The intersection of neurotoxicology and endocrine disruption
ABSTRACT Endocrine disruption, the guiding theme of the 27th International Neurotoxicology Conference, merged into the neurotoxicology agenda largely because hormones help steer the process of brain development. Although the disruption motif first attracted public health attention because of reproductive anomalies in both wildlife and humans, the neurobehavioral implications had been planted decades earlier. They stemmed from the principle that sex differences in behavior are primarily the outcomes of differences in how the brain is sexually differentiated during early development by gonadal hormones (the Organizational Hypothesis). We also now understand that environmental chemicals are capable of altering these underlying events and processes. Among those chemicals, the group labeled as endocrine disrupting chemicals (EDCs) offers the clearest evidence of such selectivity, a consequence of their actions on the endogenous sex steroids, androgens and estrogens. Two EDCs in particular offer useful and intriguing examples. One is phthalate esters. The other is bisphenol A. Both agents are used extensively in plastics manufacture, and are pervasive in the environment. Both are produced in immense quantities. Both are found in almost all humans. Phthalates are considered to function in essence as anti-androgens, while bisphenol A is labeled as an estrogen. Their associations with brain sexual differentiation are reviewed and further questions noted. Both EDCs produce a wider spectrum of health effects, however, than would be extrapolated simply from their properties as anti-androgens and estrogens. Obesity is one example. Further complicating their assessment as health risks are questions about nonmonotonic dose-response functions and about transgenerational effects incurred via epigenetic mechanisms. All these facets of endocrine disruption are pieces of a puzzle that challenge neurotoxicologists for solutions.
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ABSTRACT: Juxtaposed alongside the ongoing rise in the incidence and prevalence of dementia, is the surge of recent research confirming widespread exposure and bioaccumulation of chemical toxicants. Evidence from sources such as the Centers for Disease Control reveals that most people have accrued varying degrees of assorted toxic pollutants including heavy metals, flame retardants, and pesticide residues within their bodies. It has been well established that many of these toxicants have neurodegenerative as well as neurodevelopmental impact as a result of various pathophysiologic mechanisms including neuronal mitochondrial toxicity and disruption of neurotransmitter regulation. Elimination of stockpiled toxicants from the body may diminish adverse toxicant impact on human biology and allow restoration of normal physiological function. Incorporating a review of medical literature on toxicant exposure and dementia with a case history of a lead-exposed individual diagnosed with dementia, this paper will discuss a much overlooked and potentially widespread cause of declining brain function and dementia.Behavioural neurology 02/2015; Article ID 620143. DOI:10.1155/2015/620143 · 1.64 Impact Factor
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ABSTRACT: Environmental exposures to chemically heterogeneous endocrine-disrupting chemicals (EDCs) mimic or interfere with hormone actions and negatively affect human health. Despite public interest and the prevalence of EDCs in the environment, methods to mechanistically classify these diverse chemicals in a high throughput (HT) manner have not been actively explored. Here, we describe the use of multiparametric, HT microscopy-based platforms to examine how a prototypical EDC, bisphenol A (BPA), and 18 poorly studied BPA analogs (BPXs), affect estrogen receptor (ER). We show that short exposure to BPA and most BPXs induces ERα and/or ERβ loading to DNA changing target gene transcription. Many BPXs exhibit higher affinity for ERβ and act as ERβ antagonists, while they act largely as agonists or mixed agonists and antagonists on ERα. Finally, despite binding to ERs, some BPXs exhibit lower levels of activity. Our comprehensive view of BPXs activities allows their classification and the evaluation of potential harmful effects. The strategy described here used on a large-scale basis likely offers a faster, more cost-effective way to identify safer BPA alternatives.Chemistry & Biology 05/2014; DOI:10.1016/j.chembiol.2014.03.013 · 6.59 Impact Factor
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ABSTRACT: OBJECTIVE: Research and interventions targeting the relationship between work, its attendant occupational hazards, and obesity are evolving but merit further consideration in the public health arena. In this discussion paper, conceptual heuristic models are described examining the role of obesity as both a risk factor and health outcome in the occupational setting. METHODS: PubMed was searched using specific criteria from 2000 and onwards for evidence to support conceptual models in which obesity serves as a risk factor for occupational disease or an outcome of occupational exposures. Nine models are presented: four where obesity is a risk factor and five where it is an adverse effect. RESULTS: A broad range of work-related health effects are associated with obesity including musculoskeletal disorders, asthma, liver disease, and cardiovascular disease, among others. Obesity can be associated with occupational hazards such as shift work, sedentary work, job stress, and exposure to some chemicals. CONCLUSION: Identification of combinations of risk factors pertinent to obesity in the occupational environment will provide important guidance for research and prevention.Scandinavian Journal of Work, Environment & Health 04/2013; 39(3). DOI:10.5271/sjweh.3363 · 3.10 Impact Factor