Article

Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility

Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America.
PLoS ONE (Impact Factor: 3.53). 03/2013; 8(3):e59922. DOI: 10.1371/journal.pone.0059922
Source: PubMed

ABSTRACT Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. 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, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways 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. 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 correlates with 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.

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Available from: Carlos Guerrero-Bosagna, Aug 10, 2015
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    • "Although several studies have documented these changes, they have not been systematically investigated. In most cases, it is unclear how long these presumed environmental epimutations perdure and what molecular pathways are involved in maintaining or reversing these changes (Berger et al., 2009; Guerrero-Bosagna et al., 2013; Robison and Nestler, 2011; Zhang et al., 2013). One approach to address these questions would be to perform tightly controlled, systematic experiments in which genetically identical animals are quantitatively exposed to environmental stressors, such as psychosocial stress or substances of abuse, and then phenotyped for a suite of epigenomic brain features at different time points. "
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    ABSTRACT: Long-lived post-mitotic cells, such as the majority of human neurons, must respond effectively to ongoing changes in neuronal stimulation or microenvironmental cues through transcriptional and epigenomic regulation of gene expression. The role of epigenomic regulation in neuronal function is of fundamental interest to the neuroscience community, as these types of studies have transformed our understanding of gene regulation in post-mitotic cells. This perspective article highlights many of the resources available to researchers interested in neuroepigenomic investigations and discusses some of the current obstacles and opportunities in neuroepigenomics.
    01/2015; 1:2-13. DOI:10.1016/j.nepig.2014.10.001
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    • "Exposure in utero has been related to a number of adverse health endpoints in children, including a higher risk for overweight, alterations in psychomotor and cognitive development or urogenital abnormalities in male newborns (Forns et al., 2012; Palmer et al., 2009; Puertas et al., 2010; Valvi et al. 2013), and several studies have reported sex specific effects occurring by mechanisms that remain poorly understood (Fernandez et al., 2007; Papadopoulou et al., 2013; Vafeiadi et al., 2013; Valvi et al., 2012). A number of in vivo and in vitro studies and a few human investigations have shown effects of EDCs, mainly pesticides, on different epigenetic marks including DNA methylation as reviewed by Collotta et al. (2013) (Collotta et al., 2013), and there is some evidence in animal models of transgenerational inheritance of epigenetic alterations and disease-associated states due to EDC exposure (Guerrero-Bosagna et al., 2012; Guerrero-Bosagna et al., 2013; Manikkam et al., 2013; Skinner et al., 2013). "
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    ABSTRACT: Background Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. Objectives In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. Methods The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated. Results A significant sex interaction was observed for AluYb8 (p-value for interaction < 0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value < 0.001), while no significant effects were found in girls (p-value = 0.134). Conclusions Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
    Environment International 10/2014; 71:81–87. · 5.66 Impact Factor
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    • "Exposure in utero has been related to a number of adverse health endpoints in children, including a higher risk for overweight, alterations in psychomotor and cognitive development or urogenital abnormalities in male newborns (Forns et al., 2012; Palmer et al., 2009; Puertas et al., 2010; Valvi et al. 2013), and several studies have reported sex specific effects occurring by mechanisms that remain poorly understood (Fernandez et al., 2007; Papadopoulou et al., 2013; Vafeiadi et al., 2013; Valvi et al., 2012). A number of in vivo and in vitro studies and a few human investigations have shown effects of EDCs, mainly pesticides, on different epigenetic marks including DNA methylation as reviewed by Collotta et al. (2013) (Collotta et al., 2013), and there is some evidence in animal models of transgenerational inheritance of epigenetic alterations and disease-associated states due to EDC exposure (Guerrero-Bosagna et al., 2012; Guerrero-Bosagna et al., 2013; Manikkam et al., 2013; Skinner et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Prenatal exposure to endocrine disrupting compounds (EDCs) has previously shown to alter epigenetic marks. Objectives: In this work we explore whether prenatal exposure to mixtures of xenoestrogens has the potential to alter the placenta epigenome, by studying DNA methylation in retrotransposons as a surrogate of global DNA methylation. Methods: The biomarker total effective xenoestrogen burden (TEXB) was measured in 192 placentas from participants in the longitudinal INMA Project. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 10 different retrotransposons including 3 different long interspersed nuclear elements (LINEs), 4 short interspersed nuclear elements (SINEs) and 3 human endogenous retroviruses (HERVs). Associations were tested using linear mixed-effects regression models and sex interaction was evaluated. Results: A significant sex interaction was observed for AluYb8 (p-value for interaction <0.001, significant at Bonferroni corrected p-value threshold of 0.0025). Boys with the highest TEXB-alpha levels of exposure (third tertile) presented on average a decrease of 0.84% in methylation compared to those in the first tertile (p-value < 0.001), while no significant effects were found in girls (p-value = 0.134). Conclusions: Our findings suggest that boys may be more susceptible to the effect of exposure to xenoestrogens during prenatal development, producing shifts in DNA methylation of certain sensitive genomic repetitive sequences in a tissue important for fetal growth and development.
    Environment International 06/2014; 71C:81-87. DOI:10.1016/j.envint.2014.06.006 · 5.66 Impact Factor
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