Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

/pdf/endocrine-disrupting-chemicals-an-endocrine-society-3fgbtp8gql.pdf

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

Physiological and molecular basis of thyroid hormone action.

Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators

The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

/pdf/edc-2-the-endocrine-society-s-second-scientific-statement-on-4hbb1iz0o3.pdf

EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

https://www.normalesup.org/~vorgogoz/articles/D.pachea-references/alternative-splicing/Stamm2005-alternative-splicing-review.pdf

Function of alternative splicing.

Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism.

Polychlorinated biphenyls suppress thyroid hormone-induced transactivation.

http://www.jbc.org/content/276/36/33375.full.pdf

Identification and Characterization of RRM-containing Coactivator Activator (CoAA) as TRBP-interacting Protein, and Its Splice Variant as a Coactivator Modulator (CoAM)

BackgroundPolybrominated diphenyl ethers (PBDEs) have been used as flame retardants and are becoming a ubiquitous environmental contaminant Adverse effects in the developing brain are of great hea

Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers.

The thyroid hormone (TH) is essential for growth and development of brain, including the cerebellum. Deficiency of TH during the perinatal period results in abnormal cerebellar development, which is well documented in rodent animal models. TH exerts its major effect by binding to the nuclear TH receptor (TR), a ligand-regulated transcription factor. Although TR is highly expressed in many brain regions, including the cerebellum, TH-target genes that likely play critical roles in brain development have not yet been fully clarified. At present, however, expression of many cerebellar genes is known to be altered by perinatal hypothyroidism. Interestingly, after the critical period of TH action (first 2 weeks of postnatal life in rodent cerebellum), the activities of many genes that are altered by perinatal hypothyroidism return to the same levels as those of euthyroid animal despite morphological alterations. Several prominent candidate genes that may play key roles in TH-mediated cerebellar development are discussed in this review. On the other hand, TR-mediated transcription may be modulated by various substances. The nuclear hormone receptor superfamily contains more than 40 transcriptional factors and, most of these receptors are present in the brain. Possible interactions between TR and such transcription factors are also discussed. Further, several additional issues that need to be clarified are discussed. One such issue is the discrepancy of phenotypes among TR-knockout and perinatal hypothyroid mice. Recent studies have provided several important clues to address this issue. Another current area that needs attention is the effect of endocrine disruptors on brain development. Since the molecular structures of TH and several endocrine disrupting chemicals are similar, the effect of such chemicals on brain may be exerted at least in part through the TH system. Recent studies have shown the possible interaction between TR and such chemicals. Overall, this review provides current findings regarding molecular mechanisms on TH action in cerebellar development.

Toshiharu Iwasaki

Papers

Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism.

Polychlorinated biphenyls suppress thyroid hormone-induced transactivation.

Identification and Characterization of RRM-containing Coactivator Activator (CoAA) as TRBP-interacting Protein, and Its Splice Variant as a Coactivator Modulator (CoAM)

Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers.

Current perspectives on the role of thyroid hormone in growth and development of cerebellum.