A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.
Sex-dependent pituitary growth hormone (GH) secretory profiles—pulsatile in males and persistent in females—regulate the sex-biased, STAT5-dependent expression of hundreds of genes in mouse liver, imparting sex differences in hepatic drug/lipid metabolism and disease risk. Here, we examine transcriptional and epigenetic changes induced by continuous GH infusion (cGH) in male mice, which rapidly feminizes the temporal profile of liver STAT5 activity. cGH repressed 86% of male-biased genes and induced 68% of female-biased genes within 4 days; however, several highly female-specific genes showed weak or no feminization, even after 14 days of cGH treatment. Female-biased genes already in an active chromatin state in male liver generally showed early cGH responses; genes in an inactive chromatin state often responded late. Early cGH-responsive genes included those encoding two GH/STAT5-regulated transcriptional repressors: male-biased BCL6, which was repressed, and female-specific CUX2, which was induced. Male-biased genes activated by STAT5 and/or repressed by CUX2 were enriched for early cGH repression. Female-biased BCL6 targets were enriched for early cGH derepression. Changes in sex-specific chromatin accessibility and histone modifications accompanied these cGH-induced sex-biased gene expression changes. Thus, the temporal, sex-biased gene responses to persistent GH stimulation are dictated by GH/STAT5-regulated transcription factors arranged in a hierarchical network and by the dynamics of changes in sex-biased epigenetic states.
Background: Polybrominated diphenyl ethers (PBDE) are a group of environmental contaminants increasing in North America. Few data are available on neurobehavioral effects at low-dose exposure. Objectives: Our goal in the present study was to evaluate whether low-dose BDE-47, which is the most abundant PBDE in human samples, affects the neurobehavioral development of rats. Methods: Dams were exposed to vehicle or low-dose BDE-47 (0.002, 0.02 and 0.2 mg/kg body weight) each 5 days from gestational day 15 to postnatal day (PND) 20 by intravenous injections. Spontaneous locomotor activity of pups was assessed using the open field test on PND 15, 20 and 25. Sensorimotor coordination was assessed using a RotaRod on PND 30. Results: Exposure to BDE-47 increased locomotor activity of pups. Developmental landmarks and sensorimotor coordination were not influenced by exposure to BDE-47. BDE-47 content in adipose tissue of exposed rats was similar to that known for human populations. Conclusion: These results indicate neurodevelopmental disruption induced in rats by BDE-47 at levels found in the human population.
BackgroundIn humans, the causal link between socioeconomic status (SES) and body weight (BW) is bidirectional, as chronic stress associated with low SES may increase risk of obesity and excess weight may worsen career opportunities resulting in lower SES. We hypothesize that environmental factors affecting BW and/or social stress might reprogram physiological and social trajectories of individuals.ObjectivesTo analyze interactions between BW and social behaviors in mice perinatally exposed to one of several environmental endocrine disruptors.MethodsCD-1 mice were fed 0.2 mg/kg BW/day tetrabromobisphenol-A (TBBPA), 2,2,4,4-tetrabromodiphenyl ether (BDE-47), bisphenol S (BPS), or oil (vehicle) from pregnancy day 8 through postpartum day 21. Three male offspring (triad) from each litter were housed together until week 15 and subjected to a Sociability Test and Tube Tests. Cages were then rearranged so that animals of the same social rank from the four exposure groups were housed together in tetrads. Social hierarchy in tetrads was again analyzed by Tube Tests.ResultsIn Sociability Tests, the mean velocity of all exposed animals increased when they encountered a stranger mouse and less time was spent with conspecifics. BW and social dominance of animals in triads and tetrads were inversely associated. BDE-47 and BPS caused transient decreases in BW.ConclusionsDevelopmental exposure to environmental xenobiotics shifted behavior towards increased anxiety and decreased interest in social interactions. Our mouse model reproduces negative associations between social hierarchy status and BW. These results suggest that manipulation of BW by endocrine disruptors may affect social ranking.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-015-0051-6) contains supplementary material, which is available to authorized users.
By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe.
This work was supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests.
BackgroundPolybrominated diphenyl ethers are a group of flame-retardant chemicals appearing increasingly in the environment. Their health effects and mechanisms of toxicity are poorly understood.ObjectivesWe screened for the sensitive effects and mechanisms of toxicity of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) by analyzing the gene expression profile in rats exposed to doses comparable to human exposure.MethodsWistar dams were exposed to vehicle or BDE-47 (0.002 and 0.2 mg/kg body weight) every fifth day from gestation day 15 to postnatal day 20 by injections to caudal vein. Total RNA was extracted from the livers of pups and hybridized to the whole-genome RNA expression microarrays. The list of genes 2-fold differentially expressed was exported to PANTHER and Ingenuity Systems for analysis of enriched ontology groups and molecular pathways.ResultsOxidoreductase and transferase protein families were enriched in exposed rats as were these biological process categories: carbohydrate metabolism; electron transport; and lipid, fatty acid, and steroid metabolism. Four signaling pathways (cascades of activation of drug-metabolizing enzymes) and 10 metabolic pathways were significantly enriched. Drug-metabolizing enzymes appear to be regulated by BDE-47 through an aryl hydrocarbon receptor–independent mechanism. Direct interaction with retinoid X receptor or its upstream cascade may be involved. The main metabolic effects consisted of activation of metabolic pathways: α- and ω-oxidation of fatty acids, glycolysis, and starch hydrolysis.ConclusionsAltered expression of genes involved in metabolic and signaling pathways and functions of the organism occurs after perinatal exposure of rat offspring to BDE-47 at doses relevant for the general population.
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