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Transcriptomic modifications associated to protective effect of Pedro-Ximenez must on p,p´- DDE-induced liver injury in aged Mus spretus mice

ABSTRACT: The increase of aged population makes it necessary to find effective prevention and treatment procedures to help the elderly to enjoy a healthy and long life. The organochlorine compound p,p´-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene) is a DDT metabolic byproduct that generates great concern because its deleterious effects on both human and environment health. It is an endocrine disruptor agent and causes alterations in immune response, reproductive system, development, nervous system and endocrine homeostasis. Nutritional interventions may improve health and prolong life. A transcriptional study was carried on in order to analyze the biological responses caused by p,p´-DDE exposure in the liver of aged Mus spretus mice. Data showed that the elderly are especially sensitive to the toxicity of environmental contaminants. This work also evaluated the possible hepatoprotective effect of including sun-dried Pedro Ximenez must in the diet when p,p´-DDE exposure happens simultaneously. Our results showed that this dietary intervention controls the hepatic metabolism of carbohydrates and lipids through restoring bile acid homeostasis, improving the overall health in the elderly.

ORGANISM(S): Mus musculus Mus spretus

PROVIDER: GSE109254 | GEO | 2020/01/31

REPOSITORIES: GEO

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Project description:Although autism spectrum disorder (ASD) is among the most heritable of neurodevelopmental disorders, the rapidly rising prevalence of ASD suggests that environmental factors may interact with genetic risk for ASD. Environmental factors may impact both gene expression and phenotypes in ASD through epigenetic modifications that, in turn, could lead to intergenerational effects influencing risk for ASDs. Endocrine disrupting compounds (EDCs), such as the long-lived organochlorines, are of particular interest with respect to risk for autism because of their ability to interfere with sex hormones that have been implicated in the regulation of RORA, a dysregulated gene in ASD that is a master regulator of many other ASD risk genes. The specific aims of this study are to: 1) investigate whether high versus low exposures to the persistent organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are associated with differentially methylated regions (DMRs) in sperm from a Faroese cohort whose natural diet of pilot whale meat and blubber exposes them to higher than average levels of organic pollutants; 2) determine if genes associated with DDE DMRs are enriched for ASD risk genes; 3) identify pathways and functions over-represented among genes associated with DMRs. Whole genome bisulfite sequencing (WGBS) was used to identify genome-wide DMRs in sperm from individuals divided by high and low exposure levels. Gene ontology and pathway analyses were used to determine enrichment in functional relationships to ASD. Genes in DMRs not only could discriminate between high and low exposures to DDE, but also were enriched in autism risk genes. Gene ontology and pathway analyses of these genes show significant enrichment for neurodevelopmental processes frequently impacted by ASD. Results of this study show that elevated exposure to certain organochlorines is associated with genome-wide DNA methylation patterns in sperm affecting genes involved in neurological functions and developmental disorders, including ASD.

Project description:Evidence that persistent environmental pollutants may target the male reproductive system is increasing. The male reproductive system is regulated by secretion of testosterone by testicular Leydig cells, and perturbation of Leydig cells function may have ultimate consequences. 3-methylsulfonyl-DDE (3-MeSO2-DDE) is a potent adrenal toxicants formed from the persistent insecticide DDT. Although studies have revealed endocrine disruptive effect of 3-MeSO2-DDE, the underlying mechanisms at cellular level in steroidogenic Leydig cells remains to be established. The current study addresses the effect of 3-MeSO2-DDE viability, hormone production and proteome response of primary neonatal porcine Leydig cells. The AlamarBlue™ assay was used to evaluate cell viability. Solid phase radioimmunoassay was used to measure concentration of hormones produced by both unstimulated and luteinizing hormone (LH)-stimulated Leydig cells following 48 h exposure. Protein samples from Leydig cells exposed to a non-cytotoxic concentration of 3-MeSO2-DDE (10µM) were subjected to nano-LC-MS/MS and analyzed on a Q Exactive mass spectrometer and quantified using label-free quantitative algorithm. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were carried out for functional annotation and identification of protein interaction networks. 3-MeSO2-DDE regulated Leydig cell steroidogenesis differentially depending on cell culture condition. Whereas its effect on testosterone secretion at basal condition was stimulatory, the effect on LH-stimulated cells was inhibitory. From triplicate experiments, a total of 7540 proteins were identified in which the abundance of 87 proteins in unstimulated Leydig cells and 146 proteins in LH-stimulated Leydig cells were found to be significantly regulated in response to 3-MeSO2-DDE exposure. These proteins not only are the first reported in relation to 3-MeSO2-DDE exposure, but also display small number of proteins shared between culture conditions, suggesting the action of 3-MeSO2-DDE on several targeted pathways, including mitochondrial dysfunction, oxidative phosphorylation, EIF2-signaling, and glutathion-mediated detoxification. Further identification and characterization of these proteins and pathways may build our understanding to the molecular basis of 3-MeSO2-DDE induced endocrine disruption in Leydig cells.

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Transcriptomic modifications associated to protective effect of Pedro-Ximenez must on p,p´- DDE-induced liver injury in aged Mus spretus mice

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