Chapel Hill Bisphenol A Expert Panel Consensus Statement: Integrations of mechanism, effects in animals and potential to impact human health at current levels of exposure

Università degli Studi di Siena, Siena, Tuscany, Italy
Reproductive Toxicology (Impact Factor: 3.23). 08/2007; 24(2):131-8. DOI: 10.1016/j.reprotox.2007.07.005
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    • "A is widely used for plastic bottle, protective lining of metal-based food and beverage containers. Laboratory studies showed that adulthood BPA exposure affects normal neurodevelopment, sexually dimorphic behaviors, and hyperactivity disorder (Palanza, Gioiosa, vom Saal, & Parmigiani, 2008; vom Saal et al., 2007). Prenatal exposures to low doses of BPA lead to acceleration of neurogenesis and aberrant neuronal migration (Nakamura et al., 2006). "
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    ABSTRACT: The etiology of many brain diseases remains allusive to date after intensive investigation of genomic background and symptomatology from the day of birth. Emerging evidences indicate that a third factor, epigenetics prior to the birth, can exert profound influence on the development and functioning of the brain and over many neurodevelopmental syndromes. This chapter reviews how aversive environmental exposure to parents might predispose or increase vulnerability of offspring to neurodevelopmental deficit through alteration of epigenetics. These epigenetic altering environmental factors will be discussed in the category of addictive agents, nutrition or diet, prescriptive medicine, environmental pollutant, and stress. Epigenetic alterations induced by these aversive environmental factors cover all aspects of epigenetics including DNA methylation, histone modification, noncoding RNA, and chromatin modification. Next, the mechanisms how these environmental inputs influence epigenetics will be discussed. Finally, how environmentally altered epigenetic marks affect neurodevelopment is exemplified by the alcohol-induced fetal alcohol syndrome. It is hoped that a thorough understanding of the nature of prenatal epigenetic inputs will enable researchers with a clear vision to better unravel neurodevelopmental deficit, late-onset neuropsychiatric diseases, or idiosyncratic mental disorders.
    Full-text · Article · Aug 2014 · International Review of Neurobiology
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    • "Recent research suggests that BPA can stimulate responses via ERs associated with the cell membrane at very low (ppb) concentrations equivalent in potency to E2 (Quesada et al. 2002, Vom Saal et al. 2007, Wozniak et al. 2005, Zsarnovszky et al. 2005); however, a biologically-plausible explanation for effects that appear at low doses is currently lacking (Chapin et al. 2008). In addition, a definition of " low dose " in relation to BPA exposure is inconsistent. "
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    ABSTRACT: Chemicals with estrogenic activity are derived from many different natural and synthetic processes and products, including endogenous production (e.g., estradiol, conjugated estrogens), drugs (e.g., ethinyl estradiol, conjugated estrogens), plants used as foods (phytoestrogens such as genistein, daidzein, S-equol), and man-made chemicals (xenoestrogens such as bisphenol A). Human exposure to low doses of endogenous estrogens, estrogenic drugs, phytoestrogens, and xenoestrogens has the potential to improve health or disrupt normal endocrine activity, as well as impact the diverse systems with which estrogens interact, including the cardiovascular system, and lipid and carbohydrate metabolism. Mechanisms of action and diversity of adverse and non-adverse effects following human exposure to low doses of estrogen active chemicals (EACs, defined as chemicals which interact with an estrogen receptor [ER]) are poorly understood. This review summarizes our current understanding of the pharmacological action with a focus on pharmacokinetics (PK) and toxicokinetics (TK) of several representative EACs in both physiological and pathological processes. The goal of this review is to assess the current state-of-the-science on: (i) the potential for EACs to interfere with endocrine activity, (ii) factors which contribute to endocrine-related clinical outcomes, and (iii) existing knowledge gaps. While classical PK approaches (compartmental or non-compartmental) can be used to characterize absorption, distribution, metabolism, and elimination of EACs, many of the detailed pharmacological characteristics necessary to understand benefit-risk balance have not yet been clarified. Pharmacological complexities mirror the complexity of determining whether and under what conditions exposure to estrogens in drugs, foods or to xenoestrogenic chemicals are beneficial or harmful to human health.
    Full-text · Article · Aug 2014 · Critical Reviews in Toxicology
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    • "We specifically address recent studies that challenge the use of gavage for the study of EDCs using bisphenol A (BPA) as a model EDC. We chose BPA because human exposures are widespread [7], low doses have been linked to adverse effects in laboratory animals [8,9], exposures are associated with a wide range of human diseases [10], and there remain unanswered questions about how best to model routes and sources of exposure [11]. Although we chose to focus on BPA, the issue of a lack of detailed understanding of all potential routes of exposure applies to many chemicals used in a wide range of products [12]. "
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    ABSTRACT: For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of 'oral' exposures. It is now widely used - and in some cases required - by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, gavage exposures avoid these interactions, leading to dramatic differences in absorption, bioavailability and metabolism with implications for toxicokinetic assumptions and models. Additionally, there are well acknowledged complications associated with gavage, such as perforation of the esophagus that diminish its value in toxicological experiments. Finally, the gavage protocol itself can induce stress responses by the endocrine system and confound the assessment of EDCs. These serious flaws have not been taken into account in interpreting results of EDC research. We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic. We conclude that gavage may be preferred over other routes for some environmental chemicals in some circumstances, but it does not appropriately model human dietary exposures for many chemicals. Because it avoids exposure pathways, is stressful, and thus interferes with endocrine responses, gavage should be abandoned as the default route of administration for hazard assessments of EDCs.
    Full-text · Article · Jun 2014 · Environmental Health
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