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Genetic and nongenetic factors are involved in the individual ability to physiologically acclimatize to high-altitude hypoxia through processes that include increased heart rate and ventilation. High-altitude acclimatization is thought to have a genetic component, yet it is unclear if other factors, such as epigenetic gene regulation, are involved in acclimatization to high-altitude hypoxia in nonacclimatized individuals. We collected saliva samples from a group of healthy adults of European ancestry (n = 21) in Kathmandu (1,400 m; baseline) and three altitudes during a trek to the Everest Base Camp: Namche (3,440 m; day 3), Pheriche (4,240 m; day 7), and Gorak Shep (5,160 m; day 10). We used quantitative bisulfite pyrosequencing to determine changes in DNA methylation, a well-studied epigenetic marker, in LINE-1, EPAS1, EPO, PPARa, and RXRa. We found significantly lower DNA methylation between baseline (1,400 m) and high altitudes in LINE-1, EPO (at 4,240 m only), and RXRa. We found increased methylation in EPAS1 (at 4,240 m only) and PPARa. We also found positive associations between EPO methylation and systolic blood pressure and RXRa methylation and hemoglobin. Our results show that incremental exposure to hypoxia can affect the epigenome. Changes to the epigenome, in turn, could underlie the process of altitude acclimatization.

BackgroundCharacterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.ObjectivesOur objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.MethodsWe address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.DiscussionA common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.ConclusionThe dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.

Biological clock technologies are designed to assess the acceleration of biological age (B-age) in diverse cell types, offering a distinctive opportunity in toxicogenomic research to explore the impact of environmental stressors, social challenges, and unhealthy lifestyles on health impairment. These clocks also play a role in identifying factors that can hinder aging and promote a healthy lifestyle. Over the past decade, researchers in epigenetics have developed testing methods that predict the chronological and biological age of organisms. These methods rely on assessing DNA methylation (DNAm) levels at specific CpG sites, RNA levels, and various biomolecules across multiple cell types, tissues, and entire organisms. Commonly known as 'biological clocks' (B-clocks), these estimators hold promise for gaining deeper insights into the pathways contributing to the development of age-related disorders. They also provide a foundation for devising biomedical or social interventions to prevent, reverse, or mitigate these disorders. This review article provides a concise overview of various epigenetic clocks and explores their susceptibility to environmental stressors. [ABSTRACT FROM AUTHOR]

Background: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles. Objective: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11-18 years of age. Methods: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n = 144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction. Results: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43 [+ or -]5.16 [micro]g/dL in Trimester 1 (T1), 5.66[+ or -]5.21 [micro]g/dL in Trimester 2 (T2), and 5.86[+ or -]4.34 lg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean[+ or -]standard deviation(SD), 2.08 [+ or -]4.18%), NINJ2 (G/C: 2.01 [+ or -]5.95; GG: 0.90[+ or -]3.97), RAB5A (0.66[+ or -]0.80%), and TPPP (1.11 [+ or -]6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3[+ or -]9.63%), NINJ2 (heterozygotes: 38.6[+ or -]7.39%; GG homozygotes: 67.3[+ or -]9.83%), RAB5A (1.41 [+ or -]1.21%), and TPPP (92.5 [+ or -] 8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (b = -0.37, p = 0.03) and 5hmC in NINJ2 (b = 0.49, p = 0.003); T2 BLLs with 5mC in HCN2 (b = 0.37, p = 0.03) and 5hmC in NINJ2 (b = 0.27, p = 0.008); and T3 BLLs with 5mC in HCN2 (b = 0.50, p = 0.01) and NINJ2 (b = -0.35, p = 0.004) and 5hmC in NINJ2 (b = 0.45, p < 0.001). NINJ2 5mC was negatively correlated with gene expression (Pearson r = -0.5, p-value = 0.005), whereas 5hmC was positively correlated (r = 0.4, p-value = 0.04). Discussion: These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507, Introduction The Developmental Origins of Health and Disease (DOHaD) hypothesis (Barker 2007) postulates that in utero exposures, including exposure to environmental contaminants such as lead (Pb), can permanently modify an [...]