Environmental Epigenetics最新文献

Dichlorodiphenyltrichloroethane (DDT) has previously been shown to promote the epigenetic transgenerational inheritance of adult onset disease in rats. The current study investigated the potential that sperm epimutation biomarkers can be used to identify ancestral induced transgenerational obesity and associated pathologies. Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination, and the incidence of adult-onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the transgenerational F3 generation males were investigated. There was an increase of testis disease and early-onset puberty in the F2 generation DDT lineage males. The F3 generation males and females had significant increases in the incidence of obesity and multiple disease. The F3 generation DDT males also had significant increases in testis disease, prostate disease, and late onset puberty. The F3 generation DDT females had increases in ovarian and kidney disease. Epigenetic alterations of the germline are required for the transgenerational inheritance of pathology. Therefore, the F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, prostate disease, kidney disease, testis disease, obesity, and multiple disease pathologies. Gene associations with the DMR were also identified. The epigenetic DMR signatures identified for these pathologies provide potential biomarkers for transgenerationally inherited disease susceptibility.

Mammalian sperm RNA has recently received a lot of interest due to its involvement in epigenetic germline inheritance. Studies of epigenetic germline inheritance have shown that environmental exposures can induce effects in the offspring without altering the DNA sequence of germ cells. Most mechanistic studies were conducted in laboratory rodents and C.elegans while observational studies confirm the phenotypic phenomenon in wild populations of humans and other species including birds. Prominently, paternal age in house sparrows affects offspring fitness, yet the mechanism is unknown. This study provides a first reference of house sparrow sperm small RNA as an attempt to uncover their role in the transmission of the effects of paternal age on the offspring. In this small-scale pilot, we found no statistically significant differences between miRNA and tRNA fragments in aged and prime sparrow sperm. These results indicate a role of other epigenetic information carriers, such as distinct RNA classes, RNA modifications, DNA methylation and retained histones, and a clear necessity of future studies in wild populations.

Determinants of lifetime health are complex and emphasize the need for robust predictors of disease risk. Allostatic load (AL) has become a clinical framework to estimate the cumulative biological burden associated with chronic stress. To assist knowledge translation in the developmental origins of health and disease field, clinically valid methods for reliable AL assessment in experimental models are urgently needed. Here, we introduce the rat cumulative allostatic load measure (rCALM), as a new preclinical knowledge translation tool to assess the burden of chronic stress. First, we identified an array of stress-associated physiological markers that are particularly sensitive to hypothalamic-pituitary-adrenal axis dysregulation by ancestral prenatal stress. Second, we determined which of these markers are susceptible to an intervention by environmental enrichment (EE) to mitigate AL. The markers most responsive to stress and EE therapy were assembled to become operationalized in the rCALM. Third, the new rCALM was validated for the ability to indicate future disease risks. The results show that the rCALM estimates the burden of chronic stress and serves as a proxy to estimate stress resilience and vulnerability to disease. Using the rCALM we showed that enrichment therapy can offset the adverse health outcomes linked to a high AL. Thus, the rCALM provides a model for the development of new test strategies that facilitate knowledge translation in preclinical animal models.

Lipids play a role in many biological functions and the newly emerging field of lipidomics aims to characterize the varying classes of lipid molecules present in biological specimens. Animal models have shown associations between maternal dietary supplementation with fatty acids during pregnancy and epigenetic changes in their offspring, demonstrating a mechanism through which prenatal environment can affect outcomes in children; however, data on maternal lipid metabolite levels during pregnancy and newborn DNA methylation in humans are sparse. In this study, we assessed the relationship of maternal lipid metabolites measured in the blood from pregnant women with newborn DNA methylation profiles in the Center for the Health Assessment of Mothers and Children of Salinas cohort. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 92 metabolites in plasma samples of pregnant women at ∼26 weeks gestation. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. We uncovered numerous false discovery rate significant associations between maternal metabolite levels, particularly phospholipid and lysolipid metabolites, and newborn methylation. The majority of the observed relationships were negative, suggesting that higher lipid metabolites during pregnancy are associated with lower methylation levels at genes related to fetal development. These results further elucidate the complex relationship between early life exposures, maternal lipid metabolites, and infant epigenetic status.

[This corrects the article DOI: 10.1093/eep/dvy028.][This corrects the article DOI: 10.1093/eep/dvy028.].

Gene expression changes mediated by DNA methylation may play a role in pubertal tempo regulation, and availability of methyl donor nutrients affects these pathways. We examined first trimester maternal and adolescent diet patterns that may be associated with DNA methylation at long interspersed nucleotide (LINE-1) repetitive elements in adolescence using least absolute shrinkage and selection operator (LASSO) and calculated an 'Epigenetics-Associated Diet Score' (EADS) for each pattern; then tested the associations of these scores with pubertal tempo among adolescent boys and girls. The analytic sample included 118 boys and 132 girls aged 10-18 years. DNA methylation at LINE-1 repetitive elements was quantified. Typical maternal and adolescent nutrient intakes were estimated using food frequency questionnaires. Interval-censored time to event and ordinal regression models were used to examine associations EADS scores with pubertal tempo using physician-assessed Tanner stages and self-reported menarche, respectively, adjusted for confounders. We observed associations between maternal EADS and pubertal onset, but not pubertal progression. Each standard deviation (SD) greater maternal EADS was associated with 52% higher odds of having later onset of menarche in both cross-sectional and prospective analysis (P = 0.031 and 0.028, respectively). In contrast, we observed associations between adolescent EADS and pubertal progression, but not pubertal onset. Among boys, for each SD higher adolescent EADS, there was 13% increase in odds of slower genital progression (P = 0.050), as well as 26 and 27% increase in odds of slower left and right testicular development, respectively (P = 0.001). Epigenetic-associated diet influences pubertal tempo in a sex- and timing-specific manner.

Assessment of changes in DNA methylation (DNA-m) has the potential to identify adverse environmental exposures. To examine DNA-m among a subset of participants (n = 369) in the Isle of Wight birth cohort who reported variable near resident traffic frequencies. We used self-reported frequencies of heavy vehicles passing by the homes of study subjects as a proxy measure for TRAP, which were: never, seldom, 10 per day, 1-9 per hour and >10 per hour. Methylation of cytosine-phosphate-guanine (CpG) dinucleotide sequences in the DNA was assessed from blood samples collected at age 18 years (n = 369) in the F1 generation. We conducted an epigenome wide association study to examine CpGs related to the frequency of heavy vehicles passing by subjects' homes, and employed multiple linear regression models to assess potential associations. We repeated some of these analysis in the F2 generation (n = 140). Thirty-five CpG sites were associated with heavy vehicular traffic. After adjusting for confounders, we found 23 CpGs that were more methylated, and 11 CpGs that were less methylated with increasing heavy vehicular traffic frequency among all subjects. In the F2 generation, 2 of 31 CpGs were associated with traffic frequencies and the direction of the effect was the same as in the F1 subset while differential methylation of 7 of 31 CpG sites correlated with gene expression. Our findings reveal differences in DNA-m in participants who reported higher heavy vehicular traffic frequencies when compared to participants who reported lower frequencies.