The Experts below are selected from a list of 6144 Experts worldwide ranked by ideXlab platform

Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.

  • Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for Disease
    PloS one, 2020
    Co-Authors: Jennifer L. M. Thorson, Margaux Mcbirney, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of Disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm Disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for Disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for Testis Disease, prostate Disease, kidney Disease, lean pathology, and multiple Disease. For these pathologies, sufficient numbers of individual males with only a single specific Disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific Diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without Disease were compared to identify the Disease specific epimutation biomarkers. All pathologies were found to have Disease specific DMRs and DHRs which were found to predominantly be distinct for each Disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known Disease linked genes. This is one of the first observations of potential sperm Disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for Disease susceptibility.

  • Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational Disease
    Environmental Health, 2020
    Co-Authors: Jennifer L. M. Thorson, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Background Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of Disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational Disease. Methods Outbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple Diseases and compared to non-Diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational Disease. Results The exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational Testis Disease, prostate Disease, kidney Disease, and the presence of multiple Disease in the subsequent F3 generation great-grand offspring. The Disease DMRs were found to be Disease specific with negligible overlap between different Diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the Disease specific DMRs were investigated. Interestingly, the majority of the Disease specific sperm DMR associated genes have been previously found to be linked to relevant Disease specific genes. Conclusions Observations demonstrate the EWAS approach identified Disease specific biomarkers that can be potentially used to assess transgenerational Disease susceptibility and facilitate the clinical management of environmentally induced pathology.

  • Epigenetic transgenerational inheritance of Testis pathology and Sertoli cell epimutations: generational origins of male infertility.
    Environmental epigenetics, 2019
    Co-Authors: Ingrid Sadler-riggleman, Daniel Beck, Eric E. Nilsson, Rachel Klukovich, Yeming Xie, Wei Yan, Michael K. Skinner
    Abstract:

    Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect Testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of Testis Disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational Testis Disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male Testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and Testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with Testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of Testis pathologies and male infertility.

  • Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of Disease.
    Environmental epigenetics, 2019
    Co-Authors: Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset Disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of Testis Disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple Disease. The F3 generation DDT males also had significant increases in Testis Disease, prostate Disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney Disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate Disease, kidney Disease, Testis Disease, obesity, and multiple Disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited Disease susceptibility.

  • Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
    PloS one, 2018
    Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. Skinner
    Abstract:

    Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in Testis, prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with Testis Disease, prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.

Eric E. Nilsson - One of the best experts on this subject based on the ideXlab platform.

  • Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for Disease
    PloS one, 2020
    Co-Authors: Jennifer L. M. Thorson, Margaux Mcbirney, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of Disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm Disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for Disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for Testis Disease, prostate Disease, kidney Disease, lean pathology, and multiple Disease. For these pathologies, sufficient numbers of individual males with only a single specific Disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific Diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without Disease were compared to identify the Disease specific epimutation biomarkers. All pathologies were found to have Disease specific DMRs and DHRs which were found to predominantly be distinct for each Disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known Disease linked genes. This is one of the first observations of potential sperm Disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for Disease susceptibility.

  • Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational Disease
    Environmental Health, 2020
    Co-Authors: Jennifer L. M. Thorson, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Background Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of Disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational Disease. Methods Outbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple Diseases and compared to non-Diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational Disease. Results The exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational Testis Disease, prostate Disease, kidney Disease, and the presence of multiple Disease in the subsequent F3 generation great-grand offspring. The Disease DMRs were found to be Disease specific with negligible overlap between different Diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the Disease specific DMRs were investigated. Interestingly, the majority of the Disease specific sperm DMR associated genes have been previously found to be linked to relevant Disease specific genes. Conclusions Observations demonstrate the EWAS approach identified Disease specific biomarkers that can be potentially used to assess transgenerational Disease susceptibility and facilitate the clinical management of environmentally induced pathology.

  • Epigenetic transgenerational inheritance of Testis pathology and Sertoli cell epimutations: generational origins of male infertility.
    Environmental epigenetics, 2019
    Co-Authors: Ingrid Sadler-riggleman, Daniel Beck, Eric E. Nilsson, Rachel Klukovich, Yeming Xie, Wei Yan, Michael K. Skinner
    Abstract:

    Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect Testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of Testis Disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational Testis Disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male Testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and Testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with Testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of Testis pathologies and male infertility.

  • Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of Disease.
    Environmental epigenetics, 2019
    Co-Authors: Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset Disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of Testis Disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple Disease. The F3 generation DDT males also had significant increases in Testis Disease, prostate Disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney Disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate Disease, kidney Disease, Testis Disease, obesity, and multiple Disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited Disease susceptibility.

  • Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
    PloS one, 2018
    Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. Skinner
    Abstract:

    Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in Testis, prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with Testis Disease, prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.

Daniel Beck - One of the best experts on this subject based on the ideXlab platform.

  • Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for Disease
    PloS one, 2020
    Co-Authors: Jennifer L. M. Thorson, Margaux Mcbirney, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of Disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm Disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for Disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for Testis Disease, prostate Disease, kidney Disease, lean pathology, and multiple Disease. For these pathologies, sufficient numbers of individual males with only a single specific Disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific Diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without Disease were compared to identify the Disease specific epimutation biomarkers. All pathologies were found to have Disease specific DMRs and DHRs which were found to predominantly be distinct for each Disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known Disease linked genes. This is one of the first observations of potential sperm Disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for Disease susceptibility.

  • Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational Disease
    Environmental Health, 2020
    Co-Authors: Jennifer L. M. Thorson, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Background Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of Disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational Disease. Methods Outbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple Diseases and compared to non-Diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational Disease. Results The exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational Testis Disease, prostate Disease, kidney Disease, and the presence of multiple Disease in the subsequent F3 generation great-grand offspring. The Disease DMRs were found to be Disease specific with negligible overlap between different Diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the Disease specific DMRs were investigated. Interestingly, the majority of the Disease specific sperm DMR associated genes have been previously found to be linked to relevant Disease specific genes. Conclusions Observations demonstrate the EWAS approach identified Disease specific biomarkers that can be potentially used to assess transgenerational Disease susceptibility and facilitate the clinical management of environmentally induced pathology.

  • Epigenetic transgenerational inheritance of Testis pathology and Sertoli cell epimutations: generational origins of male infertility.
    Environmental epigenetics, 2019
    Co-Authors: Ingrid Sadler-riggleman, Daniel Beck, Eric E. Nilsson, Rachel Klukovich, Yeming Xie, Wei Yan, Michael K. Skinner
    Abstract:

    Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect Testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of Testis Disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational Testis Disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male Testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and Testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with Testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of Testis pathologies and male infertility.

  • Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of Disease.
    Environmental epigenetics, 2019
    Co-Authors: Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset Disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of Testis Disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple Disease. The F3 generation DDT males also had significant increases in Testis Disease, prostate Disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney Disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate Disease, kidney Disease, Testis Disease, obesity, and multiple Disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited Disease susceptibility.

  • Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
    PloS one, 2018
    Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. Skinner
    Abstract:

    Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in Testis, prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with Testis Disease, prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.

Margaux Mcbirney - One of the best experts on this subject based on the ideXlab platform.

  • Epigenome-wide association study for atrazine induced transgenerational DNA methylation and histone retention sperm epigenetic biomarkers for Disease
    PloS one, 2020
    Co-Authors: Jennifer L. M. Thorson, Margaux Mcbirney, Daniel Beck, Eric E. Nilsson, Millissia Ben Maamar, Michael K. Skinner
    Abstract:

    Atrazine is a common agricultural herbicide previously shown to promote epigenetic transgenerational inheritance of Disease to subsequent generations. The current study was designed as an epigenome-wide association study (EWAS) to identify transgenerational sperm Disease associated differential DNA methylation regions (DMRs) and differential histone retention regions (DHRs). Gestating female F0 generation rats were transiently exposed to atrazine during the period of embryonic gonadal sex determination, and then subsequent F1, F2, and F3 generations obtained in the absence of any continued exposure. The transgenerational F3 generation males were assessed for Disease and sperm collected for epigenetic analysis. Pathology was observed in pubertal onset and for Testis Disease, prostate Disease, kidney Disease, lean pathology, and multiple Disease. For these pathologies, sufficient numbers of individual males with only a single specific Disease were identified. The sperm DNA and chromatin were isolated from adult one-year animals with the specific Diseases and analyzed for DMRs with methylated DNA immunoprecipitation (MeDIP) sequencing and DHRs with histone chromatin immunoprecipitation (ChIP) sequencing. Transgenerational F3 generation males with or without Disease were compared to identify the Disease specific epimutation biomarkers. All pathologies were found to have Disease specific DMRs and DHRs which were found to predominantly be distinct for each Disease. No common DMRs or DHRs were found among all the pathologies. Epimutation gene associations were identified and found to correlate to previously known Disease linked genes. This is one of the first observations of potential sperm Disease biomarkers for histone retention sites. Although further studies with expanded animal numbers are required, the current study provides evidence the EWAS analysis is effective for the identification of potential pathology epimutation biomarkers for Disease susceptibility.

  • Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of Disease.
    Environmental epigenetics, 2019
    Co-Authors: Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset Disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of Testis Disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple Disease. The F3 generation DDT males also had significant increases in Testis Disease, prostate Disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney Disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate Disease, kidney Disease, Testis Disease, obesity, and multiple Disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited Disease susceptibility.

  • Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
    PloS one, 2018
    Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. Skinner
    Abstract:

    Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in Testis, prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with Testis Disease, prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.

  • Atrazine induced epigenetic transgenerational inheritance of Disease, lean phenotype and sperm epimutation pathology biomarkers.
    PloS one, 2017
    Co-Authors: Margaux Mcbirney, Stephanie E. King, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michelle Pappalardo, Elizabeth Houser, Margaret K. Unkefer, Paul D. Winchester, Michael K. Skinner
    Abstract:

    Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset Disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop Disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of Testis Disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of Testis Disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple Diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of Disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or Testis Disease. These DMRs provide potential biomarkers for transgenerational Disease. The etiology of Disease appears to be in part due to environmentally induced epigenetic transgenerational inheritance, and epigenetic biomarkers may facilitate the diagnosis of the ancestral exposure and Disease susceptibility. Observations indicate that although atrazine does not promote Disease in the directly exposed F1 generation, it does have the capacity to promote the epigenetic transgenerational inheritance of Disease.

Ingrid Sadler-riggleman - One of the best experts on this subject based on the ideXlab platform.

  • Epigenetic transgenerational inheritance of Testis pathology and Sertoli cell epimutations: generational origins of male infertility.
    Environmental epigenetics, 2019
    Co-Authors: Ingrid Sadler-riggleman, Daniel Beck, Eric E. Nilsson, Rachel Klukovich, Yeming Xie, Wei Yan, Michael K. Skinner
    Abstract:

    Male reproductive health has been in decline for decades with dropping sperm counts and increasing infertility, which has created a significant societal and economic burden. Between the 1970s and now, a general decline of over 50% in sperm concentration has been observed in the population. Environmental toxicant-induced epigenetic transgenerational inheritance has been shown to affect Testis pathology and sperm count. Sertoli cells have an essential role in spermatogenesis by providing physical and nutritional support for developing germ cells. The current study was designed to further investigate the transgenerational epigenetic changes in the rat Sertoli cell epigenome and transcriptome that are associated with the onset of Testis Disease. Gestating female F0 generation rats were transiently exposed during the period of fetal gonadal sex determination to the environmental toxicants, such as dichlorodiphenyltrichloroethane (DDT) or vinclozolin. The F1 generation offspring were bred (i.e. intercross within the lineage) to produce the F2 generation grand-offspring that were then bred to produce the transgenerational F3 generation (i.e. great-grand-offspring) with no sibling or cousin breeding used. The focus of the current study was to investigate the transgenerational Testis Disease etiology, so F3 generation rats were utilized. The DNA and RNA were obtained from purified Sertoli cells isolated from postnatal 20-day-old male Testis of F3 generation rats. Transgenerational alterations in DNA methylation, noncoding RNA, and gene expression were observed in the Sertoli cells from vinclozolin and DDT lineages when compared to the control (vehicle exposed) lineage. Genes associated with abnormal Sertoli cell function and Testis pathology were identified, and the transgenerational impacts of vinclozolin and DDT were determined. Alterations in critical gene pathways, such as the pyruvate metabolism pathway, were identified. Observations suggest that ancestral exposures to environmental toxicants promote the epigenetic transgenerational inheritance of Sertoli cell epigenetic and transcriptome alterations that associate with Testis abnormalities. These epigenetic alterations appear to be critical factors in the developmental and generational origins of Testis pathologies and male infertility.

  • Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of Disease.
    Environmental epigenetics, 2019
    Co-Authors: Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michael K. Skinner
    Abstract:

    Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset Disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of Testis Disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple Disease. The F3 generation DDT males also had significant increases in Testis Disease, prostate Disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney Disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate Disease, kidney Disease, Testis Disease, obesity, and multiple Disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited Disease susceptibility.

  • Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
    PloS one, 2018
    Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. Skinner
    Abstract:

    Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in Testis, prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with Testis Disease, prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.

  • Atrazine induced epigenetic transgenerational inheritance of Disease, lean phenotype and sperm epimutation pathology biomarkers.
    PloS one, 2017
    Co-Authors: Margaux Mcbirney, Stephanie E. King, Daniel Beck, Ingrid Sadler-riggleman, Eric E. Nilsson, Michelle Pappalardo, Elizabeth Houser, Margaret K. Unkefer, Paul D. Winchester, Michael K. Skinner
    Abstract:

    Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset Disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop Disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of Testis Disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of Testis Disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple Diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of Disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or Testis Disease. These DMRs provide potential biomarkers for transgenerational Disease. The etiology of Disease appears to be in part due to environmentally induced epigenetic transgenerational inheritance, and epigenetic biomarkers may facilitate the diagnosis of the ancestral exposure and Disease susceptibility. Observations indicate that although atrazine does not promote Disease in the directly exposed F1 generation, it does have the capacity to promote the epigenetic transgenerational inheritance of Disease.