Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE118447 | GEO | 2018/11/08
REPOSITORIES: GEO
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Project description:Previous observations have demonstrated that the agricultural fungicide vinclozolin and the pesticide DDT (dichlorodiphenyltrichloroethane) induce transgenerational sperm epimutations involving DNA methylation. These two environmental toxicants were used to investigate the impacts of parent-of-origin outcross on the epigenetic transgenerational inheritance of disease. Male and female rats were collected from a paternal outcross (POC) or a maternal outcross (MOC) F4 generation control and exposure lineages for pathology and epigenetic analysis. This model allows the parental allelic transmission of disease and epimutations to be investigated. There was increased pathology incidence in MOC outcross F4 generation male prostate, kidney, obesity and multiple diseases through a maternal allelic transmission. The POC outcross F4 generation female offspring had increase pathology incidence for kidney, obesity and multiple diseases through the paternal allelic transmission. Some disease such as testis or ovarian pathology appear to be transmitted through the combined actions of both male and female alleles. Analysis of the F4 generation sperm epigenomes identified differential DNA methylated regions (DMRs) in a genome-wide analysis. Observations demonstrate that DDT and vinclozolin have the potential to promote the epigenetic transgenerational inheritance of disease and sperm epimutations to the outcross F4 generation in a sex specific and exposure specific manner.
2019-07-23 | GSE130258 | GEO
Project description:The ability of an endocrine disruptor exposure during gonadal sex determination to promote a transgenerational prostate disease phenotype was investigated in the current study. METHODS: Exposure of an F0 gestating female rat to the endocrine disruptor vinclozolin during F1 embryo gonadal sex determination promoted a transgenerational adult onset prostate disease phenotype. The prostate disease phenotype and physiological parameters were determined for males from F1 to F4 generations and the prostate transcriptome was assessed in the F3 generation. RESULTS: Although the prostate in prepubertal animals develops normally, abnormalities involving epithelial cell atrophy, glandular dysgenesis, prostatitis, and hyperplasia of the ventral prostate develop in older animals. The ventral prostate phenotype was transmitted for four generations (F1-F4). Analysis of the ventral prostate transcriptome demonstrated 954 genes had significantly altered expression between control and vinclozolin F3 generation animals. Analysis of isolated ventral prostate epithelial cells identified 259 genes with significantly altered expression between control and vinclozolin F3 generation animals. Characterization of regulated genes demonstrated several cellular pathways were influenced, including calcium and WNT. A number of genes identified have been shown to be associated with prostate disease and cancer, including beta-microseminoprotein (Msp) and tumor necrosis factor receptor superfamily 6 (Fadd). CONCLUSIONS: The ability of an endocrine disruptor to promote transgenerational prostate abnormalities appears to involve an epigenetic transgenerational alteration in the prostate transcriptome and male germ-line. Potential epigenetic transgenerational alteration of prostate gene expression by environmental compounds may be important to consider in the etiology of adult onset prostate disease. Keywords: expression analysis, transgenerational changes due to Vinclozolin
2008-06-20 | GSE11842 | GEO
Project description:A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germline is associated with primordial germ cell development and during fetal gonadal sex determination. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation primordial germ cell transcriptome and epigenome (DNA methylation) was altered transgenerationally. Interestingly, the differential DNA methylation regions (DMR) and altered transcriptomes were distinct between the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DMR and transcriptional alterations were observed in the E13 PGC than E16 germ cells. Observations demonstrate an altered transgenerational epigenetic reprogramming and function of the primordial germ cells and subsequent male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. The combined observations demonstrate ancestral exposure of a gestating female during fetal gonadal sex determination can promote transgenerational alterations in the primordial germ cell and subsequent male germline epigenetic and transcriptional programming. This altered germline programming leads to the epigenetic transgenerational inheritance of disease and phenotypic variation. Observations support the role of the primordial germ cell programming in the molecular mechanism involved and provides insights into the molecular mechanisms that control the epigenetic transgenerational inheritance phenomena. Results suggest a cascade of epigenetic and transcriptional events during germ cell development is needed to obtain the mature germline epigenome that is then transmitted transgenerationally. RNA samples from PGC of 2 F3-control lineage groups were compared to PGC of 2 F3-vinclozolin lineage groups for two embryonic age E13 and E16
2013-01-17 | E-GEOD-43559 | biostudies-arrayexpress
Project description:Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease, including decreases in the primordial follicle pool of oocytes that are similar to what is seen in POI, and increases in ovarian cysts that are similar to what is seen in PCOS. In the current study, transgenerational changes to the epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures compared to controls. In purified granulosa cells from 20 day old F3 generation females 164 differentially methylated regions (DMRs) (p<1e-06) were found in the F3 generation vinclozolin lineage, and 293 DMRs (p<1e-06) in the DDT lineage, compared to controls.
2018-11-08 | GSE118381 | GEO
Project description:Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The exposure of a gestating female during the period of gonadal sex determination has been shown to promote sperm epimutations, differential DNA methylation regions (DMR), that transmit transgenerational disease to subsequent generations. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, a spermatogenic cell apoptosis was observed. The Sertoli cells that provide the physical and nutritional support for the spermatogenic cells were isolated and alterations in gene expression examined. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific signaling pathways and cellular processes were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified in the vinclozolin F3 generation Sertoli cell. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that then has a role in the adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset male infertility. The exposure of a gestating female during the period of gonadal sex determination has been shown to promote sperm epimutations, differential DNA methylation regions (DMR), that transmit transgenerational disease to subsequent generations. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells in the testis. The F3 generation Sertoli cells have an altered transcriptome and epigenome associated with adult onset testis disease. The environmentally induced epigenetic transgenerational inheritance of Sertoli cell abnormalities appears to be a component of the molecular etiology of male infertility. RNA samples from Sertoli cell of 3 F3-control lineage groups are compared to Sertoli cell of 3 F3-vinclozolin lineage groups
2012-09-27 | E-GEOD-41173 | biostudies-arrayexpress
Project description:Previously the agricultural fungicide vinclozolin was found to promote the transgenerational inheritance of sperm differential DNA methylation regions (DMRs) termed epimutations that help mediate this epigenetic inheritance. The current study was designed to investigate the developmental origins of the transgenerational DMRs during gametogenesis. Male control and vinclozolin lineage F3 generation rats were used as a source of embryonic day 13 (E13) primordial germ cells. The DMRs between the control versus vinclozolin lineage samples were determined for this stage.
2020-07-29 | GSE151458 | GEO
Project description:Environmental factors have been shown to induce the epigenetic transgenerational inheritance of disease through the germline. This study was designed to investigate vinclozolin induced concurrent alterations of a number of different epigenetic processes including DNA methylation and histone retention in sperm. Gestating female rats were exposed transiently to vinclozolin during fetal gonadal development and then F1, F2 and F3 generation sperm were analyzed.
2018-06-05 | GSE111441 | GEO
Project description:A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germline is associated with primordial germ cell development and during fetal gonadal sex determination. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation primordial germ cell transcriptome and epigenome (DNA methylation) was altered transgenerationally. Interestingly, the differential DNA methylation regions (DMR) and altered transcriptomes were distinct between the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DMR and transcriptional alterations were observed in the E13 PGC than E16 germ cells. Observations demonstrate an altered transgenerational epigenetic reprogramming and function of the primordial germ cells and subsequent male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. The combined observations demonstrate ancestral exposure of a gestating female during fetal gonadal sex determination can promote transgenerational alterations in the primordial germ cell and subsequent male germline epigenetic and transcriptional programming. This altered germline programming leads to the epigenetic transgenerational inheritance of disease and phenotypic variation. Observations support the role of the primordial germ cell programming in the molecular mechanism involved and provides insights into the molecular mechanisms that control the epigenetic transgenerational inheritance phenomena. Results suggest a cascade of epigenetic and transcriptional events during germ cell development is needed to obtain the mature germline epigenome that is then transmitted transgenerationally.
2013-01-17 | GSE43559 | GEO
Project description:The epigenetic transgenerational actions of environmental toxicants and relevant mixtures on ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1, F2 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling premature ovarian failure (POF). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states were induced by different classes of environmental compounds suggesting a role of environmental epigenetics in ovarian disease etiology. We used transcriptome microarray analysis to determine genes expressed differentially between F3 control and F3 vinclozolin lineage rat ovary granulosa cell and see which genes might be connected to or cause observed ovary diseases RNA samples from granulosa cell of 3 F3-control lineage groups are compared to granulosa cell of 3 F3-vinclozolin lineage groups
2012-03-01 | E-GEOD-33423 | biostudies-arrayexpress
Project description:Previously the agricultural fungicide vinclozolin was found to promote the transgenerational inheritance of sperm differential DNA methylation regions (DMRs) termed epimutations that help mediate this epigenetic inheritance. The current study was designed to investigate the developmental origins of the transgenerational DMRs during gametogenesis. Male control and vinclozolin lineage F3 generation rats were used as a source of embryonic day 16 (E16) prospermatogonia, postnatal day 10 (P10) spermatogonia, and adult pachytene spermatocytes, round spermatids, caput epididymal sperm, and caudal sperm. The DMRs between the control versus vinclozolin lineage samples were determined for each developmental stage. The top 100 statistically significant DMRs for each stage were compared and the developmental origins of the caudal epididymal sperm DMRs were assessed.
2018-11-01 | GSE117995 | GEO