Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

Thomas W. McDade, Calen Ryan,  View ORCID ProfileMeaghan J. Jones, Julia L. MacIsaac, Alexander M. Morin,  View ORCID Profile, Jess M. Meyer, Judith B. Borja, Gregory E. Miller, Michael S. Kobor, and Christopher W. Kuzawa

PNAS first published July 3, 2017 https://doi.org/10.1073/pnas.1620661114

  1. Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved May 25, 2017 (received for review December 16, 2016)

Significance

Environments in infancy and childhood influence levels of inflammation in adulthood—an important risk factor for multiple diseases of aging—but the underlying biological mechanisms remain uncertain. Using data from a unique cohort study in the Philippines with a lifetime of information on each participant, we provide evidence that nutritional, microbial, and psychosocial exposures in infancy and childhood predict adult levels of DNA methylation—biochemical marks on the genome that affect gene expression—in genes that regulate inflammation. We also show that DNA methylation in these genes relates to levels of inflammatory biomarkers implicated in cardiovascular and other diseases. These results suggest that epigenetic mechanisms may partially explain how early environments have enduring effects on inflammation and inflammation-related diseases.

Abstract

Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20–22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

Inflammation plays a central role in immune defenses against infectious disease (1), but dysregulated or chronic, low-grade inflammatory processes contribute to the pathophysiology of a wide range of diseases, including cardiovascular disease, type 2 diabetes, and autoimmune/atopic conditions (23). Inflammatory activity is also central to normal pregnancy, but dysregulated inflammation can contribute to pregnancy complications and adverse birth outcomes (45). The factors that influence the regulation of inflammation are therefore relevant to clinical practice, and they are of central interest to current research in genomics and immunology as well as epidemiology, demography, and psychobiology (611).

Recent empirical work has identified environments in infancy and early childhood as important determinants of inflammatory phenotypes, and concepts from life history theory and ecological immunology have provided a theoretical basis for anticipating these associations (1214). Individuals born at lower birth weight, and infants who are breastfed for shorter durations, have higher concentrations of C-reactive protein (CRP)—a key biomarker of inflammation—as adults (1519). Higher levels of microbial exposure in infancy are associated with reduced levels of chronic inflammation in adulthood (1820), consistent with broader human and animal model literatures showing that microbial exposures during sensitive periods of immune development have lasting beneficial effects on the regulation of inflammation (2123). In addition, an emerging body of research in developmental psychobiology reports that major psychosocial stressors (e.g., child neglect, extended parental absence) and socioeconomic adversity in childhood are associated with dysregulated and proinflammatory activity in adulthood (152426).

Although the underlying biological mechanisms that connect early nutritional, microbial, and psychosocial environments with adult inflammatory phenotypes are not known, epigenetic processes are likely candidates for preserving cellular memories of early experience in the immune system. Indeed, recent human studies suggest that socioeconomic and psychosocial environments in infancy and childhood leave a molecular imprint that has lasting effects on genomic regulation and the developing phenotype (2730). Of the many marks contributing to the epigenome, DNA methylation (DNAm) has been the major focus of human research and involves the covalent linkage of methyl groups to cytosine residues primarily in the context of CpG dinucleotides. Methylation of sites in gene promoter regions limits access of transcriptional machinery and is typically associated with reduced gene expression, whereas methylation within gene bodies often is associated with enhanced expression (31). The potential biological relevance of these processes is underscored by several studies documenting associations between DNAm and expression of genes involved in the regulation of inflammation as well as biomarkers of inflammation and risk for inflammation-related disorders (303233).

Few studies possess the range and time depth of prospectively collected measures needed to test the hypothesis that nutritional, microbial, and psychosocial environments early in development predict patterns of DNAm in inflammatory genes in adulthood. In addition, current understandings of the regulation of inflammation are based almost exclusively on studies with animal models and with human participants residing in affluent, industrialized settings like the United States (3435). A broader perspective is important, as 81% of the world’s population resides in low- and middle-income nations (36), where rates of inflammation-related diseases—including cardiovascular, metabolic, atopic, and autoimmune diseases—are rapidly rising (37). The limited variation in microbial, nutritional, and socioeconomic environments in samples drawn from affluent, industrialized settings may constrain investigations into important developmental determinants of inflammatory phenotypes (35).

We use data from a long-term birth cohort study in the Philippines to address both these limitations. Data collection began in 1983, and DNAm as well as concentrations of inflammatory biomarkers were assessed in blood samples collected in 2005, when participants were ∼21 y old. In addition to the prospective design, an advantage of the study is the relatively wide range of ecological variation represented by the sample: Participants were born into areas that were classified as urban residential, congested urban poor, peri-urban, and remote rural (38). In 1983, approximately half the homes had electricity, more than three-quarters collected water from an open source, and less than half used a flush toilet (18). Furthermore, the study initially focused on detailed and frequent assessment of the contextual determinants of maternal and infant health. Beginning with the first interview of the mother during pregnancy and continuing through the offspring’s infancy and childhood, careful attention was given to detailed measurement of proximate nutritional, microbial, psychosocial, and socioeconomic exposures of relevance to growth and development.

We implemented a hypothesis-driven investigation of the association between DNAm in young adulthood and early life environmental exposures. Analyses focused on methylation sites in 114 target genes shown previously to regulate inflammation, which were identified before statistical analyses. The rationale for our targeted analytic approach was twofold. First, limiting our analysis to genes involved in the regulation of inflammation takes advantage of existing knowledge and increases statistical power for detecting meaningful biological associations. Second, venous blood sampling provides access to the tissue of interest—immune cells that increase and decrease inflammation—where patterns of DNAm in regulatory regions are most likely to have functional relevance for inflammation due to the tissue-specific nature of epigenetic processes (39).

We hypothesized that measures of early life environmental exposures, identified in prior research as important to shaping inflammatory phenotypes, would be significant predictors of DNAm in young adulthood. To evaluate the functional relevance of associations between early environments and DNAm, we considered whether differentially methylated sites predicted concentrations of inflammatory biomarkers, measured concurrently in young adulthood. Our analyses identified 10 differentially methylated sites across nine genes, four of which were associated with a composite measure of inflammation. These results provide support for DNAm as a biological mechanism through which experiences early in life may have lasting effects on the regulation of inflammation.

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About S. R. Zelenz 119 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.