@article{915cb1299fcd4620a83ce47de4075393,
title = "Developmental origins of transgenerational sperm histone retention following ancestral exposures",
abstract = "Numerous environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Alterations in the germline epigenome are necessary to transmit transgenerational phenotypes. In previous studies, the pesticide DDT (dichlorodiphenyltrichloroethane) and the agricultural fungicide vinclozolin were shown to promote the transgenerational inheritance of sperm differential DNA methylation regions, non-coding RNAs and histone retention, which are termed epimutations. These epimutations are able to mediate this epigenetic inheritance of disease and phenotypic variation. The current study was designed to investigate the developmental origins of the transgenerational differential histone retention sites (called DHRs) during gametogenesis of the sperm. Vinclozolin and DDT were independently used to promote the epigenetic transgenerational inheritance of these DHRs. Male control lineage, DDT lineage and vinclozolin lineage F3 generation rats were used to isolate round spermatids, caput epididymal spermatozoa, and caudal sperm. The DHRs distinguishing the control versus DDT lineage or vinclozolin lineage samples were determined at these three developmental stages. DHRs and a reproducible core of histone H3 retention sites were observed using an H3 chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis in each of the germ cell populations. The chromosomal locations and genomic features of the DHRs were analyzed. A cascade of epigenetic histone retention site alterations was found to be initiated in the round spermatids and then further modified during epididymal sperm maturation. Observations show that in addition to alterations in sperm DNA methylation and ncRNA expression previously identified, the induction of differential histone retention sites (DHRs) in the later stages of spermatogenesis also occurs. This novel component of epigenetic programming during spermatogenesis can be environmentally altered and transmitted to subsequent generations through epigenetic transgenerational inheritance.",
keywords = "DDT, Epigenetics, Histones, Inheritance, Sperm, Spermatogenesis, Transgenerational, Vinclozolin",
author = "{Ben Maamar}, Millissia and Daniel Beck and Eric Nilsson and McCarrey, {John R.} and Skinner, {Michael K.}",
note = "Funding Information: The developmental origins or alterations of individual DHRs were investigated through comparing the individual stages. The developmental time course of the top 100 most statistically significant DHRs are presented in Fig. 8. The DHRs from a transgenerational exposure lineage greater than control lineage (increase in histone presence) or control lineage greater than exposure lineage (decrease in histone presence) are shown. The scaled sequencing read depth normalization is presented for all the DHRs related to the stage of development of round spermatids (rs), caput spermatozoa (caput), or cauda sperm (cauda). The asterisk indicates a statistical difference for a DHR at a specific stage. For the round spermatid DHRs, the exposure lineage DDT or vinclozolin were high and most declined in subsequent development, Fig. 8B and H. For the round spermatid DHRs, the exposure lineage DHRs generally had a reduction (control > exposure) at later stages of development, Fig. 8E and K, with those which can increase (exposure > control) remaining constant, Fig. 8F & L. For the caput DHRs, there was a mixture of an increase or decrease at the other stages for both control and exposure lineages, Fig. 8C, D, I & J. For the cauda DHRs, the DHRs had similarities between the different stages, Fig. 8E, F, K & L. Overall, the DHRs displayed dynamic patterns during development. Observations support the concept that a complex cascade of DHR change is observed during the developmental process, and that many DHRs are present throughout the developmental process, Fig. 8.The potential role of epigenetic alterations in the sperm in epigenetic transgenerational inheritance involves potential modifications in the zygote and early embryo following fertilization. The alterations in differential DNA methylation regions (DMRs) sites are retained if the DNA methylation erasure is protected like an imprinted gene site, which has the ability to alter the stem cell epigenetics and transcriptome (Jirtle and Skinner, 2007; Nilsson et al., 2018). The DHRs may also impact the early embryo following fertilization by altering early gene expression events (Ihara et al., 2014; Okada and Yamaguchi, 2017; Jenkins and Carrell, 2012; Castillo et al., 2018; Samson et al., 2014; Teperek et al., 2016). The current study supports the existence of transgenerational DHR alterations, but the functional role following fertilization remains to be established. In the event the embryo stem cell population has a modified epigenetics and corresponding transcriptome, then all somatic cells derived from the stem cell population will have an altered cascade of epigenetic and gene expression programing to result in adult differentiated cells with altered epigenetics and transcriptomes, as previously described (Guerrero-Bosagna et al., 2013; Klukovich et al., 2019). These alterations in somatic cell genome activity and epigenetics are anticipated to alter disease susceptibility. Although the potential for such germline epigenetic alterations to promote such events exist (Ihara et al., 2014; Okada and Yamaguchi, 2017; Jenkins and Carrell, 2012; Castillo et al., 2018; Samson et al., 2014; Teperek et al., 2016), many of the specific molecular aspects involved remain to be established. The current study on alterations in DHRs does support a potential role for histone retention in epigenetic transgenerational inheritance, but further studies are required to elucidate the specific molecular events and causal functional significance involved.We acknowledge Ms. Michelle Pappalardo, and Mr. Ryan Thompson for technical assistance. We acknowledge Ms. Amanda Quilty for editing and Ms. Heather Johnson for assistance in preparation of the manuscript. We thank the Genomics Core laboratory at WSU Spokane for sequencing data. This study was supported by John Templeton Foundation (50183 and 61174) (https://templeton.org/) grants to MKS and NIH (ES012974) (https://www.nih.gov/) grant to MKS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We acknowledge Ms. Michelle Pappalardo, and Mr. Ryan Thompson for technical assistance. We acknowledge Ms. Amanda Quilty for editing and Ms. Heather Johnson for assistance in preparation of the manuscript. We thank the Genomics Core laboratory at WSU Spokane for sequencing data. This study was supported by John Templeton Foundation ( 50183 and 61174 ) ( https://templeton.org/ ) grants to MKS and NIH ( ES012974 ) ( https://www.nih.gov/ ) grant to MKS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = sep,
day = "1",
doi = "10.1016/j.ydbio.2020.06.008",
language = "English (US)",
volume = "465",
pages = "31--45",
journal = "Developmental Biology",
issn = "0012-1606",
publisher = "Academic Press Inc.",
number = "1",
}