci. 2023, 24(9), 8028; https://doi.org/10.3390/ijms24098028 - 28 Apr 2023

Viewed by 940

Abstract

Bisphenol A (BPA) is a plasticizer that is widely used in the manufacturing of polycarbonate plastics (PC) and epoxy resins for use in a broad range of consumer products, including materials in contact with food and beverages, as well as medical devices, toys [...] Read more.

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

Research

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18 pages, 2245 KiB

Open AccessArticle

Combination of Bisphenol A and Its Emergent Substitute Molecules Is Related to Heart Disease and Exerts a Differential Effect on Vascular Endothelium

by Rafael Moreno-Gómez-Toledano, María Delgado-Marín, Sandra Sánchez-Esteban, Alberto Cook-Calvete, Sara Ortiz, Ricardo J. Bosch and Marta Saura

Int. J. Mol. Sci. 2023, 24(15), 12188; https://doi.org/10.3390/ijms241512188 - 29 Jul 2023

Cited by 1 | Viewed by 1332

Abstract

Plastic production, disposal, and recycling systems represent one of the higher challenges for the planet’s health. Its direct consequence is the release of endocrine disruptors, such as bisphenol A (BPA), and its emerging substitute molecules, bisphenol F and S (BPF and BPS), into the environment. Consequently, bisphenols are usually present in human biological fluids. Since BPA, BPS, and BPF have structural analogies and similar hormonal activity, their combined study is urgently needed. The present manuscript studied the effect of the mixture of bisphenols (BP_mix) in one of the world’s largest human cohorts (NHANES cohort). Descriptive and comparative statistics, binomial and multinomial logistic regression, weighted quantile sum regression, quantile g-computation, and Bayesian kernel machine regression analysis determined a positive association between BP_mix and heart disease, including confounders age, gender, BMI, ethnicity, Poverty/Income Ratio, and serum cotinine. Endothelial dysfunction is a hallmark of cardiovascular disease; thus, the average ratio of bisphenols found in humans was used to conduct murine aortic endothelial cell studies. The first results showed that BP_mix had a higher effect on cell viability than BPA, enhancing its deleterious biological action. However, the flow cytometry, Western blot, and immunofluorescence assays demonstrated that BP_mix induces a differential effect on cell death. While BPA exposure induces necroptosis, its combination with the proportion determined in the NHANES cohort induces apoptosis. In conclusion, the evidence suggests the need to reassess research methodologies to study endocrine disruptors more realistically. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

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12 pages, 2297 KiB

Open AccessArticle

Products of Bisphenol A Degradation Induce Cytotoxicity in Human Erythrocytes (In Vitro)

by Katerina Makarova, Ewa Olchowik-Grabarek, Krzysztof Drabikowski, Justyna Kurkowiak and Katarzyna Zawada

Int. J. Mol. Sci. 2023, 24(1), 492; https://doi.org/10.3390/ijms24010492 - 28 Dec 2022

Cited by 3 | Viewed by 1613

Abstract

The aim of this work has been to study the possible degradation path of BPA under the Fenton reaction, namely to determine the energetically favorable intermediate products and to compare the cytotoxicity of BPA and its intermediate products of degradation. The DFT calculations of the Gibbs free energy at M06-2X/6-311G(d,p) level of theory showed that the formation of hydroquinone was the most energetically favorable path in a water environment. To explore the cytotoxicity the erythrocytes were incubated with BPA and three intermediate products of its degradation, i.e., phenol, hydroquinone and 4-isopropylphenol, in the concentrations 5–200 μg/mL, for 1, 4 and 24 h. BPA induced the strongest hemolytic changes in erythrocytes, followed by hydroquinone, phenol and 4-isopropylphenol. In the presence of hydroquinone, the highest level of RONS was observed, whereas BPA had the weakest effect on RONS generation. In addition, hydroquinone decreased the level of GSH the most. Generally, our results suggest that a preferable BPA degradation path under a Fenton reaction should be controlled in order to avoid the formation of hydroquinone. This is applicable to the degradation of BPA during waste water treatment and during chemical degradation in sea water. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

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15 pages, 4226 KiB

Open AccessArticle

Developmental and Reproductive Impacts of Four Bisphenols in Daphnia magna

by Lingling Qian, Chen Chen, Liguo Guo, Junping Deng, Xiangling Zhang, Jiexiang Zheng, Genmei Wang and Xiaofei Zhang

Int. J. Mol. Sci. 2022, 23(23), 14561; https://doi.org/10.3390/ijms232314561 - 23 Nov 2022

Cited by 5 | Viewed by 1682

Abstract

Bisphenol A (BPA) is a typical endocrine-disrupting chemical (EDC) used worldwide. Considering its adverse effects, BPA has been banned or strictly restricted in some nations, and many analogs have been introduced to the market. In this study, we selected three representative substitutes, BPS, BPF, and BPAF, along with BPA, to assess the developmental and reproductive effects on Daphnia magna. The F0 generation was exposed to bisphenols (BPs) at an environmentally relevant concentration (100 μg/L) for 21 d; then the embryo spawn at day 21 was collected. Behavior traits, the activity of antioxidant enzymes, and gene transcription were evaluated at three developmental stages (days 7, 14, and 21). Notably, body length, heart rate, and thoracic limb beating were significantly decreased, and D. magna behaved more sluggishly in the exposed group. Moreover, exposure to BPs significantly increased the antioxidant enzymatic activities, which indicated that BPs activated the antioxidant defense system. Additionally, gene expression indicated intergenerational effects in larvae, particularly in the BPAF group. In conclusion, BPA analogs such as BPF and BPAF showed similar or stronger reproductive and developmental toxicity than BPA in D. magna. These findings collectively deepen our understanding of the toxicity of BPA analogs and provide empirical evidence for screening safe alternatives to BPA. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

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31 pages, 6265 KiB

Open AccessArticle

BPA Decreases PDCD4 in Bovine Granulosa Cells Independently of miR-21 Inhibition

by Reem Sabry, Makenna Williams, Nicholas Werry, Jonathan LaMarre and Laura A. Favetta

Int. J. Mol. Sci. 2022, 23(15), 8276; https://doi.org/10.3390/ijms23158276 - 27 Jul 2022

Cited by 8 | Viewed by 2142

Abstract

microRNAs (miRNAs) are susceptible to environmental factors that might affect cellular function and impose negative effects on female reproduction. miR-21 is the most abundant miRNA in bovine granulosa cells and is widely reported as affected by Bisphenol A (BPA) exposure, yet the cause and consequences are not entirely elucidated. BPA is a synthetic endocrine disruptor associated with poor fertility. miR-21 function in bovine granulosa cells is investigated utilizing locked nucleic acid (LNA) oligonucleotides to suppress miR-21. Before measuring apoptosis and quantifying miR-21 apoptotic targets PDCD4 and PTEN, transfection was optimized and validated. BPA was introduced to see how it affects miR-21 regulation and which BPA-mediated effects are influenced by miR-21. miR-21 knockdown and specificity against additional miRNAs were confirmed. miR-21 was found to have antiapoptotic effects, which could be explained by its effect on the proapoptotic target PDCD4, but not PTEN. Previous findings of miR-21 overexpression were validated using BPA treatments, and the temporal influence of BPA on miR-21 levels was addressed. Finally, BPA effects on upstream regulators, such as VMP1 and STAT3, explain the BPA-dependent upregulation of miR-21 expression. Overall, this research enhances our understanding of miR-21 function in granulosa cells and the mechanisms of BPA-induced reproductive impairment. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

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19 pages, 5370 KiB

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Exposure to Bisphenol A Caused Hepatoxicity and Intestinal Flora Disorder in Rats

by Ruijing Liu, Boping Liu, Lingmin Tian, Xinwei Jiang, Xusheng Li, Dongbao Cai, Jianxia Sun, Weibin Bai and Yulong Jin

Int. J. Mol. Sci. 2022, 23(14), 8042; https://doi.org/10.3390/ijms23148042 - 21 Jul 2022

Cited by 17 | Viewed by 2857

Abstract

Bisphenol A (BPA) is a globally utilized industrial chemical and is commonly used as a monomer of polycarbonate plastics and epoxy resins. Recent research reveals that BPA could cause potential adverse biological effects and liver dysfunction. However, the underlying mechanisms of BPA-induced hepatoxicity and gut dysbiosis remain unclear and deserve further study. In this study, male Sprague Dawley rats were exposed to different doses (0, 30, 90, and 270 mg/kg bw) of BPA by gavage for 30 days. The results showed that the high dose of BPA decreased superoxide dismutase (SOD), glutathione (GSH), and increased malondialdehyde (MDA) levels. Moreover, a high dose of BPA caused a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), while high-density lipoprotein cholesterol (HDL-C) was significantly decreased in BPA-treated rats. The gene expression of PGC-1α and Nrf1 were decreased in the liver of high doses of BPA-administrated rats, as well as the protein levels of SIRT1, PGC-1α, Nrf2, and TFAM. However, the protein expression of IL-1β was significantly increased in BPA-treated rats. In addition, BPA weakened the mitochondrial function of hepatocytes and promoted cell apoptosis in the liver by up-regulating the protein levels of Bax, cleaved-Caspase3, and cleaved-PARP1 while down-regulating the Bcl-2 in the liver. More importantly, a high dose of BPA caused a dramatic change in microbiota structure, as characterized at the genus level by increasing the ratio of Firmicutes to Bacteroidetes (F/B), and the relative abundance of Proteobacteria in feces, while decreasing the relative abundance of Prevotella_9 and Ruminococcaceae_UCG-014, which is positively correlated with the content of short-chain fatty acids (SCFAs). In summary, our data indicated that BPA exposure caused hepatoxicity through apoptosis and the SIRT1/PGC-1α pathway. BPA-induced intestinal flora and SCFA changes may be associated with hepatic damage. The results of this study provide a new sight for the understanding of BPA-induced hepatoxicity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bisphenol A Toxicity and Effects of Environmental Levels on Health)

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