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      A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

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          Abstract

          Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle-related conditions suggest a paternal influence on the offspring’s future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non-coding RNAs are viable mechanistic candidates for a non-genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health-related effects in future generations.

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          Most cited references122

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          Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.

          Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting, the lethality of Dnmt3a and Dnmt3b knockout mice has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.
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            Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations

            Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1–F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the “plastics” or “lower dose plastics” mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
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              Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

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                Author and article information

                Journal
                8510851
                1014
                Bioessays
                Bioessays
                BioEssays : news and reviews in molecular, cellular and developmental biology
                0265-9247
                1521-1878
                15 May 2014
                16 January 2014
                April 2014
                06 June 2014
                : 36
                : 4
                : 359-371
                Affiliations
                [1) ]Epidemiology Research Group, Department of Public Health and Primary Care, Faculty of Medicine, KU Leuven, Leuven, Belgium
                [2) ]Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
                [3) ]Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA
                [4) ]Department of Sport and Exercise Sciences, Institute of Sport and Physical Activity Research (ISPAR), University of Bedfordshire, Bedford, Bedfordshire, UK
                Author notes
                [* ]Corresponding author: Adelheid Soubry, adelheid.soubry@ 123456hotmail.com
                Article
                NIHMS584616
                10.1002/bies.201300113
                4047566
                24431278
                de69f95c-26ad-4ca2-80f2-a6bc52fa9d77
                © 2014 The Authors.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non–commercial and no modifications or adaptations are made.

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                Categories
                Article

                Cell biology
                developmental origins of health and disease (dohad),environment,epigenetics,imprinted genes,offspring,paternal exposures,spermatogenesis,transgenerational effects

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