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. 2024 Sep 12;16(17):1175–1183. doi: 10.1080/17501911.2024.2390823

From womb to wellness: early environmental exposures, cord blood DNA methylation and disease origins

Hooman Mirzakhani a,*
PMCID: PMC11457657  PMID: 39263926

ABSTRACT

Fetal exposures can induce epigenetic modifications, particularly DNA methylation, potentially predisposing individuals to later health issues. Cord blood (CB) DNA methylation provides a unique window into the fetal epigenome, reflecting the intrauterine environment’s impact. Maternal factors, including nutrition, smoking and toxin exposure, can alter CB DNA methylation patterns, associated with conditions from obesity to neurodevelopmental disorders. These epigenetic changes underscore prenatal exposures’ enduring effects on health trajectories. Technical challenges include tissue specificity issues, limited coverage of current methylation arrays and confounding factors like cell composition variability. Emerging technologies, such as single-cell sequencing, promise to overcome some of these limitations. Longitudinal studies are crucial to elucidate exposure-epigenome interactions and develop prevention strategies. Future research should address these challenges, advance public health initiatives to reduce teratogen exposure and consider ethical implications of epigenetic profiling. Progress in CB epigenetics research promises personalized medicine approaches, potentially transforming our understanding of developmental programming and offering novel interventions to promote lifelong health from the earliest stages of life.

Keywords: : cord blood, disease origin, DNA methylation, DOHaD, early life, environmental exposure, epigenome

Plain language summary

Article highlights.

Tracing the roots: early-life factors shape adult health

  • The Developmental Origins of Health and Disease hypothesis suggests that early-life exposures can induce lasting epigenetic modifications.

  • Environmental factors during fetal development can influence long-term health trajectories.

Epigenetics & the significance of cord blood DNA methylation

  • DNA methylation is a key epigenetic mechanism regulating gene expression and development.

  • Cord blood (CB) DNA methylation offers unique insights into the intrauterine environment and fetal exposures.

The gestational environment & its epigenetic impact

  • The intrauterine milieu directly impacts implantation, placentation and epigenetic remodeling.

  • CB DNA methylation patterns can reflect the efficiency of epigenetic programming during fetal development.

Environmental factors influencing CB DNA methylation signature

  • Maternal factors (e.g., nutrition, smoking, stress) significantly affect CB DNA methylation.

  • Environmental toxins and placental function contribute to variations in fetal epigenetic patterns.

Implications & applications

  • CB DNA methylation serves as a biomarker for evaluating fetal environmental exposures.

  • Epigenetic profiles may guide personalized medicine approaches and early intervention strategies.

Methodological challenges in CB DNA methylation studies

  • Issues include tissue specificity, limited coverage of methylation arrays and cell composition variability.

  • Integrating multi-omics data and establishing causality remain significant hurdles.

Ethical considerations of using CB epigenetic data

  • Privacy protection, informed consent and potential genetic discrimination are key individual-level concerns.

  • Equitable access to benefits and preventing health disparities are crucial population-level considerations.

Future perspective

  • Advancements in single-cell technologies and integrative omics are enhancing our understanding of environmental influences on epigenetics.

  • Transgenerational epigenetic inheritance is an emerging area of research with significant public health implications.

  • To investigate aberrant methylation alterations, researchers should establish baseline methylation profiles for various cell types throughout normal development.

  • Longitudinal studies tracking methylation changes in individuals exposed to different environmental factors are crucial, using appropriate statistical methods to control for cell composition and developmental stage.

  • This structured approach allows for the identification of methylation patterns that deviate from developmental norms and their relationship with specific exposures.

  • There is a pressing need for effective intervention strategies to mitigate adverse effects of prenatal exposures on fetal development.

1. Tracing the roots: early-life factors shape adult health?

During periods of rapid growth, the developing embryo or fetus is susceptible to influences of perturbations of the maternal environment. Adverse environmental exposures can disturb the processes of cell proliferation and differentiation, leading to changes in the normal developmental pathways for mature organs and tissues. The maternal-fetus coordination mounts adaptive responses to ensure the maintenance of critical tissue functions and survival of the insult. As development involves the well-ordered formation of key structures, these adaptive responses are likely to result in deviant tissue structure and function. These will be observable in later life and will have the capacity to modulate physiological function and susceptibility to disease. This concept of ‘developmental plasticity’ underscores how early-life adaptations can have long-lasting impacts on health trajectories [1].

The characteristics of programmed responses are dependent upon the nature of the stimulus or insult and upon the timing of the exposure. Data obtained from historical cohorts is suggestive of associations between early-life nutritional factors and risk of diseases such as cardiovascular disease and type 2 diabetes in adulthood [2]. These findings lend support to the Developmental Origins of Health and Disease hypothesis. This paradigm suggests that exposures during critical periods of fetal development can induce lasting epigenetic modifications, which may serve as one of the key mechanisms predisposing individuals to various health issues later in life [3–5]. Subsequently, the paradigm was extended to other, non-dietary, factors that were demonstrated to have great potential to influence the organism’s health status. More empirically and in line with the identification of early factors prospectively influencing health in later life, The Pregnancy and Childhood Epigenetics (PACE) consortium was comprised, a global collaboration focused on understanding how early-life environmental factors impact human health through epigenetic modifications. PACE primarily investigates DNA methylation changes in relation to various exposures during pregnancy and childhood, aiming to uncover the epigenetic mechanisms that could lead to diseases later in life. Findings from these research efforts have been crucial to show that determinants during the pre- and perinatal periods might influence long-term health through changes in epigenetic patterns [3,6].

2. Epigenetics & the significance of cord blood DNA methylation

Epigenetics is central to understanding the intricate balance between physiology and pathophysiology, particularly during the vital developmental period. Among the various epigenetic mechanisms, DNA methylation stands out as a key player in regulating gene expression, influencing chromatin structure, transcription factor activity and other regulatory pathways that are crucial for development, cellular differentiation and the maintenance of tissue-specific gene expression patterns [7]. The advent of high-throughput sequencing technologies revolutionized the study of DNA methylation, allowing for genome-wide analysis of methylation patterns with high resolution.

Early development is a period of profound changes in DNA methylation and may, as such, be a critical period for environmentally induced DNA methylation changes [8]. Hence, this period is of specific interest for DNA methylation studies focused on specific exposures and their long-term health outcomes [8]. The study of cord blood (CB) has emerged as a powerful tool for advancing our understanding of offspring health. Its availability offers unparalleled insights into fetal development, the early onset of diseases and strategies for disease prevention [9]. Within this context, CB epigenetics, particularly DNA methylation patterns, offers a unique window into the intrauterine environment and the various maternal and environmental exposures experienced by the developing fetus [10]. Analyzing CB DNA methylation could reveal developmental anomalies that may predispose individuals to disease later in life by highlighting aberrant profiles or patterns. Such anomalies could manifest as perturbations in the normal methylation patterns of immune-related genes. Hence, epigenetic changes can influence the balance of innate and adaptive immunity, potentially setting a ‘set point’ that affects susceptibility to diseases later in life. For instance, certain DNA methylation patterns in CB have been associated with an increased risk of asthma, a condition linked to immune dysregulation [11].

2.1. The gestational environment & its epigenetic impact

Recent advancements in research have underscored the critical influence of the gestational environment on epigenetic programming, demonstrating its lasting effects on an individual’s trajectory across the lifespan [12]. The intrauterine milieu can directly impact the implantation and placentation phases, as well as induce extensive remodeling of epigenetic patterns during prenatal development [13]. These epigenetic changes are crucial for establishing long-term health trajectories in offspring. Embryonic stem cells, with their pluripotent capacity to differentiate into diverse cell types, underscore the dynamic interplay between genetic and epigenetic mechanisms, where DNA methylation plays a pivotal regulatory role [14]. This highlights the intricate relationship between our early-life environment and gene regulation, underscoring the profound impact of early developmental conditions on future health outcomes [3,6]. The significance of DNA methylation extends beyond its role in cellular memory, as it also ensures that cells not only acquire but also maintain their specialized functions throughout development, cellular differentiation and the preservation of tissue-specific gene expression patterns. In the context of CB DNA methylation research, the focus on ‘early life’ pertains to the prenatal and perinatal (at birth) periods when the fetus is subject to a myriad of environmental influences. The impact of these early environmental exposures on CB DNA methylation patterns might affect offspring health and disease susceptibility later in life. For example, genome-scale DNA methylation modifications in CB associated with preeclampsia have been observed, linking these changes to pathobiological pathways involved in cardiovascular conditions [15,16]. Furthermore, studies have identified specific CpG sites and methylation patterns associated with cardiovascular diseases [17], highlighting the potential of DNA methylation as an early biomarker for these conditions. Notably, CB DNA methylation patterns can provide insights into the efficiency and completeness of epigenetic programming, a process critical for normal fetal development. Dissecting the nuances of how early environmental factors shape CB DNA methylation signatures is pivotal for decoding the mechanisms of developmental programming and identifying intervention targets and preventive measures against diseases with roots in epigenetic deviations during early development.

2.2. Environmental factors influencing CB DNA methylation signature & potential mechanisms

The influence of environmental factors on DNA methylation patterns in CB is multifaceted. Notably, the research indicates that such epigenetic modifications are not just random occurrences but are associated with specific health outcomes in offspring, including risks for obesity, allergic diseases, altered lung function and potentially long-term cardiometabolic consequences [18,19]. Maternal elements and environmental exposures are key determinants of alterations in CB DNA methylation patterns (Figure 1). These include maternal elements, such as nutritional status, with a particular emphasis on folate, vitamin B12 and other nutrients critical for one-carbon metabolism (vitamins B6 and B9) [20]. Additionally, vitamin D levels in CB have been implicated in DNA methylation processes [21]. Deficiencies or imbalances in these nutrients can lead to discernible shifts in CB methylation landscapes. Additionally, maternal lifestyle choices, like smoking and alcohol consumption during pregnancy, have been correlated, though not consistently, with modifications in CB DNA methylation, likely mediated through pathways involving oxidative stress and inflammation [10,22,23].

Figure 1.

Figure 1.

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Conceptual framework of prenatal exposures influencing DNA methylation and phenotypic outcomes. This figure illustrates the complex interplay between maternal and placental factors, environmental exposures and epigenetic mechanisms – particularly DNA methylation – in affecting fetal development, emphasizing how early-life experiences can have lasting effects on health and development throughout the lifespan. The diagram shows: (A) Maternal factors: Maternal conditions and exposures that can influence fetal development. (B) Placental factors: Key placental functions that mediate maternal–fetal interactions. The central pathway depicts: 1) The prenatal exposome affecting the fetus. 2) DNA methylation process, including key molecules like PRC2, RNAPII and SAM. 3) Methylation of gene promoters, potentially altering gene expression. 4) The resulting impact on the developing fetus. 5) Long-term phenotypic outcomes across the lifespan.

Smoking during pregnancy influences widespread and highly reproducible differences in DNA methylation at birth. A genome-wide meta-analysis conducted by the PACE consortium analyzed data from over 6000 mothers and their newborns across 13 cohorts. The study found that maternal smoking during pregnancy is associated with differential DNA methylation at over 6000 CpG sites in newborns. Many of these changes were linked to genes involved in diseases such as developmental defects, asthma and certain cancers. Importantly, these methylation changes persisted into childhood, indicating the long-term effects of prenatal exposure to smoking [24]. Less pronounced effects have been observed for maternal BMI, preeclampsia and gestational diabetes [25–27]. Studies within the PACE consortium have explored how maternal BMI during pregnancy affects offspring DNA methylation patterns and their subsequent health outcomes, including the risk of developing cardiovascular diseases [28]. The associations between CB methylation changes and BMI trajectories from birth to adolescence further suggest that maternal obesity may have lasting effects on offspring’s epigenetic landscape, influencing disease susceptibility well into later life stages [29]. Maternal psychological factors, such as exposure to stressful life events, have also been implicated in alterations of CB methylation patterns, potentially affecting the fetus’s stress response mechanisms [30]. Other notable maternal elements include pre-pregnancy weight, gestational weight gain, maternal microbiome, gestational age and diabetes, all of which have been associated with variations in CB DNA methylation [16,31–36].

In addition to maternal factors, environmental toxin exposure also plays a crucial role. Exposure to environmental toxins such as air pollution, heavy metals (e.g., lead and cadmium), persistent organic pollutants and endocrine-disrupting chemicals, represent other significant factors that can alter CB DNA methylation [37–40]. Notably, the placenta acts as a critical intermediary between maternal and fetal environments, with changes in its DNA methylation patterns not only reflecting maternal exposures but also influencing fetal responses to environmental challenges [41,42]. The placenta’s critical regulatory role in nutrient, gas and waste exchange, as well as placental inflammation and oxidative stress [26], might be contributors to variations in CB DNA methylation [10,38]. This underscores the complex interplay between maternal physiology, placental function and fetal epigenetic programming.

It is worth noting that certain exposures at birth, such as mode of delivery and anesthesia, could also potentially influence CB methylation as well [43,44]. Investigations into the outcomes of children conceived through Intracytoplasmic Sperm Injection have shown that this assisted reproductive technology might induce specific DNA methylation changes, albeit within the normal variation range, pointing toward the subtle yet the impact of early embryonic interventions on the epigenome [45]. These studies collectively highlight the intricate relationship between maternal and environmental factors with alterations in CB DNA methylation patterns. Regarding aging, DNA methylation age has been indicated as an epigenetic clock with biological significance in the context of age acceleration. CB DNA methylation age has been shown to inversely correlate with other aging biomarkers, suggesting prenatal programming may be an early influential factor in the aging process [46]. These underline the potential of epigenetic markers as predictive tools for assessing disease risk and the importance of a healthy prenatal environment. Furthermore, these studies emphasize the critical role of the early-life period in establishing an epigenetic foundation that may determine health trajectories, advocating for interventions that could modulate epigenetic programming toward healthier outcomes.

While progress has been made in understanding some mechanisms of the environmental impact and prenatal factors on CB DNA methylation, ongoing research is essential to fully elucidate the mechanisms and long-term implications of prenatal environmental influences on the epigenome. Environmental factors can affect DNA methylation in CB through direct engagement with methylation machinery, shifts in the supply of methyl donors and cofactors and indirectly through alterations in cellular signaling and stress response pathways. Endocrine-disrupting chemicals, such as phthalates and bisphenols, potentially disrupt hormonal signaling, causing atypical methylation patterns that may hinder normal development and growth [47].

The intricate interplay between environmental exposures and DNA methylation, which influences gene activity, involves complex dynamics between genetic predispositions and external elements [48]. Research on the combined environmental and genetic impacts on CB DNA methylation underscores epigenetics’ role in merging these factors to modulate cellular functions [49]. Analyzing data from 2365 participants across four cohorts, a study found that the combination of genetic and environmental factors best explains the variability in DNA methylation at specific regions, highlighting the importance of both influences in shaping epigenetic outcomes [49]. The study of CB DNA methylation in newborns from high familial risk cohorts reveals early dysregulation in neurodevelopmental and X-linked genes, with significant differences in DNA methylation patterns between newborns who later developed autism spectrum disorder and typically developing controls [50]. These epigenetic differences, particularly notable in neurodevelopmental and X-linked genes, suggest that changes detectable at birth may contribute to autism spectrum disorder etiology. These studies highlight how prenatal environmental influences, along with genetic predispositions, collectively shape the fetal epigenetic landscape, emphasizing the necessity for further exploration into these mechanisms for a deeper understanding of their implications on development and health potentially affecting disease risk later in life.

3. Implications & applications

CB DNA methylation can serve as a valuable biomarker for evaluating the impact of various environmental factors experienced by the fetus during pregnancy, helping identify populations at increased risk of adverse health outcomes. By recognizing epigenetic markers indicative of environmental impact during crucial developmental stages, healthcare practitioners can implement strategies to mitigate the identified risks, such as smoking cessation programs, improved nutrition counseling, or targeted environmental remediation efforts. CB DNA methylation profiles may serve as a window into the epigenetic programming associated with disease risk later in life, shedding light on the mechanisms linking early-life exposures to an increased risk of neurological, metabolic, cardiovascular and other disorders. Longitudinal research connecting CB methylation markers with health trajectories can elucidate the lasting effects of prenatal exposures, aiding in the development of prevention and monitoring programs.

By studying the relationships between CB DNA methylation, in utero exposures and long-term health outcomes, researchers can identify potential biomarkers and develop targeted interventions to mitigate the developmental origins of the disease. This knowledge can guide personalized medicine approaches, enabling early identification of high-risk individuals and implementation of tailored preventive strategies based on one’s epigenetic makeup and environmental history, potentially recognizing individuals at risk before clinical symptoms emerge.

4. Methodological challenges in CB DNA methylation studies

Analyzing CB DNA methylation presents several complex challenges that researchers must navigate. Tissue specificity issues arise as blood samples may not accurately represent methylation patterns in disease-relevant tissues, complicating interpretation and limiting cross-tissue concordance. Limited coverage of current methylation arrays, focusing primarily on CpG islands and gene regions, potentially overlooks significant sites across the broader methylome. Blood cell composition variability and the risk of maternal blood contamination necessitate complex adjustments, as observed associations may reflect compositional changes rather than true epigenetic alterations. Technical covariates, including batch effects, require careful consideration to prevent result distortion. In cross-sectional studies, the possibility of reverse causality – where diseases influence DNA methylation – must be accounted for. Integrating DNA methylation data with other ’omics’ information and studying diverse socioeconomic populations pose additional challenges. Finally, the scarcity of evidence directly linking epigenetic changes to health outcomes hinders definitive conclusions about the implications of observed methylation patterns, making causality establishment a noteworthy hurdle in the field.

Additionally, challenges such as understanding the reversibility of DNA methylation, its functional importance in natural populations, identifying sensitive periods for methylation changes and interindividual variability are crucial. Developing nutritional and lifestyle interventions to favorably modify DNA methylation patterns is essential, along with overcoming technological limitations of methylation platforms, improving sample quality and meeting complex data analysis requirements. Collaborative efforts and meticulous planning are needed to enhance the reliability and impact of DNA methylation studies, emphasizing comprehensive approaches to tackle these multifaceted challenges effectively.

5. Ethical considerations of using CB epigenetic data

The use of CB epigenetic data in personalized medicine raises several ethical concerns at both individual and population levels. At the individual level, key considerations include protecting the privacy and confidentiality of sensitive health information, ensuring truly informed parental consent for data use, respecting the child’s future autonomy, mitigating potential psychosocial impacts of risk disclosure and safeguarding against genetic discrimination. These personal concerns emphasize the need for robust data protection, clear communication about research implications and mechanisms for individuals to control their genetic information as they mature.

At the population level, ethical challenges primarily revolve around ensuring equitable access to the benefits of precision medicine while preventing the exacerbation of health disparities. These challenges involve promoting inclusive research practices to ensure the broad applicability of findings, addressing issues of distributive justice given unequal environmental exposures across different populations and establishing comprehensive governance frameworks for ethical data use and sharing [51,52]. Balancing individual rights with societal benefits requires ongoing dialogue with stakeholders, including researchers, policymakers, ethicists and community representatives. This dialogue should align research practices with evolving ethical standards and carefully consider the long-term societal implications of epigenetic-based interventions. Moreover, it is crucial to invest in public education about epigenetics to enable informed decision-making and foster trust in research and medical applications.

6. Future perspective

Advancements in epigenomic technologies, particularly single-cell approaches and integrative omics, are revolutionizing our understanding of how environmental exposures influence epigenetic changes across generations. To investigate aberrant methylation alterations, distinct from normal developmental processes, researchers can employ a structured approach, starting with the establishment of baseline methylation profiles for various cell types throughout normal development and cataloging lineage-defining patterns. Longitudinal studies should track methylation changes in individuals exposed to different environmental factors, using appropriate statistical methods to control for cell composition and developmental stage (e.g., postnatal catch-up growth). This allows for the identification of methylation patterns that deviate from developmental norms and their relationship with specific exposures. Furthermore, DNA methylation perturbations in normal cells could enable direct investigation of the roles of epigenetic modifications in cellular processes [53].

Emerging evidence highlights the potential for these epigenetic repercussions to affect not just the exposed individual but also subsequent generations, a phenomenon known as transgenerational inheritance [54]. Research has found that exposure to certain environmental toxins in grandparents can result in DNA methylation changes in their grandchildren, bypassing the directly exposed generation. For example, maternal vitamin D depletion might have long-term effects on the epigenome of subsequent generations [8]. These groundbreaking discoveries have significant public health implications, underscoring the necessity for both longitudinal and transgenerational studies to grasp the full spectrum of environmental exposure effects.

While establishing causal relationships between early methylation patterns and later health outcomes remains complex, this evolving field holds promise for developing epigenetic therapies and effective intervention strategies, potentially mitigating health risks across multiple generations. By elucidating the persistent nature of epigenetic consequences on disease susceptibility and health throughout life, this research informs public health initiatives aimed at optimizing fetal development and lifelong well-being.

Given the substantial impact of environmental factors on CB DNA methylation and offspring health, there is a pressing need for effective intervention and prevention strategies. This could include public health initiatives aimed at reducing exposure to known teratogens, dietary recommendations for pregnant individuals and policies to minimize air pollution. Additionally, identifying at-risk populations and implementing targeted interventions based on specific exposure profiles could mitigate the adverse effects on fetal development. As the field of CB epigenetics advances, ethical, legal and social considerations must be addressed. The potential for misuse of genetic and epigenetic information raises concerns about privacy, consent and the possibility of discrimination. We must navigate these challenges with a commitment to equity and justice, striving to ensure that advancements in epigenetic research benefit all segments of society while actively working to reduce existing health disparities

Funding Statement

H Mirzakhani has received research support from NIH NHLBI (U03 HL091528 and 1 K01HL146977 01A1).

Author contributions

H Mirzakhani did the conceptualization, writing (original draft), writing (review and editing) and visualization.

Financial disclosure

H Mirzakhani has received research support from NIH NHLBI (U03 HL091528 and 1 K01HL146977 01A1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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