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.
"Many toxicants are known endocrine disruptors: some of the most notable disruptors are pesticides such as DDE  and plasticizers such as Bisphenol A and phthalates . These latter toxicants have also been implicated in neurotoxicity as a result of their hormonal impact on neurological function . Moreover, it has been suggested that epigenetic alterations resulting from histone modification from exposure to these plasticizers may be a causative mechanism in toxicant induced neurodegeneration . "
[Show abstract][Hide abstract] 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.
"The steroid receptor subfamily of NRs is the best studied in the context of EDCs, as it comprises the receptors for estrogens (ERa and ERb), androgens, progestins, and glucocorticoids. Not surprisingly, given widespread environmental exposure, EDCs have been consistently associated in epidemiological studies with increased incidence of a number of pathological conditions, including hormone-dependent cancers (e.g., breast, prostate) and metabolic (e.g., diabetes and obesity), fertility, neurological, behavioral (Weiss, 2012), and developmental defects (De Coster and van Larebeke, 2012; Rochester, 2013). The list of potential EDCs comprises a large and growing number of individual compounds or mixtures and their metabolic and environmental derivatives. "
[Show abstract][Hide abstract] 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.
"In this relatively uncharted research area, these findings clearly require independent replication. Nonetheless, the general results of this growing body of research support the earlier speculation (14) that the exaggerated rise in T secretion in preterm infants (15) or exposure to hormone disruptors in early postnatal life (16) may have adverse consequences for male primate reproductive development. Today, it is known that higher postnatal salivary T concentrations in very low birth weight babies are associated with greater health problems, including delays in growth and longer hospitalizations (76) and infants are widely exposed to substances in formula, food, breast-milk that can disrupt normal hormonal processes in postnatal life (77). "
[Show abstract][Hide abstract] ABSTRACT: Converging evidence from over 40 years of behavioral research indicates that higher testicular androgens in prenatal life and at puberty contribute to the masculinization of human behavior. However, the behavioral significance of the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in early postnatal life remains largely unknown. Although early research on non-human primates indicated that suppression of the postnatal surge in testicular androgens had no measurable effects on the later expression of the male behavioral phenotype, recent research from our laboratory suggests that postnatal testosterone concentrations influence male infant preferences for larger social groups and temperament characteristics associated with the later development of aggression. In later assessment of gender-linked behavior in the second year of life, concentrations of testosterone at 3-4 months of age were unrelated to toy choices and activity levels during toy play. However, higher concentrations of testosterone predicted less vocalization in toddlers and higher parental ratings on an established screening measure for autism spectrum disorder. These findings suggest a role of the transient activation of the HPG axis in the development of typical and atypical male social relations and suggest that it may be useful in future research on the exaggerated rise in testosterone secretion in preterm infants or exposure to hormone disruptors in early postnatal life to include assessment of gender-relevant behavioral outcomes, including childhood disorders with sex-biased prevalence rates.
Frontiers in Endocrinology 02/2014; 5:15. DOI:10.3389/fendo.2014.00015
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