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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    ABSTRACT: Previously a variety of environmental toxicants were found to promote the epigenetic transgenerational inheritance of disease through differential DNA methylation regions (DMRs), termed epimutations, present in sperm. The transgenerational epimutations in sperm and somatic cells identified in a number of previous studies were further investigated.
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    ABSTRACT: Decreasing male fertility has been observed for the past fifty years. Examples of affected reproductive parameters include decreases in sperm count and sperm quality and increases in testicular cancer, cryptorchidism and hypospadias. Exposures to environmental toxicants during fetal development and early postnatal life have been shown to promote infertility. Environmental exposures inducing epigenetic changes related to male infertility range from life style, occupational exposures, environmental toxicants and nutrition. Exposures during fetal gonadal sex determination have been shown to alter the epigenetic programming of the germline that then can transmit this altered epigenetic information to subsequent generations in the absence of any exposures. This environmentally induced epigenetic transgenerational inheritance of disease will be a component of the etiology of male infertility.
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    ABSTRACT: BACKGROUND Obesity and overweight are significantly involved in several reproductive pathologies contributing to infertility in men and women. In addition, several cancers of the reproductive system, such as endometrial, ovarian, breast, testicular and prostate cancers, are strongly influenced by obesity. However, the molecular mechanisms involved in the association between obesity and reproductive disorders remain unclear. Our proposal is to review the current scientific evidence regarding the effect of obesity-related factors as the core of the collective mechanisms directly and indirectly involved in the relationship between obesity and reproductive disorders, with a special and original focus on the effect of the obesity state microenvironment on the epigenetic profile as a reversible mechanistic link between obesity and the reproductive disorders.
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