Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects
01 Oct 2011-The Journal of Steroid Biochemistry and Molecular Biology (J Steroid Biochem Mol Biol)-Vol. 127, Iss: 1, pp 27-34
TL;DR: Although many questions remain to be answered, it is becoming increasingly apparent that exposure to BPA is ubiquitous and that the effects of this endocrine disruptor are complex and wide-ranging.
About: This article is published in The Journal of Steroid Biochemistry and Molecular Biology.The article was published on 2011-10-01. It has received 1076 citations till now. The article focuses on the topics: Environmental exposure & Endocrine disruptor.
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TL;DR: It is concluded that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses, and fundamental changes in chemical testing and safety determination are needed to protect human health.
Abstract: For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...
2,475 citations
TL;DR: There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise.
Abstract: Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Prostate cancer may be asymptomatic at the early stage and often has an indolent course that may require only active surveillance. Based on GLOBOCAN 2018 estimates, 1,276,106 new cases of prostate cancer were reported worldwide in 2018, with higher prevalence in the developed countries. Differences in the incidence rates worldwide reflect differences in the use of diagnostic testing. Prostate cancer incidence and mortality rates are strongly related to the age with the highest incidence being seen in elderly men (> 65 years of age). African-American men have the highest incidence rates and more aggressive type of prostate cancer compared to White men. There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise. Screening is highly recommended at age 45 for men with familial history and African-American men. Up-to-date statistics on prostate cancer occurrence and outcomes along with a better understanding of the etiology and causative risk factors are essential for the primary prevention of this disease.
1,215 citations
Additional excerpts
...BPA has been used to harden plastic since the 1950s in the manufacture of polycarbonate plastic and epoxy resins that appear in thousands of consumer products since then [315]....
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TL;DR: Biotransformation of BPA in animals, plants and microorganisms, resulting in the formation of various metabolites that exhibit different from BPA toxicity will be described.
718 citations
TL;DR: Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm.
Abstract: Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the "plastics" or "lower dose plastics" mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
712 citations
Cites background from "Bisphenol A: An endocrine disruptor..."
...A lower dose of half this was also used, which should not be considered ‘‘low dose’’ as previously described [12], but simply a lower dose....
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TL;DR: In this article, the authors highlight five research topics, including the synthesis of renewable monomers and degradable polymers, the development of chemical recycling strategies, new classes of reprocessable thermosets, and the design of advanced catalysts.
Abstract: It is likely that a half-century ago even enthusiastic and optimistic proponents of the synthetic polymer industry (Mr. McGuire included) could not have predicted the massive scale on which synthetic polymers would be manufactured and used today. Ultimately, the future success of this industry will rely on the development of sustainable polymers—materials derived from renewable feedstocks that are safe in both production and use and that can be recycled or disposed of in ways that are environmentally innocuous. Meeting these criteria in an economical manner cannot be achieved without transformative basic research that is the hallmark of this journal. In this Perspective we highlight five research topics—the synthesis of renewable monomers and of degradable polymers, the development of chemical recycling strategies, new classes of reprocessable thermosets, and the design of advanced catalysts—that we believe will play a vital role in the development of sustainable polymers. We also offer our outlook on sev...
603 citations
References
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TL;DR: The estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ERα or ERβ protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ERβ complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid are investigated.
Abstract: The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 >> zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 >> genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.
4,078 citations
TL;DR: The reported levels of BPA in human fluids are higher than the BPA concentrations reported to stimulate molecular endpoints in vitro and appear to be within an order of magnitude of the levels needed to induce effects in animal models.
2,391 citations
TL;DR: Urine concentrations of total BPA differed by race/ethnicity, age, sex, and household income, and these first U.S. population representative concentration data for urinary BPA and tOP should help guide public health research priorities.
Abstract: Of the more than 2,000 high-production volume chemicals that are manufactured in or imported into the United States in amounts of one million pounds or more per year (U.S. Environmental Protection Agency 2004), many are widely used in consumer products. Among these chemicals are bisphenol A [BPA; 2,2-bis(4-hydroxyphenyl)propane; CAS no. 80-05-7] and 4-tertiary-octylphenol [tOP; 4-(1,1,3,3-tetramethylbutyl)phenol; CAS no. 140-66-9]. BPA is used in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry [Center for the Evaluation of Risks to Human Reproduction (CERHR) 2007; European Union 2003]. Exposure to BPA is thought to result primarily from ingestion of food containing BPA (Kang et al. 2006; Vandenberg et al. 2007). tOP is both a degradation product of and an intermediate in the manufacture of octylphenol ethoxylates, which are nonionic surfactants used in detergents, pesticide formulations, and other applications (Ying et al. 2002). Exposure to tOP may occur from contact with personal care products, detergents, water, and food containing tOP.
Exposures to tOP can result in developmental and reproductive alterations in aquatic species (Segner et al. 2003) and in laboratory animals (Aydogan and Barlas 2006; Bian et al. 2006; Blake et al. 2004; Nagao et al. 2001; Willoughby et al. 2005). At high doses, BPA demonstrates estrogen-like effects on uterine and prostate organ weights in experimental animals. At doses below the putative lowest observed adverse effect level, exposure to BPA has reportedly resulted in decreased sperm production, increased prostate gland volume, altered development and tissue organization of the mammary gland, altered vaginal morphology and estrous cycles, disruption of sexual differentiation in the brain, and accelerated growth and puberty (Durando et al. 2007; Howdeshell et al. 1999; Kubo et al. 2003; Richter et al. 2007; Rubin et al. 2006; Schonfelder et al. 2002; Timms et al. 2005; vom Saal et al. 1998). At present, the interpretation of the evidence related to the low-dose effects of BPA is a subject of scientific debate (European Union 2003; Goodman et al. 2006; Gray et al. 2004; National Toxicology Program 2001; vom Saal and Hughes 2005).
BPA and tOP are of concern to environmental public health because of the high potential for exposure of humans to these phenols and their demonstrated animal toxicity. Information about the concentrations of these compounds in the general population is important for understanding human exposure to BPA and tOP. The National Health and Nutrition Examination Survey (NHANES), conducted continuously since 1999 by the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC), is designed to measure the health and nutritional status of the civilian noninstitutionalized U.S. population ≥ 2 months of age (CDC 2003). The surveys include household interviews; collection of medical histories; standardized physical examinations; and collection of biologic specimens (e.g., blood and urine from participants ≥ 1 and ≥ 6 years of age, respectively) for clinical chemistry testing, nutritional indicators assessments, and assessment of exposure to environmental chemicals (CDC 2005, 2006).
Previously, we analyzed 394 urine samples collected from adult participants of NHANES III, conducted during 1988–1994, to estimate urinary concentrations of total BPA (free plus conjugated species) in selected demographic groups (Calafat et al. 2005). We now report the first estimate of urinary concentrations of total BPA and tOP in NHANES 2003–2004 participants, a representative sample of the noninstitutionalized U.S. population ≥ 6 years of age.
1,590 citations
TL;DR: This review has covered the above-mentioned controversies plus six additional issues that have divided scientists in the field of BPA research, namely: mechanisms of bisphenol-A action; levels of human exposure; 3) routes of human Exposure; 4) pharmacokinetic models of Bpa metabolism; 5) effects of B PA on exposed animals; and 6) links between BPA and cancer.
Abstract: In 1991, a group of 21 scientists gathered at the Wingspread Conference Center to discuss evidence of developmental alterations observed in wildlife populations after chemical exposures. There, the term "endocrine disruptor" was agreed upon to describe a class of chemicals including those that act as agonists and antagonists of the estrogen receptors (ERs), androgen receptor, thyroid hormone receptor, and others. This definition has since evolved, and the field has grown to encompass hundreds of chemicals. Despite significant advances in the study of endocrine disruptors, several controversies have sprung up and continue, including the debate over the existence of nonmonotonic dose response curves, the mechanisms of low-dose effects, and the importance of considering critical periods of exposure in experimental design. One chemical found ubiquitously in our environment, bisphenol-A (BPA), has received a tremendous amount of attention from research scientists, government panels, and the popular press. In this review, we have covered the above-mentioned controversies plus six additional issues that have divided scientists in the field of BPA research, namely: 1) mechanisms of BPA action; 2) levels of human exposure; 3) routes of human exposure; 4) pharmacokinetic models of BPA metabolism; 5) effects of BPA on exposed animals; and 6) links between BPA and cancer. Understanding these topics is essential for educating the public and medical professionals about potential risks associated with developmental exposure to BPA and other endocrine disruptors, the design of rigorously researched programs using both epidemiological and animal studies, and ultimately the development of a sound public health policy.
1,263 citations
TL;DR: This paper showed that maternal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function.
Abstract: The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine-active compound shifted the coat color distribution of viable yellow agouti (Avy) mouse offspring toward yellow by decreasing CpG (cytosine-guanine dinucleotide) methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene. CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (CabpIAP). DNA methylation at the Avy locus was similar in tissues from the three germ layers, providing evidence that epigenetic patterning during early stem cell development is sensitive to BPA exposure. Moreover, maternal dietary supplementation, with either methyl donors like folic acid or the phytoestrogen genistein, negated the DNA hypomethylating effect of BPA. Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements.
1,246 citations