initiated its fifth year of operations with this Volume 5 Issue 1.We are a completely Open Access journal listed in PMC and PubMed, along with numerous other access sites.Environmental Epigenetics initiated its review to obtain an impact factor this year.Two special issues are planned this year in Epigenetics, Environment and Reproduction and in Epigenetic Transgenerational Inheritance, both associated with corresponding scientific meetings around the world.The amount and diversity of our published studies is increasing as the field of environmental epigenetics grows and expands.We are looking forward to another productive year and encourage you to consider submissions to Environmental Epigenetics.The heart of the journal has always been the quality and breadth of the Environmental Epigenetics Editorial Boards.

Epigenetic processes allow organisms to respond to their environment with changes in gene expression. Epigenetic molecular processes include DNA methylation, histone modifications, non-coding RNAs, RNA methylation and chromatin structure. Epigenetic information and epimutations can be transmitted to subsequent generations through sperm or eggs, and can change gene expression and an organism's phenotype even in transgenerational generations that were themselves never exposed to an inducing factor. All cell types and tissues derived from germ cells carrying epimutations will have the potential for an altered epigenome and altered gene expression. Tissues sensitive to an altered gene expression profile will have a different phenotype and have susceptibility to develop disease or abnormalities as the individual ages. Environmental exposures in past generations could have contributed to the incidence of abnormalities and disease in the current human population.

Environmentally induced epigenetic transgenerational inheritance of phenotypic variation and disease susceptibility requires the germ cell (sperm or egg) transmission of integrated epigenetic mechanisms involving DNA methylation, histone modifcations, and noncoding RNA (ncRNA) actions. Previous studies have demonstrated that transgenerational exposure and disease-specifc differential DNA methylation regions (DMRs) in sperm are observed and that ncRNA-mediated DNA methylation occurs. The current study was designed to determine if transgenerational exposure-specifc ncRNAs exist in sperm. Specifcally, toxicants with distinct mechanisms of action including the fungicide vinclozolin (anti-androgenic), pesticide dichlorodiphenyltrichloroethane (estrogenic), herbicide atrazine (endocrine disruptor at cyclic adenosine monophosphate level), and hydrocarbon mixture jet fuel (JP8) (aryl hydrocarbon receptor disruptor) were used to promote transgenerational disease phenotypes in F3 generation outbred rats. New aliquots of sperm, previously collected and used for DNA methylation analyses, were used in the current study for ncRNA sequencing analyses of nuclear RNA. Signifcant changes in transgenerational sperm ncRNA were observed for each transgenerational exposure lineage. The majority of ncRNA was small noncoding RNAs including piwi-interacting RNA, tRNA-derived small RNAs, microRNAs, rRNA-derived small RNA, as well as long ncRNAs. Although there was some overlap among the different classes of ncRNA across the different exposures, the majority of differentially expressed ncRNAs were exposure-specifc with no overlapping ncRNA between the four different exposure lineages in the transgenerational F3 generation sperm nuclear ncRNAs. The ncRNA chromosomal locations and gene associations were identifed for a small number of differential expressed ncRNA. Interestingly, an overlap analysis between the transgenerational sperm DMRs and ncRNA chromosomal locations demonstrated small populations of overlapping ncRNA, but a large population of nonoverlapping ncRNAs. Observations suggest that transgenerational sperm ncRNAs have both exposure-specifc populations within the different classes of ncRNA, as well as some common populations of ncRNAs among the different exposures. The lack of co-localization of many of the ncRNAs with previously identifed transgenerational DMRs suggests a distal integration of the different epigenetic mechanisms. The potential use of ncRNA analyses for transgenerational toxicant exposure assessment appears feasible

The development of molecular biomarkers for disease makes it possible for preventative medicine approaches to be considered. Therefore, therapeutics, treatments, or clinical management can be used to delay or prevent disease development. The problem with genetic mutations as biomarkers is the low frequency with genome-wide association studies (GWASs), generally at best a 1% association of the patients with the disease. In contrast, epigenetic alterations have a high-frequency association of greater than 90%-95% of individuals with pathology in epigenome-wide association studies (EWASs). A wide variety of human diseases have been shown to have epigenetic biomarkers that are disease specific and that detect pathology susceptibility. This review is focused on the epigenetic biomarkers for disease susceptibility, and it distinct from the large literature on epigenetics of disease etiology or progression. The development of efficient epigenetic biomarkers for disease susceptibility will facilitate a paradigm shift from reactionary medicine to preventative medicine.

Preterm birth (PTB) has dramatically increased within the population (i.e. >10%) and preeclampsia is a significant sub-category of PTB. Currently, there are no practical clinical parameters or biomarkers which predict preeclampsia induced PTB. The current study investigates the potential use of epigenetic (DNA methylation) alterations as a maternal preeclampsia biomarker. Non-preeclampsia term births were compared to preeclampsia PTBs to identify DNA methylation differences (i.e. potential epigenetic biomarker). Maternal buccal cell cheek swabs were used as a marker cell for systemic epigenetic alterations in the individuals, which are primarily due to environmentally induced early life or previous generations impacts, and minimally impacted or associated with the disease etiology or gestation variables. A total of 389 differential DNA methylation regions (DMRs) were identified and associated with the presence of preeclampsia. The DMRs were genome-wide and were predominantly low CpG density (<2 CpG/100 bp). In comparison with a previous PTB buccal cell epigenetic biomarker there was a 15% (60 DMR) overlap, indicating that the majority of the DMRs are unique for preeclampsia. Few previously identified preeclampsia genes have been identified, however, the DMRs had gene associations in the P13 K-Akt signaling pathway and metabolic gene family, such as phospholipid signaling pathway. Preliminary validation of the DMR use as a potential maternal biomarker used a cross-validation analysis on the samples and provided 78% accuracy. Although prospective expanded clinical trials in first trimester pregnancies and clinical comparisons are required, the current study provides the potential proof of concept a preeclampsia epigenetic biomarker may exist. The availability of a preeclampsia PTB maternal susceptibility biomarker may facilitate clinical management and allow preventative medicine approaches to identify and treat the preeclampsia condition prior to its occurrence.

Deep learning involves an artificial intelligence (AI) approach and has been shown to provide superior performance for automating image recognition tasks, as well as exceeding human capabilities in both time and accuracy. Histopathology diagnostics is one of the more popular challenges at the intersection of artificial intelligence, computer vision, and medicine. Developing methods to automatically detect and identify pathologies in digitized histology slides imposes unique challenges due to the large size of these images and the complexity of the features present in biological tissue. Most methods that are capable of human-level recognition in histopathology are tuned to a specific problem since the computational complexity exceeds that of traditional image classification problems. In the current study, a deep learning approach is developed and presented that can be trained to locate and accurately classify different types of pathologies in gigapixel digitized histology slides along with completing the binary disease classification for the entire image. The approach uses a novel pyramid tiling approach to take advantage of spatial awareness around the area to be classified, while maintaining efficiency and scalability for gigapixel images. The approach is trained and validated on a wide variety of tissue types (i.e., testis, ovary, prostate, kidney) and pathologies taken from an epigenetically altered histology study at Washington State University. The newly developed procedure was optimized and validated along with comparison and validation on public histology datasets. The current developed procedure was found to be optimal and more reproducible when compared to manual procedures, and optimal to previous protocols that used fragmented tissue or slide analysis. Observations demonstrate that the deep learning histopathology analysis is significantly more efficient and accurate than standard manual histopathology analysis.

The epigenome and epigenetic inheritance were not included in the original modern synthesis theory or more recent extended evolutionary synthesis of evolution. In a broad range of species, the environment has been shown to play a significant role in natural selection, which more recently has been shown to occur through epigenetic alterations and epigenetic inheritance. However, even with this evidence, the field of epigenetics and epigenetic inheritance has been left out of modern evolutionary synthesis, as well as other current evolutionary models. Epigenetic mechanisms can direct the regulation of genetic processes (e.g. gene expression) and also can be directly changed by the environment. In contrast, DNA sequence cannot be directly altered by the environment. The goal of this review is to present the evidence of how epigenetics and epigenetic inheritance can alter phenotypic variation in numerous species. This can occur at a significantly higher frequency than genetic change, so correlates with the frequency of evolutionary change. In addition, the concept and importance of generational stability of transgenerational inheritance is incorporated into evolutionary theory. For there to be a better understanding of evolutionary biology, we must incorporate all aspects of molecular (e.g. genetics and epigenetics) and biological sciences (e.g. environment and adaptation).

Although male infertility is currently diagnosed when abnormal sperm parameters are found, the poor predictive ability of sperm parameters on natural fecundity and medically assisted reproduction outcome poses the need for improved diagnostic techniques for male infertility. The accumulating evidence about the role played by the sperm epigenome in modulation of the early phases of embryonic development has led researchers to focus on the epigenetic mechanisms within the sperm epigenome to find new molecular markers of male infertility. Indeed, sperm epigenome abnormalities could explain some cases of unexplained male infertility in men showing normal sperm parameters and were found to be associated with poor embryo development in IVF cycles. The present mini-review summarizes the current knowledge about this interesting topic, starting from a description of the epigenetic mechanisms of gene expression regulation (i.e. DNA methylation, histone modifications, and non-coding RNAs' activity). We also discuss possible mechanisms by which environmental factors might cause epigenetic changes in the human germline and affect embryonic development, as well as subsequent generations' phenotypes. Studies demonstrating sperm epigenome abnormalities in men with male infertility are reviewed, with particular emphasis on those with the more severe form of spermatogenic dysfunction. Observations demonstrate that the diagnostic and prognostic efficacy of sperm epigenome evaluation will help facilitate the management of men with male factor infertility.

Treponeme-associated hoof disease (TAHD) is an emerging disease of elk ( Cervus canadensis ) in the U.S. Pacific West. Because environmental epigenetics is the primary molecular process that mediates environmental factor impacts on a host organism and disease, the role of epigenetics in TAHD etiology was examined. The current study was designed to examine potential effects of TAHD on systemic epigenetic modifications in infected elk over a range of TAHD lesion severity. Leg tendons that contain predominantly fibroblast connective tissue cells were used to isolate fibroblast cells for epigenetic analysis in unaffected and TAHD-positive male and female Roosevelt and Rocky Mountain elk. Differential DNA methylation regions (DMRs) between the unaffected and TAHD-positive elk were identified for both female and male elk. The presence of TAHD was associated with alteration of the connective tissue cell epigenetics, and DMR associated genes identified. Therefore, the infected elk were found to have a systemic epigenetic alteration that was associated with the disease, despite pathology being generally limited to feet. If the elk germline epigenetics is altered then generational transmission of susceptibility to TAHD may impact subsequent generations through epigenetic inheritance. This first study of epigenetic changes associated with disease in elk suggests that TAHD promotes a systemic effect on the elk epigenetics which could exert health impacts on the elk.

The current study was designed to use an epigenome-wide association approach (EWAS) to identify potential systemic DNA methylation alterations that are associated with obesity using 22 discordant twin pairs. Buccal cells (from a cheek swab) were used as a non-obesity relevant purified marker cell for the epigenetic analysis. Analysis of differential DNA methylation regions (DMRs) was used to identify epigenetic associations with metabolic and dietary measures related to obesity with discordant twins. An edgeR analysis provided a DMR signature with p < 1e-04, but statistical significance was reduced due to low sample size and known multiple origins of obesity. A weighted gene coexpression network analysis (WGCNA) was performed and identified modules (p < 0.005) of epigenetic sites that correlated with different metabolic and dietary measures. The DMR and WGCNA epigenetic sites were near genes (e.g., CIDEC, SPP1, ZFPG9, and POMC) with previously identified obesity associated pathways (e.g., metabolism, cholesterol, and fat digestion). Observations demonstrate the feasibility of identifying systemic epigenetic biomarkers for obesity, which can be further investigated for clinical relevance in future research with larger sample sizes. The availability of a systemic epigenetic biomarker for obesity susceptibility may facilitate preventative medicine and clinical management of the disease early in life.

Abnormal penile foreskin development in hypospadias is the most frequent genital malformation in male children, which has increased dramatically in recent decades. A number of environmental factors have been shown to be associated with hypospadias development. The current study investigated the role of epigenetics in the etiology of hypospadias and compared mild (distal), moderate (mid shaft), and severe (proximal) hypospadias. Penile foreskin samples were collected from hypospadias and non-hypospadias individuals to identify alterations in DNA methylation associated with hypospadias. Dramatic numbers of differential DNA methylation regions (DMRs) were observed in the mild hypospadias, with reduced numbers in moderate and low numbers in severe hypospadias. Atresia (cell loss) of the principal foreskin fibroblast is suspected to be a component of the disease etiology. A genome-wide (> 95%) epigenetic analysis was used and the genomic features of the DMRs identified. The DMR associated genes identified a number of novel hypospadias associated genes and pathways, as well as genes and networks known to be involved in hypospadias etiology. Observations demonstrate altered DNA methylation sites in penile foreskin is a component of hypospadias etiology. In addition, a potential role of environmental epigenetics and epigenetic inheritance in hypospadias disease etiology is suggested.

Exposure to environmental toxicants can lead to epimutations in the genome and an increase in differential DNA methylated regions (DMRs) that have been linked to increased susceptibility to various diseases. However, the unique effect of particular toxicants on the genome in terms of leading to unique DMRs for the toxicants has been less studied. One hurdle to such studies is the low number of observed DMRs per toxicants. To address this hurdle, a previously validated hybrid deep-learning cross-exposure prediction model is trained per exposure and used to predict exposure-specific DMRs in the genome. Given these predicted exposure-specific DMRs, a set of unique DMRs per exposure can be identified. Analysis of these unique DMRs through visualization, DNA sequence motif matching, and gene association reveals known and unknown links between individual exposures and their unique effects on the genome. The results indicate the potential ability to define exposure-specific epigenetic markers in the genome and the potential relative impact of different exposures. Therefore, a computational approach to predict exposure-specific transgenerational epimutations was developed, which supported the exposure specificity of ancestral toxicant actions and provided epigenome information on the DMR sites predicted.

The security and privacy of personal information have become a particular concern in health care. Where the individual, technology and information are combined in personal health devices, these issues become more acute. However, as more people take an interest in monitoring their fitness and healthcare providers recognise the need for individualised care solutions, questions emerge about the control and ownership of data. Mobile data gathering from health promoting wearable technologies presents operational and functional challenges for the user and analytic, data management, and ethical problems for the service providers. Health tracking not only harvests sensitive information but can allow data sharing with communities of other uses, as well as third parties. One leader in this field is Fitbit and original research examined how users understand the significance of connectivity, temporality and agency. The results demonstrate the importance that users place on autonomy over their fitness and other health objectives and show that user attitudes to data sharing are determined by the sensitivity of their information. But it also pinpoints that in general users are unaware of how the company is using their personal data. The chapter concludes with a discussion of mobile, ‘always on’ data gathering and its implications for privacy and regulation.

Three successive multiple generations of rats were exposed to different toxicants and then bred to the transgenerational F5 generation to assess the impacts of multiple generation different exposures. The current study examines the actions of the agricultural fungicide vinclozolin on the F0 generation, followed by jet fuel hydrocarbon mixture exposure of the F1 generation, and then pesticide dichlorodiphenyltrichloroethane on the F2 generation gestating females. The subsequent F3 and F4 generations and F5 transgenerational generation were obtained and F1-F5 generations examined for male sperm epigenetic alterations and pathology in males and females. Significant impacts on the male sperm differential DNA methylation regions were observed. The F3-F5 generations were similar in similar to 50% of the DNA methylation regions. The pathology of each generation was assessed in the testis, ovary, kidney, and prostate, as well as the presence of obesity and tumors. The pathology used a newly developed Deep Learning, artificial intelligence-based histopathology analysis. Observations demonstrated compounded disease impacts in obesity and metabolic parameters, but other pathologies plateaued with smaller increases at the F5 transgenerational generation. Observations demonstrate that multiple generational exposures, which occur in human populations, appear to increase epigenetic impacts and disease susceptibility.

Germline transmission of epigenetic information is a critical component of epigenetic inheritance. Previous studies have suggested that an erasure of DNA methylation is required to develop stem cells in the morula embryo. An exception involves imprinted genes that escape this DNA methylation erasure. Transgenerational differential DNA methylation regions (DMRs) have been speculated to be imprinted-like and escape this erasure. The current study was designed to assess if morula embryos escape the erasure of dichlorodiphenyltrichloroethane-induced transgenerational sperm DMR methylation. Observations demonstrate that the majority (98%) of transgenerational sperm DMR sites retain DNA methylation and are not erased, so appearing similar to imprinted-like sites. Interestingly, observations also demonstrate that the majority of low-density CpG genomic sites had a significant increase in DNA methylation in the morula embryo compared to sperm. This is in contrast to the previously observed DNA methylation erasure of higher-density CpG sites. The general erasure of DNA methylation during embryogenesis appears applicable to high-density DNA methylation sites (e.g. CpG islands) but neither to transgenerational DMR methylation sites nor to low-density CpG deserts, which constitute the vast majority of the genome's DNA methylation sites. The role of epigenetics during embryogenesis appears more dynamic than the simple erasure of DNA methylation.