Abstract Nutritional challenges and obesity can contribute to the transmission of metabolic diseases through epigenetic mechanisms. Among them, DNA methylation stands out as a potential carrier of information because germline cytosine methylation responds to environmental factors and can be transmitted across generations. Yet, it remains unclear whether inherited DNA methylation plays an active role in the inheritance of metabolic phenotypes or solely influences expression of a few genes that cannot recapitulate the whole metabolic spectrum in the next generation offspring. Previously, we established a mouse model of childhood obesity by reducing litter size at birth. Mice raised in small litters (SL) developed obesity, insulin resistance, and hepatic steatosis. The offspring (SL-F1) and grand-offspring (SL-F2) of SL males also exhibited hepatic steatosis. Here, we aimed to investigate whether germline DNA methylation could serve as a carrier of phenotypic information, hepatic steatosis, between generations. Litter size reduction significantly altered global DNA methylation profile in the sperm of SL-F0 males. Remarkably, 8% of these methylation marks remained altered in the sperm of SL-F1 mice and in the liver of SL-F2 mice. These data suggest that germline DNA methylation is sensitive to environmental challenges and holds significant heritability, either through direct germline transmission and/or through sequential erasure and reestablishment of the marks in the following generations. Yet, DNA methylation did not strongly correlate with the hepatic transcriptome in SL-F2 mice, suggesting that it does not directly drive phenotypes in the F2. As an alternative, germline DNA methylation could potentially influence the phenotype of the next generation by modulating the expression of a reduced number of key transcription factors that, through an amplification cascade, drive phenotypic outcomes in subsequent generations. HighlightsEarly obesity induced epigenetic inheritance of hepatic steatosis until the F2Childhood obesity broadly modified sperm DNA methylation in the exposed individualsA substantial number of sperm-borne methyl-marks were transmitted (i.e., inherited) to the offspring and grand-offspring.Sperm-bone methyl-marks do not seem to influence global transcription profile, and therefore phenotypic outcomes, in the F2.Instead, germline DNA methylation may influence the phenotype of the next generation by modulating the expression of a select group of key transcription factors.

Abstract Mesoamerican nephropathy (MeN) is a leading cause of morbidity and mortality in Central America, yet its aetiology remains unclear. Environmental exposures including heat stress, pesticides and heavy metals have all been suggested as possible causes or exacerbating factors of the disease, but intermittent and cumulative exposures are difficult to capture using conventional biomonitoring. Locus-specific differential DNA-methylation (DNAm) which is known to occur in association with these environmental exposures can be readily measured in peripheral blood leucocytes, and therefore have the potential to be used as biomarkers of these exposures. In this study, we aimed first to perform a hypothesis-free epigenome-wide association study of MeN to identify disease-specific methylation signatures, and second to explore the association of DNAm changes associated with potentially relevant environmental exposures and MeN onset. Whole-blood epigenome-wide DNAm was analysed from a total of 312 blood samples: 53 incident cases (pre- and post-evidence of disease onset), 61 matched controls and 16 established cases, collected over a 5-year period. Mixed-effect models identified three unique differentially methylated regions that associated with incident kidney injury, two of which lie within the intron of genes (Amphiphysin on chromosome 7, and SLC29A3 chromosome 10), none of which have been previously reported with any other kidney disease. Next, we conducted a hypothesis-driven analysis examining the coefficients of CpG sites reported to be associated with ambient temperature, pesticides, arsenic, cadmium and chromium. However, none showed an association with MeN disease onset. Therefore, we did not observe previously reported patterns of DNA methylation that might support a role of pesticides, temperature or the examined metals in causing MeN.

ABSTRACT Fine particulate matter (PM2.5), an atmospheric pollutant that settles deep in the respiratory tract, is highly harmful to human health. Despite its well-known impact on lung function and its ability to exacerbate asthma, the molecular basis of this effect is not fully understood. This integrated transcriptomic and epigenomic data analysis from publicly available datasets aimed to determine the impact of PM2.5 exposure and its association with asthma in human airway epithelial cells. Differential gene expression and binding analyses identified 349 common differentially expressed genes and genes associated with differentially enriched H3K27ac regions in both conditions. Co-expression network analysis revealed three preserved modules (Protein Folding, Cell Migration, and Hypoxia Response) significantly correlated with PM2.5 exposure and preserved in asthma networks. Pathways dysregulated in both conditions included epithelial function, hypoxia response, IL-17 and TNF signaling, and immune/inflammatory processes. Hub genes like TGFB2, EFNA5, and PFKFB3 were implicated in airway remodeling, cell migration, and hypoxia-induced glycolysis. These findings elucidate common altered expression patterns and processes between PM2.5 exposure and asthma, helping to understand their molecular connection. This provides guidance for future research to utilize them as potential biomarkers or therapeutic targets and generates evidence supporting the need for implementing effective air quality management strategies.

Abstract Environmental exposures, including air pollutants and lack of natural spaces, are associated with suboptimal health outcomes in children. We aimed to study the associations between environmental exposures and gene expression in children. Associations of exposure to particulate matter with diameter < 2.5 (PM2.5) and < 10 (PM10) micrometers, nitrogen dioxide, green spaces, and blue space, with whole blood gene expression were explored in children from the Dutch Generation R Study (n=172). Analyses were adjusted for age, sex, batch, maternal education, and area socioeconomic status. Follow-up analysis was carried out using lymphoblastoid cell line gene expression in children from the ALSPAC Study (n=946). Gene set enrichment analysis using hallmark and immune gene sets from the molecular signature database was carried out to identify significantly over-represented gene sets for insights into biological mechanisms. Exposure to PM2.5 was associated with expression of 86 genes in discovery analyses in the Generation R Study (false discovery rate-adjusted p-value < 0.25). Of these, PM2.5 was also associated with GNG11 expression in the same direction in follow-up analysis (false discovery rate-adjusted p-value < 0.05). The remaining exposures showed much fewer associations in the discovery analyses. Gene set enrichment analysis using PM2.5 association results for both cohorts indicated suppression of gene sets related to interferon response and response to bacterial and viral exposure. In conclusion, gene expression analysis performed in two independent cohorts, suggests that PM2.5 exposure in children may be involved in interferon and microbial infection responses.

Abstract Background: The increasing prevalence of neurodegenerative diseases poses a significant public health challenge, prompting a growing focus on addressing modifiable risk factors of disease (e.g. physical inactivity, mental illness and air pollution). The environment is a significant contributor of risk factors which are known to impact the brain and contribute to disease risk (e.g. air pollution, noise pollution, green and blue spaces). Epigenetics can offer insights into how various environmental exposures impact the body to contribute to cognitive outcomes. Main body: In this systematic review, we examined studies which have associated an environmental exposure to a type of epigenetic modification, DNA methylation, and a cognitive outcome. We searched four databases with keywords “environmental exposures”, “epigenetics” and “cognition”. We yielded 6886 studies that we screened by title/abstract followed by full text. We included 14 studies which focused on four categories of environmental exposure: air pollution (n=3), proximity to roads (n=1), heavy metals (n=6) and pesticides (n=4). Overall, n=10/14 studies provided evidence that DNA methylation is statistically significant in the association between the environment and a cognitive outcome. Further, we identified that n=5/14 studies performed a type of biological pathway analysis to determine the presence of biological pathways between their environmental exposure and cognitive outcome. Conclusion: Our findings underscore the need for methodological improvements and considerations in future studies, including investigation of other environmental exposures considering tissue-specificity of methylation profiles and stratifying analysis by sex, ethnicity and socio-economic determinants of disease. This review demonstrates that further investigation is warranted, the findings of which may be of use in the development of preventative measures and risk management strategies for neurodegenerative disease.

Abstract Among the various environmental pollutants, dioxin, a highly toxic and widely used compound, is associated with numerous adverse health effects, including a potentially toxic multi-generational effect. Understanding the mechanisms by which dioxin exposure can affect sperm epigenetics is critical to comprehending the potential consequences for offspring health and development. This study investigates the possible association between weighted epimutations, hypothesised as markers of epigenetic drift, and dioxin exposure in sperm tissues. We used a public online methylation dataset consisting of 37 participants: 26 Vietnam veterans exposed to Agent Orange, an herbicide contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 11 individuals not directly exposed to TCDD but whose serum dioxin levels are equivalent to the background. In our study, conducted at the gene level, 437 epimutated genes were identified as significantly associated with each single-digit increase in serum dioxin levels. We found no significant association between the rise in total epimutation load and serum dioxin levels. The pathway analysis performed on the genes reveals biological processes mainly related to changes in embryonic morphology, development and reproduction. Results from our current study suggest the importance of further investigations on the consequences of dioxin exposure in humans with specific reference to germinal tissue and related heredity.

Abstract Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by a broad range of symptoms. The etiology of ASD is thought to involve complex gene-environment interactions, which are crucial to understanding its various causes and symptoms. DNA methylation is an epigenetic mechanism that potentially links genetic predispositions to environmental factors in the development of ASD. This review provides a global perspective on ASD, focusing on how DNA methylation studies may reveal gene-environment interactions characteristic of specific geographical regions. It delves into the role of DNA methylation in influencing the causes and prevalence of ASD in regions where environmental influences vary significantly. We also address potential explanations for the high ASD prevalence in North America, considering lifestyle factors, environmental toxins, and diagnostic considerations. Asian and European studies offer insights into endocrine-disrupting compounds (EDC), persistent organic pollutants (POP), maternal smoking, and their associations with DNA methylation alterations in ASD. In areas with limited data on DNA methylation and ASD, such as Africa, Oceania, and South America, we discuss prevalent environmental factors based on epidemiological studies. Additionally, the review integrates global and country-specific prevalence data from various studies, providing a comprehensive picture of the variables influencing ASD diagnoses over region and year of assessment. This prevalence data, coupled with regional environmental variables and DNA methylation studies, provides a perspective on the complexities of ASD research. Integrating global prevalence data, we underscore the need for a comprehensive global understanding of ASD’s complex etiology. Expanded research into epigenetic mechanisms of ASD is needed, particularly in underrepresented populations and locations, to enhance biomarker development for diagnosis and intervention strategies for ASD that reflect the varied environmental and genetic landscapes worldwide.

Abstract Preterm birth has dramatically increased within the population (i.e., >10%) and preeclampsia is a significant sub-category of preterm birth. Currently, there are no practical clinical parameters or biomarkers which predict preeclampsia induced preterm birth. 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 preterm births 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 preterm birth buccal cell epigenetic biomarker there was a 15% (60 DMR) overlap, indicating 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 P13K-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 a 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 preterm birth maternal susceptibility biomarker may facilitate clinical management and allow preventative medicine approaches to identify and treat the preeclampsia condition prior to its occurrence.

ABSTRACT Background: Little is understood about the role of mitochondria in pregnancy-related adaptations. Therefore, we evaluated associations of maternal early-to-mid pregnancy mitochondrial DNA copy number (mtDNAcn) and mtDNA methylation with birth size and gestational length. Methods: Michigan women (n=396) provided venous bloodspots at median 11 weeks gestation to quantify mtDNAcn marker NADH-ubiquinone oxidoreductase chain 1 (ND1) using real-time quantitative PCR and mtDNA methylation at several regions within four mitochondria-specific genes using pyrosequencing: MTTF (mitochondrially encoded tRNA phenylalanine), DLOOP (D-loop promoter region, heavy strand), CYTB (cytochrome b), and LDLR (D-loop promoter region, light strand). We abstracted gestational length and birthweight from birth certificates and calculated birthweight z-scores using published references. We used multivariable linear regression to evaluate associations of mtDNAcn and mtDNA methylation with birthweight and birthweight z-scores. Cox Proportional Hazards Models (PHMs) and quantile regression characterized associations of mitochondrial measures with gestational length. We also considered differences by fetal sex. Results: Using linear regression and Cox PHMs, mtDNAcn was not associated with birth outcomes, whereas associations of mtDNA methylation with birth outcomes were inconsistent. However, using quantile regression, mtDNAcn was associated with shorter gestation in female newborns at the upper quantiles of gestational length, but with longer gestational length in males at the lower quantiles of gestational length. Maternal LDLR, DLOOP, and MTTF methylation was associated with longer gestational length in females at the upper quantiles and in males at lower gestational length quantiles. Conclusions: Maternal mtDNAcn and mtDNA methylation were associated with gestational length in babies born comparatively early or late, which could reflect adaptations in mitochondrial processes that regulate the length of gestation.

ABSTRACT Air pollution is a hazardous contaminant, exposure to which has substantial consequences for health during critical periods, such as pregnancy. MicroRNA (miRNA) are an epigenetic mechanism that modulates transcriptome responses to the environment and have been found to change in reaction to air pollution exposure. The data are limited regarding extracellular-vesicle (EV) miRNA variation associated with air pollution exposure during pregnancy and in susceptible populations who may be disproportionately exposed. This study aimed to identify EV-miRNA expression associated with ambient, residential exposure to PM2.5, PM10, NO2, O3 and with traffic-related NOx in 461 participants of the MADRES cohort, a low income, predominantly Hispanic pregnancy cohort based in Los Angeles, CA. This study used residence-based modeled air pollution data as well as Nanostring panels for EVmiRNA extracted with Qiagen exoRNeasy kits to evaluate 483 miRNA in plasma in early and late pregnancy. Average air pollution exposures were considered separately for 1-day, 1-week and 8-week windows before blood collection in both early and late pregnancy. This study identified 63 and 66 EV-miRNA significantly associated with PM2.5 and PM10, respectively, and 2 miRNA associated with traffic-related NOX (FDR-adjusted p-value<0.05). Of 103 unique EV-miRNA associated with PM, 92% were associated with lung conditions according to HMDD (Human miRNA Disease Database) evidence. In particular, EV-miRNA previously identified with air pollution exposure also associated with PM2.5 and PM10 in this study were: miR-126, miR-16-5p, miR-187-3p, miR200b-3p, miR486-3p, and miR-582-3p. There were no significant differences in average exposures in early vs late pregnancy. Significant EV-miRNA were only identified in late pregnancy with an eight-week exposure window, suggesting a vulnerable timeframe of exposure, rather than an acute response. These results describe a wide array of EV-miRNA for which expression is affected by PM exposure and may be in part mediating the biological response to ambient air pollution, with potential for health implications in pregnant women and their children.

Abstract Ocean acidification significantly affects marine calcifiers like oysters, warranting the study of molecular mechanisms like DNA methylation that contribute to adaptive plasticity in response to environmental change. However, a consensus has not been reached on the extent to which methylation modules gene expression, and in turn plasticity, in marine invertebrates. In this study, we investigated the impact of pCO2 on gene expression and DNA methylation in the eastern oyster, Crassostrea virginica. After a 30-day exposure to control (572 ppm) or elevated pCO2 (2,827 ppm), whole genome bisulfite sequencing (WGBS) and RNA-Seq data were generated from adult female gonad tissue and male sperm samples. Although differentially methylated loci (DML) were identified in females (89) and males (2,916), there were no differentially expressed genes, and only one differentially expressed transcript in females. However, gene body methylation impacted other forms of gene activity in sperm, such as the maximum number of transcripts expressed per gene and changes in the predominant transcript expressed. Elevated pCO2 exposure increased gene expression variability (transcriptional noise) in males but decreased noise in females, suggesting a sex-specific role of methylation in gene expression regulation. Functional annotation of genes with changes in transcript-level expression or containing DML revealed several enriched biological processes potentially involved in elevated pCO2 response, including apoptotic pathways and signal transduction, as well as reproductive functions. Taken together, these results suggest that DNA methylation may regulate gene expression variability to maintain homeostasis in elevated pCO2 conditions and could play a key role in environmental resilience in marine invertebrates.

Abstract Blood-based, observational, and cross-sectional epidemiological studies suggest that air pollutant exposures alter biological aging. In a single-blinded randomized crossover human experiment of seventeen volunteers, we examined the effect of randomized 2-hour controlled air pollution exposures on respiratory tissue epigenetic aging. Bronchial epithelial cell DNA methylation (DNAm) 24-hours post-exposure was measured using the HumanMethylation450K BeadChip, and there was a minimum 2-week washout period between exposures. All seventeen volunteers were exposed to ozone, but only thirteen were exposed to diesel exhaust. Horvath DNAmAge (Pearson coefficient [r]=0.64; Median Absolute Error [MAE]=2.7-years), GrimAge (r=0.81; MAE=13-years), and DNAm Telomere Length (DNAmTL) (r=-0.65) were strongly correlated with chronological age in this tissue. Compared to clean air, ozone exposure was associated with longer DNAmTL (median difference 0.11kb, Fisher-exact p-value=0.036). This randomized trial suggests a weak relationship of ozone exposure with DNAmTL in target respiratory cells. Still, causal relationships with long-term exposures need to be evaluated.

Abstract A prior study reported no association between prenatal-smoking methylation scores and adult lung cancer risk adjusting for methylation-predicted adult smoking, without considering maternal smoking trends by birth cohort. To address this gap, we examined the association between prenatal-smoking methylation scores and adult lung cancer, independent of methylation-predicted adult packyears, and by birth cohort, in a study nested in CLUE II. Included were 208 incident lung cancer cases ascertained by cancer registry linkage and 208 controls matched on age, sex, and smoking. DNA methylation was measured in prediagnostic blood. We calculated two prenatal-smoking scores, using 19 (Score-19) and 15 (Score-15) previously-identified CpGs and a methylation-predicted adult packyears score. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for adult packyears score and batch effects. Score-15 was positively associated with lung cancer (per SD, OR=1.40, 95%CI 1.10-1.79, p-trend=0.006), especially in the 1930-38 birth cohort (OR=3.43, 95%CI 1.55-7.60, p-trend=0.002). Score-19 was associated only in the 1930-38 birth cohort (OR=2.12, 95%CI 1.15-3.91). Participants with both prenatal scores below the median (vs all other combinations) had lower risk (OR=0.44, 95%CI 0.27-0.72), especially in the 1930-38 birth cohort (OR=0.16, 95%CI 0.04-0.62). Among ever smokers, participants with higher prenatal smoking scores had higher risk, irrespective of adult packyears (low: OR=2.81, 95%CI 1.38-5.72, high: OR=2.67, 95%CI 1.03-6.95). This prospective study suggests a positive association between prenatal smoking exposure and adult lung cancer risk, especially in the 1930-38 birth cohort, independent of active smoking. Future studies with multiple birth cohorts are needed.

Abstract 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 modifications, and non-coding RNA (ncRNA) actions. Previous studies have demonstrated that transgenerational exposure and disease-specific 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-specific ncRNAs exist in sperm. Specifically, toxicants with distinct mechanisms of action including the fungicide vinclozolin (anti-androgenic), pesticide DDT (dichlorodiphenyltrichloroethane) (estrogenic), herbicide atrazine (endocrine disruptor at cAMP level), and hydrocarbon mixture jet fuel (JP8) (aryl hydrocarbon receptor (AHR) 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. Significant changes in transgenerational sperm ncRNA were observed for each transgenerational exposure lineage. The majority of ncRNA was small noncoding RNAs (sncRNA) including piwi-interacting RNA (piRNAs), tRNA-derived small RNAs (tsRNA), microRNAs (miRNAs), rRNA-derived small RNA (rsRNA), as well as long ncRNAs (lncRNAs). Although there was some overlap among the different classes of ncRNA across the different exposures, the majority of differentially expressed ncRNAs were exposure-specific 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 identified 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 non-overlapping ncRNAs. Observations suggest transgenerational sperm ncRNAs have both exposure-specific 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 identified transgenerational DMRs suggests a distal integration of the different epigenetic mechanisms. The potential use of ncRNA analyses for transgenerational toxicant exposure assessment appears feasible.

ABSTRACT This study sheds new light on the timescale through which histone post-translational modifications (PTMs) respond to environmental stimuli, demonstrating that the histone PTM response does not necessarily precede the proteomic response or acclimation. After a variety of salinity treatments were administered to Mozambique tilapia (Oreochromis mossambicus) throughout their lifetimes, we quantified 343 histone PTMs in the gills of each fish. We show here that histone PTMs differ dramatically between fish exposed to distinct environmental conditions for 18 months, and that the majority of these histone PTM alterations persist for at least four weeks, irrespective of further salinity changes. However, histone PTMs respond minimally to four-week-long periods of salinity acclimation during adulthood. The results of this study altogether signify that patterns of histone PTMs in individuals reflect their prolonged exposure to environmental conditions.

Abstract The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue. We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of brown adipose tissue. To address this, we exposed C57BL/6J mice to DDT or DDE from gestational day 11.5 to postnatal day 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA-sequencing of brown adipose tissue from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway- and gene-level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mTOR signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. In vitro exposure led to limited changes in RNA expression; however mitochondrial membrane potential was decreased in vitro with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse brown adipose tissue, and the mitochondrial function of human brown adipocytes.

Abstract Violence against women is a pervasive global issue with profound impacts on victims’ well-being, extending across cultural boundaries. Besides immediate physical harm, it triggers mental health consequences such as post-traumatic stress disorder (PTSD). Indeed, it is the trauma experienced during a violent event that can lead to epigenetic modifications, ultimately contributing to the onset of PTSD. While research on trauma’s epigenetic effects initially focused on war veterans and disaster survivors, there’s a dearth of studies on violence against women. In this article, we performed a systematic review aimed to fill this gap, examining existing studies on violence’s epigenetic impact on adult women. The review assessed sample sizes, study validity and gene-specific investigations. Currently, there’s insufficient data for a comprehensive meta-analysis, highlighting a nascent stage in understanding this complex issue. Future research is crucial for deeper insights into epigenetic mechanisms related to violence against women, contributing to improved interventions and support health care systems for affected individuals.

Abstract Exposure to trace elements influences DNA methylation patterns, which may be associated with disease development. Vulnerable populations, such as adolescents undergoing maturity, are susceptible to the effects of trace element exposure. The aim of this study was to analyze the association of hair trace elements concentration with DNA methylation in a sample from female adolescents living in two communities in the Colombian Caribbean coast. Hair and blood samples were obtained from 45 females, between 13 and 16 years of age. Seventeen trace elements were quantified in hair samples. DNA methylation was measured in leukocytes using the Infinium MethylationEPIC BeadChip. Linear models were employed to identify differentially methylated positions (DMPs) adjusting for age, body mass index, mother’s education, and cell type composition. Among the tested elements, vanadium, chromium, nickel, copper, zinc, yttrium, tin and barium were significantly associated with DMPs (FDR < 0.05), registering 225, 1, 2, 184, 1, 209,189 and 104 hits, respectively. Most of the DMPs were positively associated with trace elements and located in open sea regions. The greatest number of DMPs were annotated to the HOXA3 and FOXO3 genes, related to regulation of gene expression and oxidative stress, respectively. These findings suggest that DNA methylation may be involved in linking exposure to trace elements among female adolescents to downstream health risks.

Abstract Gene therapy is a focus of interest in both human and veterinary medicine, especially in recent years due to the potential applications of CRISPR/Cas9 technology. Another relatively new approach is that of epigenetic therapy, which involves an intervention based on epigenetic marks, including DNA methylation, histone post-translational modifications, and post-transcription modifications of distinct RNAs. The epigenome results from enzymatic reactions which regulate gene expression without altering DNA sequences. In contrast to conventional CRISP/Cas9 techniques, the recently established methodology of epigenetic editing mediated by the CRISPR/dCas9 system is designed to target specific genes without causing DNA breaks. Both natural epigenetic processes and epigenetic editing regulate gene expression and thereby contribute to maintaining the balance between physiological functions and pathophysiological states. From this perspective, knowledge of specific epigenetic marks has immense potential in both human and veterinary medicine. For instance, the use of epigenetic drugs (chemical compounds with therapeutic potential affecting the epigenome) seems to be promising for the treatment of cancer, metabolic, and infectious diseases. Also, there is evidence that an epigenetic diet (nutrition-like factors affecting epigenome) should be considered as part of a healthy lifestyle and could contribute to the prevention of pathophysiological processes. In summary, epigenetic-based approaches in human and veterinary medicine have increasing significance in targeting aberrant gene expression associated with various diseases. In this case, CRISPR/dCas9, epigenetic targeting, and some epigenetic nutrition factors could contribute to reversing an abnormal epigenetic landscape to a healthy physiological state.

Abstract In recent decades, the use of pesticides in agriculture has increased dramatically. This has resulted in these substances being widely dispersed in the environment, contaminating both exposed workers, communities living near agricultural areas, and via contaminated foodstuffs. In addition to acute poisoning, chronic exposure to pesticides can lead to molecular changes that are becoming better understood. Therefore, the aim of this study was to assess, through a systematic review of the literature, what epigenetic alterations are associated with pesticide exposure. We performed a systematic review and meta-analysis including case-control, cohort, and cross-sectional observational epidemiological studies to verify the epigenetic changes, such as DNA methylation, histone modification, and differential microRNA expression, in humans that had been exposed to any type of pesticide. Articles published between the years 2005 to 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI software. Post-completion, the data of selected articles were extracted and analyzed. Most of the 28 articles included evaluated global DNA methylation levels, and the most commonly reported epigenetic modification in response to pesticide exposure was global DNA hypomethylation. The meta-analysis revealed a significant negative correlation between Alu methylation levels and β-HCH, pp’-DDT, and pp’-DDE levels. In addition, some specific genes were reported to be hypermethylated in promoter regions, such as CDKN2AIGF2, WRAP53α, and CDH1, while CDKN2B and H19 were hypomethylated due to pesticide exposure. The expression of microRNAs was also altered in response to pesticides, as miR-223, -518d-3p, -597, -517b, and 133b that are associated with many human diseases. Therefore, this study provides evidence that pesticide exposure could lead to epigenetic modifications, possibly altering global and gene-specific methylation levels, epigenome-wide methylation, and micro-RNA differential expression.

Abstract Exposure to air pollutants has been associated with adverse health outcomes in adults and children who were prenatally exposed. In addition to reducing exposure to air pollutants, it is important to identify their biologic targets in order to mitigate the health consequences of exposure. One molecular change associated with prenatal exposure to air pollutants is DNA methylation (DNAm), which has been associated with changes in placenta and cord blood tissues at birth. However, little is known about how air pollution exposure impacts the sperm epigenome, which could provide important insights into the mechanism of transmission to offspring. In the present study, we explored whether exposure to particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, nitrogen dioxide (NO2), or ozone (O3) was associated with DNAm in sperm contributed by participants in the Early Autism Risk Longitudinal Investigation prospective pregnancy cohort. Air pollution exposure measurements were calculated as the average exposure for each pollutant measured within 4 weeks prior to the date of sample collection. Using array-based genome-scale methylation analyses, we identified 80, 96, 35, and 67 differentially methylated regions (DMRs) significantly associated with particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, NO2, and O3, respectively. While no DMRs were associated with exposure to all four pollutants, we found that genes overlapping exposure-related DMRs had a shared enrichment for gene ontology biological processes related to neurodevelopment. Together, these data provide compelling support for the hypothesis that paternal exposure to air pollution impacts DNAm in sperm, particularly in regions implicated in neurodevelopment.