In vitro molecular mechanisms of bisphenol A action.

Wetherill, Yelena B.; Akingbemi, Benson T.; Kanno, Jun; McLachlan, John A.; Nadal, Angel; Sonnenschein, Carlos; Watson, Cheryl S.; Zoeller, R. Thomas; Belcher, Scott M.

doi:10.1016/j.reprotox.2007.05.010

Cited by 920Effects and risks of endocrine disrupting chemicalsEstrogen and related hormone effectsEpigenetics and DNA Methylation

In vitro molecular mechanisms of bisphenol A action.

Wetherill, Yelena B., Akingbemi, Benson T., Kanno, Jun, McLachlan, John A., Nadal, Angel, Sonnenschein, Carlos, Watson, Cheryl S., Zoeller, R. Thomas +1 more·2007·Reproductive Toxicology

DOI 10.1016/j.reprotox.2007.05.010

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Abstract

Bisphenol A (BPA, 2,2-bis (4-hydroxyphenyl) propane; CAS# 80-05-7) is a chemical used primarily in the manufacture of polycarbonate plastic, epoxy resins and as a non-polymer additive to other plastics. Recent evidence has demonstrated that human and wildlife populations are exposed to levels of BPA which cause adverse reproductive and developmental effects in a number of different wildlife species and laboratory animal models. However, there are major uncertainties surrounding the spectrum of BPA's mechanisms of action, the tissue-specific impacts of exposures, and the critical windows of susceptibility during which target tissues are sensitive to BPA exposures. As a foundation to address some of those uncertainties, this review was prepared by the "In vitro" expert sub-panel assembled during the "Bisphenol A: An Examination of the Relevance of Ecological, In vitro and Laboratory Animal Studies for Assessing Risks to Human Health" workshop held in Chapel Hill, NC, Nov 28-29, 2006. The specific charge of this expert panel was to review and assess the strength of the published literature pertaining to the mechanisms of BPA action. The resulting document is a detailed review of published studies that have focused on the mechanistic basis of BPA action in diverse experimental models and an assessment of the strength of the evidence regarding the published BPA research.

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BPA binds the estrogen membrane receptor (GPER) with high affinity.
“It also binds the estrogen membrane receptor (GPER) with high affinity [23] as well as androgen and thyroid receptors [24], [25], [26], [27].”
From Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice (2011) · cites this paper as [23]
BPA has steroid-like properties and binds to both estrogen receptors (ERα, ERβ) with low affinity.
“BPA has steroid-like properties and binds to both estrogen receptors (ERα, ERβ) with low affinity [22], [23].”
From Gestational Exposure to Low Dose Bisphenol A Alters Social Behavior in Juvenile Mice (2011) · cites this paper as [23]

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Coumestrol, Bisphenol-A, DDT, and TCDD Modulation of Interleukin-2 Expression in Activated CD+4 Jurkat T Cells
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Mac1 Positive Cells Are Required for Enhancement of Splenocytes Proliferation Caused by Bisphenol A
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Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement
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Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses
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Human exposure to bisphenol A (BPA)
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EDC-2: the endocrine society's second scientific statement on endocrine-disrupting chemicals
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Bisphenol A and human health: A review of the literature
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Bisphenol S and F: A Systematic Review and Comparison of the Hormonal Activity of Bisphenol A Substitutes
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Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption
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State-of-the-science of endocrine disrupting chemicals, 2012
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Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A
Vandenberg, L. N., Chahoud, I., Heindel, J. J., Padmanabhan, V., Paumgartten, F. J. R., & Schönfelder, G. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.0901716 · Cited by 1,232 · see citing works
Bisphenol A – Sources, toxicity and biotransformation
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Early Life Exposure to Endocrine Disrupting Chemicals and Childhood Obesity and Neurodevelopment
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Phthalates and other additives in plastics: human exposure and associated health outcomes
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Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure
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Prenatal environmental exposures, epigenetics, and disease
Perera, F. P., & Herbstman, J. B. (2011) · Reproductive Toxicology · doi:10.1016/j.reprotox.2010.12.055 · Cited by 642 · see citing works
Components of plastic: experimental studies in animals and relevance for human health
Talsness, C. E., Martino‐Andrade, A. J., Kuriyama, S. N., Taylor, J. A., & Saal, F. S. V. (2009) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.0281 · Cited by 639 · see citing works
Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review
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Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review
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Bisphenol A: Food Exposure and Impact on Human Health
Almeida, S., Raposo, A., Almeida‐González, M., & Carrascosa, C. (2018) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.12388 · Cited by 518 · see citing works
Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons
Le, H. H., Carlson, E. M., Chua, J. P., & Belcher, S. M. (2007) · Toxicology Letters · doi:10.1016/j.toxlet.2007.11.001 · Cited by 501 · see citing works
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Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure
Kundakovic, M., Gudsnuk, K., Franks, B., Madrid, J., Miller, R. L., Perera, F. P., & Champagne, F. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214056110 · Cited by 490 · see citing works
Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish
Kinch, C. D., Ibhazehiebo, K., Jeong, J.-H., Habibi, H. R., & Kurrasch, D. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417731112 · Cited by 485 · see citing works
Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease
Cimmino, I., Fiory, F., Perruolo, G., Miele, C., Bèguinot, F., Formisano, P., & Oriente, F. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165761 · Cited by 486 · see citing works
Bisphenol A Exposure during Pregnancy Disrupts Glucose Homeostasis in Mothers and Adult Male Offspring
Alonso‐Magdalena, P., Vieira, E. C., Soriano, S., Menes, L., Burks, D. J., Quesada, I., & Nadal, Á. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.1001993 · Cited by 472 · see citing works
The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity
Saal, F. S. V., Nagel, S. C., Coe, B., Angle, B. M., & Taylor, J. A. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.01.001 · Cited by 449 · see citing works
Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A
Vandenberg, L. N., Chahoud, I., Heindel, J. J., Padmanabhan, V., Paumgartten, F. J. R., & Schönfelder, G. (2012) · Ciência & Saúde Coletiva · doi:10.1590/s1413-81232012000200015 · Cited by 433 · see citing works
Endocrine disruptors in the etiology of type 2 diabetes mellitus
Alonso-Magdalena, P., Quesada, I., & Nadal, A. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.56 · Cited by 404 · see citing works
Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic
Meeker, J. D., Ehrlich, S., Toth, T. L., Wright, D. L., Calafat, A. M., Trisini, A. T., Ye, X., & Hauser, R. B. (2010) · Reproductive Toxicology · doi:10.1016/j.reprotox.2010.07.005 · Cited by 413 · see citing works
Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study
Vandenberg, L. N. (2013) · Dose-Response · doi:10.2203/dose-response.13-020.vandenberg · Cited by 406 · see citing works
Pancreatic Insulin Content Regulation by the Estrogen Receptor ERα
Alonso‐Magdalena, P., Ropero, A. B., Carrera-González, M. P., Cederroth, C. R., Baquié, M., Gauthier, B. R., Nef, S., Stefani, E., & Nadal, Á. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002069 · Cited by 396 · see citing works
Urine bisphenol-A (BPA) level in relation to semen quality
Li, D., Zhou, Z., Miao, M., He, Y., Wang, J., Ferber, J. R., Herrinton, L. J., Gao, E., & Yuan, W. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.09.026 · Cited by 381 · see citing works
Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways
Alonso‐Magdalena, P., Ropero, A. B., Soriano, S., García‐Arévalo, M., Ripoll, C., Fuentes, E., Quesada, I., & Nadal, Á. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.12.012 · Cited by 359 · see citing works
Photodegradation of bisphenol A by highly stable palladium-doped mesoporous graphite carbon nitride (Pd/mpg-C3N4) under simulated solar light irradiation
Chang, C., Fu, Y., Hu, M., Wang, C., Shan, G., & Zhu, L. Y. (2013) · Applied Catalysis B: Environmental · doi:10.1016/j.apcatb.2013.05.044 · Cited by 354 · see citing works
Prenatal Bisphenol A Exposure and Child Behavior in an Inner-City Cohort
Perera, F., Vishnevetsky, J., Herbstman, J. B., Calafat, A. M., Xiong, W., Rauh, V., & Wang, S. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1104492 · Cited by 332 · see citing works
Relationship between Urinary Phthalate and Bisphenol A Concentrations and Serum Thyroid Measures in U.S. Adults and Adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007–2008
Meeker, J. D., & Ferguson, K. K. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1103582 · Cited by 341 · see citing works
The effects of phthalates in the cardiovascular and reproductive systems: A review
Mariana, M., Feiteiro, J., Verde, I., & Cairrão, E. (2016) · Environment International · doi:10.1016/j.envint.2016.07.004 · Cited by 333 · see citing works
Induction of oxidative stress by bisphenol A and its pleiotropic effects
Gassman, N. R. (2017) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22072 · Cited by 337 · see citing works
Why Public Health Agencies Cannot Depend on Good Laboratory Practices as a Criterion for Selecting Data: The Case of Bisphenol A
Myers, J. P., Saal, F. S. V., Akingbemi, B. T., Arizono, K., Belcher, S. M., Colborn, T., Chahoud, I., Crain, D. A., Farabollini, F., Guillette, L. J., et al. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.0800173 · Cited by 306 · see citing works
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Bisphenol A Electrochemical Sensor Using Graphene Oxide and β-Cyclodextrin-Functionalized Multi-Walled Carbon Nanotubes
Alam, A. U., & Deen, M. J. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c00402 · Cited by 297 · see citing works
Effects of the environmental estrogenic contaminants bisphenol A and 17α-ethinyl estradiol on sexual development and adult behaviors in aquatic wildlife species
Bhandari, R. K., Deem, S. L., Holliday, D. K., Jandegian, C. M., Kassotis, C. D., Nagel, S. C., Tillitt, D. E., Saal, F. S. V., & Rosenfeld, C. S. (2014) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2014.09.014 · Cited by 298 · see citing works
Occupational exposure to bisphenol-A (BPA) and the risk of Self-Reported Male Sexual Dysfunction
Li, D., Zhou, Z., Qing, D., He, Y., Wu, T., Miao, M., Wang, J., Weng, X., Ferber, J. R., Herrinton, L. J., et al. (2009) · Human Reproduction · doi:10.1093/humrep/dep381 · Cited by 296 · see citing works
Adsorption of bisphenol A from aqueous solution onto activated carbons with different modification treatments
Liu, G., Ma, J., Li, X., & Qin, Q. (2008) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2008.09.038 · Cited by 290 · see citing works
Oxidative Stress and BPA Toxicity: An Antioxidant Approach for Male and Female Reproductive Dysfunction
Meli, R., Monnolo, A., Annunziata, C., Pirozzi, C., & Ferrante, M. C. (2020) · Antioxidants · doi:10.3390/antiox9050405 · Cited by 301 · see citing works
The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes
Nadal, Á., Alonso‐Magdalena, P., Soriano, S., Quesada, I., & Ropero, A. B. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.02.016 · Cited by 288 · see citing works
From BPA to its analogues: Is it a safe journey?
Usman, A., & Ahmad, M. (2016) · Chemosphere · doi:10.1016/j.chemosphere.2016.05.070 · Cited by 276 · see citing works
Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function
Hectors, T. L. M., Vanparys, C., van der Ven, K., Martens, G. A., Jorens, P. G., Gaal, L. F. V., Covaci, A., Coen, W. D., & Blust, R. (2011) · Diabetologia · doi:10.1007/s00125-011-2109-5 · Cited by 277 · see citing works
Effects of developmental exposure to bisphenol A on brain and behavior in mice
Palanza, P., Gioiosa, L., Saal, F. S. V., & Parmigiani, S. (2008) · Environmental Research · doi:10.1016/j.envres.2008.07.023 · Cited by 276 · see citing works
Bisphenol A exposure leads to specific microRNA alterations in placental cells
Avissar-Whiting, M., Veiga, K. R., Uhl, K., Maccani, M. A., Gagne, L. A., Moen, E. L., & Marsit, C. J. (2010) · Reproductive Toxicology · doi:10.1016/j.reprotox.2010.04.004 · Cited by 272 · see citing works
Epigenetic perspective on the developmental effects of bisphenol A
Kundaković, M., & Champagne, F. A. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.02.005 · Cited by 270 · see citing works
Enhanced photocatalytic degradation of bisphenol A with Ag-decorated S-doped g-C3N4 under solar irradiation: Performance and mechanistic studies
Oh, W., Lok, L.-W., Veksha, A., Giannis, A., & Lim, T. (2017) · Chemical Engineering Journal · doi:10.1016/j.cej.2017.09.182 · Cited by 271 · see citing works
Health risk of exposure to Bisphenol A (BPA).
Konieczna, A., Rutkowska, A. Z., & Rachoń, D. (2015) · PubMed · Cited by 269 · see citing works
Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome
Ben‐Jonathan, N., Hugo, E. R., & Brandebourg, T. D. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.02.022 · Cited by 267 · see citing works
Neonatal Exposure to Bisphenol A and Reproductive and Endocrine Alterations Resembling the Polycystic Ovarian Syndrome in Adult Rats
Fernandez, M. O., Bourguignon, N. S., Lux-Lantos, V. A., & Libertun, C. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.0901257 · Cited by 266 · see citing works
Bisphenol A and its analogues: A comprehensive review to identify and prioritize effect biomarkers for human biomonitoring
Mustieles, V., D’Cruz, S. C., Couderq, S., Rodríguez‐Carrillo, A., Fini, J., Hofer, T., Steffensen, I., Dirven, H. A. A. M., Barouki, R., Olea, N., et al. (2020) · Environment International · doi:10.1016/j.envint.2020.105811 · Cited by 269 · see citing works
Prenatal and Postnatal Bisphenol A Exposure and Body Mass Index in Childhood in the CHAMACOS Cohort
Harley, K. G., Schall, R. A., Chevrier, J., Tyler, K., Aguirre, H., Bradman, A., Holland, N., Lustig, R. H., Calafat, A. M., & Eskenazi, B. (2013) · Environmental Health Perspectives · doi:10.1289/ehp.1205548 · Cited by 258 · see citing works
Maternal bisphenol-A levels at delivery: a looming problem?
Padmanabhan, V., Siefert, K., Ransom, S. B., Johnson, T. D., Pinkerton, J., Anderson, L., Tao, L., & Kannan, K. (2008) · Journal of Perinatology · doi:10.1038/sj.jp.7211913 · Cited by 257 · see citing works
Highly active Bi/BiOI composite synthesized by one-step reaction and its capacity to degrade bisphenol A under simulated solar light irradiation
Chang, C., Zhu, L. Y., Fu, Y., & Chu, X. (2013) · Chemical Engineering Journal · doi:10.1016/j.cej.2013.08.048 · Cited by 257 · see citing works
Urinary Bisphenol A Concentrations in Relation to Serum Thyroid and Reproductive Hormone Levels in Men from an Infertility Clinic
Meeker, J. D., Calafat, A. M., & Hauser, R. B. (2009) · Environmental Science & Technology · doi:10.1021/es9028292 · Cited by 255 · see citing works
Evidence for bisphenol A-induced female infertility: a review (2007–2016)
Ziv‐Gal, A., & Flaws, J. A. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.06.027 · Cited by 247 · see citing works
Update on the Health Effects of Bisphenol A: Overwhelming Evidence of Harm
Saal, F. S. V., & Vandenberg, L. N. (2020) · Endocrinology · doi:10.1210/endocr/bqaa171 · Cited by 249 · see citing works
Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life
Newbold, R. R., Jefferson, W. N., & Padilla-Banks, E. (2009) · Environmental Health Perspectives · doi:10.1289/ehp.0800045 · Cited by 236 · see citing works
Are Environmental Levels of Bisphenol A Associated with Reproductive Function in Fertile Men?
Mendiola, J., Jørgensen, N., Andersson, A., Calafat, A. M., Ye, X., Redmon, J. B., Drobnis, E. Z., Wang, C., Sparks, A. E., Thurston, S. W., et al. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.1002037 · Cited by 236 · see citing works
Low dose effects of bisphenol A
Vandenberg, L. N., Ehrlich, S., Belcher, S. M., Ben‐Jonathan, N., Dolinoy, D. C., Hugo, E. R., Hunt, P. A., Newbold, R. R., Rubin, B. S., Saili, K. S., et al. (2013) · Endocrine Disruptors · doi:10.4161/endo.26490 · Cited by 238 · see citing works
Self-citation
Differential Estrogenic Actions of Endocrine-Disrupting Chemicals Bisphenol A, Bisphenol AF, and Zearalenone through Estrogen Receptor α and β in Vitro
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Authors: Wetherill, Y. B., Akingbemi, B. T., Kanno, J., McLachlan, J. A., Nadal, A., Sonnenschein, C., Watson, C. S., Zoeller, R. T., & Belcher, S. M.
Affiliations: Harvard University (US)
Auburn University (US)
National Institute of Health Sciences (JP)
Tulane University (US)
Tufts University (US)
The University of Texas Medical Branch at Galveston (US)
University of Massachusetts Amherst (US)
University of Cincinnati (US)
Corresponding author: Belcher, Scott M.
ORCID: Akingbemi, Benson T.
Kanno, Jun
McLachlan, John A.
Sonnenschein, Carlos
Zoeller, R. Thomas
Belcher, Scott M.
Venue: Reproductive Toxicology
Publisher: Elsevier BV
Published: 2007-08
Volume: 24
Issue: 2
Pages: 178-198
ISSN: 0890-6238 (ISSN-L)
DOI: 10.1016/j.reprotox.2007.05.010
OpenAlex: W2001085078
Cited by: 920
References: 181
Citations by year: 2026: 16 · 2025: 28 · 2024: 36 · 2023: 30 · 2022: 52 · 2021: 54 · 2020: 71 · 2019: 64 · 2018: 64 · 2017: 71 · 2016: 72 · 2015: 65 · 2014: 57 · 2013: 51 · 2012: 55
FWCI: 3.22
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Reproductive Toxicology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Environmental Health Sciences (P30ES006096, T32ES007069, R01ES015145, T32 ES07069-26, P30 ES-06096)
Topics: Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords: bisphenol A, endocrine disruption, molecular mechanisms of action, reproductive toxicity, developmental toxicity, tissue-specific effects, polymer additives, evidence evaluation, in vitro studies
MeSH terms: Bisphenol A Compounds, Animals, Benzhydryl Compounds, Dose-Response Relationship, Drug, Environmental Exposure, Female, Fertility, Humans, Male, Phenols, Reproduction, Endocrine Disruptors

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