Perinatal exposure to lead and DEHP change DNA methylation profile in mouse liver and blood
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150670 | GEO | 2020/07/01
REPOSITORIES: GEO
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Project description:The developing epigenome changes rapidly, potentially making it more sensitive to toxicant exposures. DNA modifications, including methylation and hydroxymethylation, are important parts of the epigenome that may be affected by environmental exposures. However, most studies do not differentiate between these two DNA modifications, possibly masking significant effects. To investigate the relationship between DNA hydroxymethylation and developmental exposure to common contaminants, a collaborative, NIEHS-sponsored consortium, TaRGET II, initiated longitudinal mouse studies of developmental exposure to human-relevant levels of the phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP), and the metal lead (Pb). Exposures to 25 mg DEHP/kg of food (approximately 5 mg DEHP/kg body weight) or 32 ppm Pb-acetate in drinking water were administered to nulliparous adult female mice. Exposure began 2 weeks before breeding, and continued throughout pregnancy and lactation, until offspring were 21 days old. At 5 months, perinatally exposed offspring blood and cortex tissue were collected, for a total of 25 male mice and 17 female mice (n=5-7 per tissue and exposure). DNA was extracted and hydroxymethylation was measured using hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq). Differential peak and pathway analysis was conducted comparing across exposure groups, tissue types, and animal sex, using an FDR cutoff of 0.15. DEHP-exposed females had two genomic regions with lower hydroxymethylation in blood and no differences in cortex hydroxymethylation. For DEHP-exposed males, ten regions in blood (six higher and four lower) and 246 regions (242 higher and four lower) and four pathways in cortex were identified. Pb-exposed females had no statistically significant differences in blood or cortex hydroxymethylation compared to controls. Pb-exposed males, however, had 385 regions (all higher) and six pathways altered in cortex, but no differential hydroxymethylation was identified in blood. Overall, perinatal exposure to human-relevant levels of two common toxicants showed differences in DNA hydroxymethylation specific to sex, exposure type, and tissue, but male cortex was most susceptible to hydroxymethylation differences by exposure. Future assessments should focus on understanding if these findings indicate potential biomarkers of exposure or are related to functional long-term health effects.
2023-04-28 | GSE229717 | GEO
Project description:BACKGROUND: Phthalates are manmade industrial additives used mostly as plasticizers. In addition to their deleterious effects on male genital development, population studies have recently documented correlations between phthalates exposure and subtle impacts on reproductive tract development and on the metabolic syndrome in male adults. In mature rodents liver di-(2-ethylhexyl)-phthalate (DEHP) activates the peroxisome proliferators-activated receptor (PPARalpha), a member of the nuclear receptor (NR) superfamily. OBJECTIVES: Using a systems biology approach, we aimed at defining potential mechanisms underlying the impacts of DEHP on adult mouse liver and testis. METHODS: Thus, we performed a parallel analysis of transcript and metabolic profiles in the liver from adult mice exposed to varying DEHP doses. Moreover, we obtained pangenomic mRNA profiles of laser-captured Leydig and Sertoli cells from mature animals exposed to DEHP. RESULTS: Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of some prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways. Integration of hepatic transcriptomic and metabonomic profiles further revealed a correlation between the impacts of DEHP on a cluster of genes and metabolites linked to heme synthesis and on a cluster of Rev-erbalpha target genes related to metabolic and circadian clock pathways. Cell-specific effects of DEHP were investigated in the adult testis and a noticeable impact of DEHP was observed on Leydig cells transcriptome. CONCLUSIONS: We report a detailed analysis of DEHP interference with hepatic Constitutive Androstane Receptor (CAR) and Rev-erbalpha pathways and a novel transcriptional impact of DEHP on adult endocrine cells of the testis. Keywords: Treatment effect
2009-02-19 | GSE13240 | GEO
Project description:BACKGROUND: Phthalates are manmade industrial additives used mostly as plasticizers. In addition to their deleterious effects on male genital development, population studies have recently documented correlations between phthalates exposure and subtle impacts on reproductive tract development and on the metabolic syndrome in male adults. In mature rodents liver di-(2-ethylhexyl)-phthalate (DEHP) activates the peroxisome proliferators-activated receptor (PPARalpha), a member of the nuclear receptor (NR) superfamily. OBJECTIVES: Using a systems biology approach, we aimed at defining potential mechanisms underlying the impacts of DEHP on adult mouse liver and testis. METHODS: Thus, we performed a parallel analysis of transcript and metabolic profiles in the liver from adult mice exposed to varying DEHP doses. Moreover, we obtained pangenomic mRNA profiles of laser-captured Leydig and Sertoli cells from mature animals exposed to DEHP. RESULTS: Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of some prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways. Integration of hepatic transcriptomic and metabonomic profiles further revealed a correlation between the impacts of DEHP on a cluster of genes and metabolites linked to heme synthesis and on a cluster of Rev-erbalpha target genes related to metabolic and circadian clock pathways. Cell-specific effects of DEHP were investigated in the adult testis and a noticeable impact of DEHP was observed on Leydig cells transcriptome. CONCLUSIONS: We report a detailed analysis of DEHP interference with hepatic Constitutive Androstane Receptor (CAR) and Rev-erbalpha pathways and a novel transcriptional impact of DEHP on adult endocrine cells of the testis. Keywords: Treatment effect
2009-02-19 | GSE13237 | GEO
Project description:Perinatal exposure to lead and DEHP change DNA methylation profile in mouse liver and blood
| PRJNA633133 | ENA
Project description:BACKGROUND: Phthalates are manmade industrial additives used mostly as plasticizers. In addition to their deleterious effects on male genital development, population studies have recently documented correlations between phthalates exposure and subtle impacts on reproductive tract development and on the metabolic syndrome in male adults. In mature rodents liver di-(2-ethylhexyl)-phthalate (DEHP) activates the peroxisome proliferators-activated receptor (PPARalpha), a member of the nuclear receptor (NR) superfamily. OBJECTIVES: Using a systems biology approach, we aimed at defining potential mechanisms underlying the impacts of DEHP on adult mouse liver and testis. METHODS: Thus, we performed a parallel analysis of transcript and metabolic profiles in the liver from adult mice exposed to varying DEHP doses. Moreover, we obtained pangenomic mRNA profiles of laser-captured Leydig and Sertoli cells from mature animals exposed to DEHP. RESULTS: Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of some prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways. Integration of hepatic transcriptomic and metabonomic profiles further revealed a correlation between the impacts of DEHP on a cluster of genes and metabolites linked to heme synthesis and on a cluster of Rev-erbalpha target genes related to metabolic and circadian clock pathways. Cell-specific effects of DEHP were investigated in the adult testis and a noticeable impact of DEHP was observed on Leydig cells transcriptome. CONCLUSIONS: We report a detailed analysis of DEHP interference with hepatic Constitutive Androstane Receptor (CAR) and Rev-erbalpha pathways and a novel transcriptional impact of DEHP on adult endocrine cells of the testis. Experiment Overall Design: two condition experiment, Leydig cells from DEHP-treated mice vs. Leydig cells from vehicle-treated mice. Biological replicates: 2 DEHP-treated samples and 3 vehicle-treated samples. Each treated sample has been hybridized against each vehicle-treated sample in a dye-swap design. N=2 DEHP-treated x 3 vehicle-treated x 2 microarrays=12 microarrays
2009-04-10 | E-GEOD-13240 | biostudies-arrayexpress
Project description:BACKGROUND: Phthalates are manmade industrial additives used mostly as plasticizers. In addition to their deleterious effects on male genital development, population studies have recently documented correlations between phthalates exposure and subtle impacts on reproductive tract development and on the metabolic syndrome in male adults. In mature rodents liver di-(2-ethylhexyl)-phthalate (DEHP) activates the peroxisome proliferators-activated receptor (PPARalpha), a member of the nuclear receptor (NR) superfamily. OBJECTIVES: Using a systems biology approach, we aimed at defining potential mechanisms underlying the impacts of DEHP on adult mouse liver and testis. METHODS: Thus, we performed a parallel analysis of transcript and metabolic profiles in the liver from adult mice exposed to varying DEHP doses. Moreover, we obtained pangenomic mRNA profiles of laser-captured Leydig and Sertoli cells from mature animals exposed to DEHP. RESULTS: Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of some prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways. Integration of hepatic transcriptomic and metabonomic profiles further revealed a correlation between the impacts of DEHP on a cluster of genes and metabolites linked to heme synthesis and on a cluster of Rev-erbalpha target genes related to metabolic and circadian clock pathways. Cell-specific effects of DEHP were investigated in the adult testis and a noticeable impact of DEHP was observed on Leydig cells transcriptome. CONCLUSIONS: We report a detailed analysis of DEHP interference with hepatic Constitutive Androstane Receptor (CAR) and Rev-erbalpha pathways and a novel transcriptional impact of DEHP on adult endocrine cells of the testis. Experiment Overall Design: two condition experiment, Sertoli cells-rich areas from DEHP-treated mice vs. Sertoli cells-rich areas from vehicle-treated mice. Biological replicates: 4 DEHP-treated samples and 4 vehicle-treated samples. Dye-swap design. N=4 DEHP-treated vs vehicle-treated x 2 microarrays (dye-swap)=8 microarrays
2009-04-10 | E-GEOD-13237 | biostudies-arrayexpress
Project description:Phthalate esters, such as DEHP (bis(2-ethylhexyl) phthalate, are a ubiquitous class of chemicals used as plasticizers in plastic products such as toys and hospital supplies. They are not covalently bound to the polymer matrix and can leach out of products. The goal of this study is to determine whether DEHP adversely affect the zebrafish (Danio rerio) microbiome-gut axis, specifically gut transcriptome. We exposed the fish to 3 ppm DEHP via food for 8 weeks to stimulate chronic exposure. To identify genomic responses of DEHP in gut, we used microarrays followed by differential gene expression analysis. The data were then mapped to changes in cell processes and signaling pathways using Pathway Studio.
2020-01-08 | GSE136285 | GEO
Project description:Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this study we investigated potential mechanisms underlying the impact of di-(2-ethylhexyl)-phthalate (DEHP) on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARα targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and on the Rev-erbα pathway that senses endogenous heme level. Keywords: Treatment effect
2009-02-19 | GSE14629 | GEO
Project description:In this study we analyzed the effects of lead-exposure up hippocampal gene expression in males and females exposed to 0ppm, 250ppm and 750ppm lead during two different developmental periods, perinatal (in utero through to weaning at PND21) and postnatal (PND0-PND45). All tissue was taken at PND 55. We used affymetrix Rat Gene 1.0ST arrays to obtain global gene expression data from each animal, with a group size of 4 for all conditions (Total number of Arrays = 40) Gene expression was profiled in hippocampus at no lead exposure (0ppm), 250ppm and 750 ppm lead exposure level at peinatal and postnaltal developmental period.
2012-05-30 | E-GEOD-38348 | biostudies-arrayexpress
Project description:Gene expression analysis was conducted on the wildtype Caenorhabditis elegans exposed to bisphenol A (BPA), di(2-ethylhexyl) phthalate (DEHP) and nonylphenol (NP) using whole genome microarray. The microarray study was conducted in an ecotoxicological context, by investigating the response of global gene expression with that of classical toxicological endpoints, such as, mortality, growth, reproduction and development. Results provide insight into global transcription response of C.elegans to these endocrine disrupting chemicals exposure and also contribute to enhance the potential of C.elegans microarray in ecotoxicology (ecotoxicogenomics). key word : ecotoxicogenomics Experiment Overall Design: Young adults of wildtype C.elegans from age-synchronized population were exposed to NP, DEHP and BPA at the concentrations equivalent to 1/100 of 24h LC50 of each chemical, for 24 h and RNA extraction and hybridization were subsequently conducted using C.elegans Genome array (Affymetrix).
2009-03-07 | E-GEOD-15016 | biostudies-arrayexpress