Epigenetic inheritance is a form of transmission of features or traits acquired by experience or environmental exposure that does not involve any changes in the DNA sequence unlike genetic heredity. Epigenetic inheritance is actively studied in animal models and humans and has major implications for biology, health, and society. While it is well established in plants and invertebrates, its mechanisms and importance in mammals have not been fully delineated. Several key questions remain open for instance, which life experiences and environmental exposures can induce heritable phenotypic changes and how induced changes can be propagated from exposed parents to descendants, and whether and how germ cells contribute to such inheritance. These questions were the focus of the fifth edition of the symposium "Epigenetic Inheritance: Impact for Biology and Society" held in Zurich, Switzerland, on 27-29 August 2025. They were discussed by experts from diverse disciplines who presented epidemiological data in humans, results in animal models, new findings on transmission mechanisms, methodological advances, and societal and evolutionary implications. This report summarizes the research presented during the symposium and highlights current conceptual and technical challenges. It also presents other scientific activities during the symposium, which included poster sessions, an art exhibition, and a documentary movie on war trauma across generations.
Chronic psychological stress is an environmental factor associated with chronic disease risk and health disparities. Since environmental stressors alter gene expression and physiologic responses through epigenetic mechanisms, perceived discrimination (PD), or the subjective experience of receiving negative treatment related to personal characteristics may influence DNA methylation (DNAm) of CpGs within genes linked to chronic disease. Using the Illumina 850K EPIC chip and psychosocial stress-associated discrimination scales, including the lifetime, racial, and everyday discrimination scales, we identified novel CpGs and differentially methylated positions (DMPs) associated with PD in the context of age, sex, and poverty status among African American and White adults and ones that overlap previous findings of differentially methylated sites (or genes) with discrimination, inflammation, and chronic disease. Ingenuity Pathway Analysis identified several pathways associated with the DNAm patterns and PD with age, sex, and/or poverty status. With age, the white adipose tissue browning pathway was activated among African American participants. This was related to the differential methylation found in the CACNA1H, PRDM16, and BDNF genes. Among White participants, the opioid signaling pathway was activated and significantly enriched for the genes FGR, POMC, and RPS6KA2. Additionally, CpG sites associated with PD among White participants with poverty status revealed that the netrin signaling, opioid signaling, and calcium signaling pathways were activated and significantly enriched for differentially methylated genes, including NFATC1 and NFATC2. The identified novel DNAm genes associated with PD transduce effects through biological pathways related to inflammation and immune response, white adipose tissue browning, and calcium signaling.
The impacts of chemotherapy exposure on adolescent male osteosarcoma survivors as adults were investigated using a number of physiological parameters, with a focus on chemotherapy, reproduction, and sperm. The Children's Oncology Group (COG) clinical sites (protocol ALTE16C1) of previously collected and stored sperm samples were obtained for this analysis. The epigenetic DNA methylation alterations in sperm were assessed in 176 control adult male patients' sperm, and 183 chemotherapy-exposed osteosarcoma survivors' adult male sperm were provided by COG sites. The current study used a weighted gene co-expression network analysis computational approach that was adopted for use as a weighted epigenetic site correlation network analysis. This analysis identified correlation coefficients between differential DNA methylation regions and other DNA methylation sites with physiological and chemotherapy parameters. Module-trait relationships in the data were determined for epigenetic modules, which highly correlated with sperm parameters, reproductive hormones, and several chemotherapies (e.g. cisplatin). Gene associations of these epigenetic sites were identified and correlated to chemotherapy-associated genes and pathways, as well as reproductive parameters. Observations demonstrate dramatic impacts of adolescent chemotherapy on later adult life sperm epigenetics. Clearly, epigenetics has the potential to mediate the actions of chemotherapy on later life physiology and may potentially impact future generations through epigenetic transgenerational inheritance mechanisms, but this needs further investigation.
Lead (Pb2+) is a well-established neurotoxin that impairs motor, learning, and memory functions, particularly in children and younger adults. However, its impact on older adults remains less understood. Pb2+ toxicity involves disruption of DNA methyltransferase activity and associated epigenetic pathways, potentially altering the expression of specific genes relevant to neurological functions. As methylation patterns naturally shift during aging, Pb2+ exposure may induce additional neurological risks in aged populations. Using a zebrafish model, we investigated the combined effects of Pb2+ exposure and brain aging. Two-year-old male zebrafish were exposed to 1, 10, 100, 1000, 10 000 µg/l Pb2+ or fish water control for five days. Brain tissues were collected for DNA extraction and whole-genome bisulfite sequencing to assess global and gene-specific methylation changes. Our results found that Pb2+ exposures ≥ 100 μg/l significantly increased global methylation levels in the aged brain. Differentially methylated genes (DMGs) exhibited methylation changes within gene body regions and were mostly annotated with ion transportation and signal transduction pathways. Although only a limited number of DMGs showed corresponding changes in gene expression, several of them were associated with locomotor-related functions, including shank1 at 10 000 Pb2+ μg/l, and ptprsa, plxna2, and aopep at 100 μg/l Pb2+. These findings suggest that Pb2+ exposure during aging predominantly induces gene body-localized DNA methylation changes, and the role of such epigenetic regulation in Pb-associated neurobehavioral outcomes warrants further investigation.
Alpha (α)-radiation is a genotoxic and epigenotoxic agent capable of increasing the risk of cancer and other diseases. DNA hydroxymethylation (DNAhm) can modulate gene expression and is considered an under-researched epigenetic event in ionizing radiation studies. Here, the genome-wide DNAhm profile was examined in 64 α-irradiated human embryonic lung fibroblast samples from our 2023 methylome study. These cells were exposed to seven doses (N = 4 per dose) of americium-241 α-particles ranging from 2 to 2200 mGy, using either single-fraction (SF) or multi-fraction (MF) exposure regimens. We report that SF and MF α-irradiation primarily increased DNAhm levels, with a greater number of alterations observed following MF exposure, particularly in gene body regions. Pathway analysis of genes with increased DNAhm levels due to MF exposure suggested disruption of inflammatory responses and other cellular pathways. We also detected DNAhm changes in key genes encoding enzymes involved in DNA methylation (DNAm) and demethylation processes, which support our 2023 DNAm findings. Similar to DNAm, MF α-irradiation induced a greater number of DNAhm changes in aging-associated genes. Compared with equivalent SF doses, MF α-irradiation resulted in more mitochondrial damage. These findings demonstrate that even at comparable doses, SF and MF α-radiation induce radically different effects on the DNAhm and mitochondrial DNA. The DNAhm changes help explain the effects observed in our 2023 methylome study. Altogether, this study supports the idea that environmental radiation exposure regimens are an important consideration when assessing DNAm and DNAhm biomarkers and the potential health effects of α-radiation.
Post-traumatic stress disorder (PTSD) is a chronic and disabling psychiatric condition that affects millions of people worldwide, producing persistent disturbances in emotional regulation, cognition, and physiological functioning. Although exposure to traumatic or life-threatening events is a defining feature of PTSD, only a subset of exposed individuals develop enduring symptoms, highlighting variability in vulnerability and recovery. The biological mechanisms underlying PTSD remain incompletely understood. Increasing evidence suggests that epigenetic processes play a central role in shaping individual responses to trauma. Among these, microRNAs (miRNAs), small, noncoding RNA molecules that fine-tune gene expression by regulating the translation and stability of multiple target genes simultaneously, have emerged as important epigenetic regulators of PTSD-related neurobiology. Because a single miRNA can influence extensive gene networks, alterations in miRNA expression affect a broad range of biological processes relevant to PTSD, including hypothalamic-pituitary-adrenal (HPA) axis function, synaptic plasticity, immune signaling, and memory formation. Recent studies demonstrate that dysregulated miRNAs can modify glucocorticoid receptor sensitivity, shape fear memory acquisition and extinction, and contribute to the proinflammatory phenotype frequently observed in PTSD. Progress of miRNA research in this field has been driven by integrative strategies that combine human peripheral tissues, plasma, and extracellular vesicles, complemented by animal models of stress and fear learning, including fear conditioning, restraint stress, and single-prolonged stress paradigms. Together, these approaches provide converging evidence for a critical role of miRNAs in PTSD pathophysiology. This review synthesizes findings across species to clarify miRNA-mediated mechanisms and highlight future directions for biomarker discovery and therapeutic development.
Fine particulate matter (PM2.5) exposure leads to cardiovascular diseases (CVDs) by promoting cardiac fibrosis has been demonstrated. However, the mechanisms by which PM2.5 induces cardiac fibrosis remain unclear. Here, we confirm that the endoplasmic reticulum stress (ERS)/thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) signaling pathway is the mechanism of action in PM2.5-induced cardiac fibrosis, which also plays a crucial role across multiple cell types implicated in this condition. PM2.5 exposure resulted in increased levels of reactive oxygen species (ROS), the occurrence of ERS, and upregulation of TXNIP expression, as well as pyroptosis and apoptosis in macrophages and cardiomyocytes, subsequently leading to the activation of MCF. The pyroptosis and apoptosis in macrophages and cardiomyocytes, along with MCF activation induced by PM2.5, were significantly attenuated with the inhibitors of ERS and TXNIP. We also observed that ERS and TXNIP are involved in multiple mechanisms related to oxidative stress and the inflammatory response. We provide insights into the specific mechanisms underlying PM2.5-induced cardiac fibrosis and suggest potential targets to control PM2.5-induced cardiac fibrosis.
The androgen receptors (Ar) are fundamental mediators of androgen signaling, critical for male fertility. Environmental endocrine disruptors (EEDs) can impair male fertility; however, it remains unclear whether EED-induced fertility impairments are linked to DNA methylation alterations in the ar promoter within germ cells, or if a germline-to-soma transfer of these epigenetic profiles affects ar transcription in the testis leading to fertility impairment. To address this, we exposed medaka (Oryzias latipes) to bisphenol A (BPA, 100 µg/l, an EED) and determined fertility defects, testis histology, DNA methylation alterations in the CpG island of arα promoter, and mRNA levels of arα mRNA in the testicular germ cells and soma. Reduced fertility was observed in F0 and F2 generations, which was accompanied by alterations in the testicular tubular structure and germ cell landscape. In F0 males, the testicular germ cells maintained increased levels of DNA methylation on the CpG island of the arα promoter at the ground state of epigenetic reprogramming of germ cells (15 days post-fertilization, dpf) and as such in sperm. In F2 males, testis showed elevated expression of DNA methyltransferase enzyme genes. F2 germ cells maintained significantly higher levels of DNA methylation. The elevated DNA methylation profile was maintained in testicular somatic cells and correlated with significantly decreased arα mRNA levels. The present results demonstrate that ancestral BPA exposure induces transgenerational male subfertility by altering the methylation profile of arα promoter and gene expression, highlighting the profound risk EEDs pose to reproductive health in vertebrates and population stability in wildlife.
Ambient air pollutant levels during pregnancy are known to impact the offspring’s health. DNA Methylation (DNAm) may be sensitive to air pollutants throughout pregnancy. This study estimated the effect of ambient air pollution (PM2.5, PM10, NO2, O3) mixture levels in early and late pregnancy on paired maternal prenatal DNAm (N = 116) levels. The impact of average prenatal pollutant mixture on neonatal cord blood DNAm signatures was also evaluated (N = 114). Lastly, the association of pollutant-related maternal DNAm profiles (N = 78 maternal-child dyads) with neonatal DNAm profiles was investigated. Quantile g-computation was applied to maternal and neonatal datasets to test the effect of the pollutant mixture on DNAm signatures. To test the correlation of pollutant associated alteration in maternal DNAm with cord blood DNAm signatures, independent cord blood epigenome wide association studies (EWASs) were applied within the subset of significant maternal CpGs identified in the mixture model. Sex was explored as a modifying variable. We identified 18 maternal prenatal CpGs whose methylation levels were associated with ambient air pollution mixtures in pregnancy on average. 1 CpG, cg00723044, displayed significance in models for the neonatal mixtures analysis only among male neonates. Neonatal CpGs were not associated with maternal CpGs identified in the maternal mixtures analysis. Ambient air pollution mixtures were associated with maternal methylation levels in 18 CpGs (q < 0.1) in pregnancy, and there was some evidence that air pollutant mixture levels in pregnancy affected cord blood DNAm in 1 CpG in male neonates.
Humid heat exposures over pregnancy impact birth outcomes but mechanisms are poorly described. We leveraged the Ghana Randomized Air Pollution and Health Study (GRAPHS) to examine associations between maximum shaded wet bulb globe temperature (WBGT) and cord blood extracellular vesicle (EV)-associated microRNA. We also considered heat index (HI) and dry air temperature as secondary exposures. Cord blood was collected at delivery and EVs isolated and RNAs sequenced and small RNA libraries constructed. We assigned participants' trimester and whole pregnancy average heat exposures using satellite reanalysis heat exposures at the level of participant community of residence. We then performed linear regression to examine associations between prenatal heat exposures and log2-transformed miRNA counts and considered significance with an unadjusted P-value ≤ .01 and |beta| > 0.2. In 44 participants, we identified 91 microRNAs that were detected in at least 70% of samples. We identified that miR-146b-5p (β = 0.94 [95% CI = 0.27, 1.6], per 1-degree increase in WBGT); miR-381-3p (β = 2.23 [1.3, 3.15]), miR-378a-3p (β = -1.4, [-2.42, -0.39]), and miR-744-5p (β = 1.51 [0.46, 2.57]); and miR-126-3p (β = -0.75 [-1.2, -0.29]) were associated with first-, second-, and third-trimester WBGT, respectively. miR-1307-3p (β = 2.27 [0.61, 3.94] per 1-degree increase in WBGT) was associated with WBGT averaged over the whole pregnancy. Similar findings were observed with HI. In the GRAPHS cohort, we identified that humid-heat exposure over pregnancy alters the cord blood EV-associated miRNA profiles.
In Ausimmune, an Australian multicenter incident case-control study, Epstein-Barr virus (EBV)-related measures, including anti-EBNA antibodies and infectious mononucleosis, show multiple sclerosis (MS) associations mediated by DNA methylation (DNAm). Human herpesvirus-6 (HHV-6) DNA has also been linked to increased MS onset risk, though its mechanisms remain unknown. Therefore, we examined an expanded set of human herpesvirus indices including HHV-6 indices. We first tested associations with MS-associated DNAm modules, then assessed whether HHV-6 DNA contributes to MS onset through DNAm pathways. Serological (serum) and viral load (whole blood) measures of EBV (DNA, viral capsid antigen, early antigen diffuse and restricted), HHV-6 (DNA, IgM, IgG), cytomegalovirus (CMV) (IgG), and varicella zoster virus (DNA, IgG) were collected. DNAm was measured from whole blood (Illumina Infinium Human Methylation EPIC v1). DNAm-module (A1-A5) scores were derived using an epigenome-wide association study for MS onset risk and dimension-reduction methods. A total of 206 cases and 348 matched controls were analyzed. Multivariable linear regression demonstrated associations between HHV-6 DNA positivity and the A2-module, and between higher CMV IgG and the A4 module. Counterfactual mediation analysis indicated that 45% of the positive association of HHV-6 DNA positivity with MS onset risk was mediated through the A2 module (P indirect = .008). The A2 module showed enrichment for lymphatic and immune pathways. These results provide evidence for a distinct DNAm module as a plausible mechanism underlying the associations of HHV-6 with MS onset. Importantly, these epigenetic pathways appear to mediate associations with human herpesviruses beyond EBV. These findings provide further insights into how environmental factors relate to MS onset through epigenetic programming.
Exposure to adverse environments early in life can shape health trajectories across the lifespan. A key mechanism by which this life-long reprogramming occurs is via epigenetic modifications, including altered DNA methylation (DNAm), histone modifications, and microRNA (miRNA) regulation. This invited perspective highlights key human population studies and selected animal studies from our group and collaborators that have examined toxicant exposure occurring during or prior to pregnancy including metals, pharmaceuticals, microorganisms, air pollution, and socioeconomic stressors and their impact on the epigenome. Exposure to these substances is associated with altered epigenetic patterning in fetal blood and placenta, often in a gene- and sex-specific manner. This gene specificity may be tied to the transcription factor occupancy, where environmental exposures alter transcription factor binding at regulatory regions, influencing downstream epigenetic patterns. In relation to adverse health outcomes, these epigenetic modifications have been associated with adverse pregnancy outcomes such as preeclampsia as well as neonatal health (i.e. preterm birth, retinopathy of prematurity, chronic lung disease, and congenital heart defects). Additionally, these epigenetic alterations have been associated with outcomes later in childhood, including cognition, neurodevelopmental disorders [e.g. autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD)], obesity, metabolic dysregulation, asthma, and immune dysfunction. Collectively, these studies highlight the relationships among early-life environmental factors, epigenetic biomarkers, and maternal and child health outcomes.
Bisphenol A (BPA), which is a common ingredient of plastics and epoxy resins, is among the most commonly found endocrine-disrupting chemicals in the human environment. Chronic human exposure has raised concerns over its effects on reproductive health. There is growing evidence showing that BPA causes epigenetic changes, primarily DNA methylation, histone changes, and non-coding RNA changes that result in hormonal imbalances, a disruption in gametogenesis, and fertility impairment. This review summarizes current understanding of how BPA alters male reproductive performance in exposed individuals, including impaired spermatogenesis and sperm quality, endocrine imbalance, and disruption of hypothalamic-pituitary-gonadal (HPG) signaling, often in concert with oxidative stress and altered steroidogenesis. We then discuss evidence that BPA exposure, especially during critical developmental windows, can reprogram the paternal germline, such that epigenetic alterations carried by sperm, such as DNA methylation changes, abnormal histone acetylation (H3K9ac, H3K27ac, H4K12ac), disrupted histone-to-protamine transition, and altered sperm small RNAs/miRNA profiles, can contribute to fertility defects in subsequent generations. Moreover, various therapeutic methods, like epigenetic drugs and natural products such as resveratrol, naringenin, and genistein, are being studied to reverse or alleviate the impact of BPA. Given BPA's ubiquity, these findings also highlight the necessity of stricter regulation, health education to the general population, along with research into potential safer alternatives. Learning the ways BPA is remodeling the epigenome and fertility through generations is essential to protecting reproductive health and the basis of policy intervention.
6-methyladenosine (m6A) RNA methylation, regulated by writer, eraser, and reader proteins, modulates mRNA stability, splicing, and translation, thereby influencing key cellular processes. Environmental stressors, such as alcohol, may disrupt this epitranscriptomic machinery and contribute to disease vulnerability. In this study, we investigated how chronic exposure to ethanol, its toxic metabolite acetaldehyde, and subsequent withdrawal affect the expression of m6A regulatory genes. Neuron-like (SH-SY5Y) and non-neuronal (SW620) cells were exposed for 3 weeks to ethanol (40 mM) or acetaldehyde (30 μM) (concentrations comparable to blood levels after heavy drinking), followed by a 24-h withdrawal period. Gene expression of seven writers (KIAA1429, METTL3, METTL4, METTL14, RBM15, RBM15B, and WTAP), two erasers (ALKBH5, FTO), and nine readers (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPA2B1) was quantified by RT-qPCR. Concurrently, RNA-seq data from eight reward-related brain regions of 24 individuals of European ancestry (12 with alcohol use disorder [AUD] and 12 controls) were analyzed for AUD-associated expression changes in m6A regulatory genes. In cell models, ethanol broadly suppressed the expression of most m6A regulatory genes, whereas withdrawal largely restored their levels. Acetaldehyde induced subtler gene expression changes, likely reflecting its lower exposure concentration and rapid metabolism. Postmortem brain analysis revealed trends toward altered expression of m6A regulatory genes across multiple brain regions in individuals with AUD. Collectively, these findings suggest that chronic alcohol exposure dysregulates m6A regulatory gene expression and may impact downstream RNA regulatory pathways involved in AUD pathophysiology. Further studies are warranted to elucidate the mechanisms by which alcohol-induced dysregulation of m6A regulators influences AUD risk.
All plants and animals must time their annual reproduction to seasonal variation in resources to optimize reproductive fitness. Environmental factors such as photoperiod and temperature are well known to influence seasonal timing of reproduction but how organisms incorporate environmental cues to alter physiological responses and initiate reproduction remains poorly characterized at the genetic level. A growing number of studies have found that epigenetic mechanisms, such as noncoding RNA, histone modification, and DNA methylation, can have an important role in modifying transcriptional regulation of traits related to seasonal timing. While epigenetic modifications act differently across taxa, there is consistent evidence for their involvement in the timing of seasonal life-history transitions. Here, we discuss the way in which environmental cues trigger epigenetic modifications and propose several roles for their involvement in the regulation of seasonal phenotypes in plants, invertebrates, and vertebrates.
High altitude presents a significant environmental stressor in the form of hypobaric hypoxia. The body responds to this condition with various acclimatization mechanisms, yet the role of epigenetic modifications, particularly DNA methylation, remains unclear. To address this gap, we investigated DNA methylation patterns in response to acute high-altitude exposure. Twelve healthy sea-level residents, aged 19-32 years, traveled to 3800 m, and DNA from peripheral blood mononuclear cells was collected both at sea level and after 24 h at high altitude. DNA methylation was assessed using the Illumina MethylationEPIC array. We identified 58,046 differentially methylated positions at high altitude compared to sea level, with a large majority of these sites showing increased methylation levels at high altitude, supporting the hypothesis that acute exposure to hypoxia may result in global hypermethylation. Notably, differentially methylated sites were located in genes enriched for pathways related to the hypoxia-inducible factor (HIF) pathway, such as "Notch signaling" and "AKT1 signaling in cancer." Moreover, several pathways associated with calcium regulation and DNA damage repair were implicated, suggesting an association between DNA methylation and calcium processes affected by hypoxia. In addition to single positions, we explored differentially methylated regions, resulting in top differentially methylated regions being associated with calcium processes, zinc finger proteins, glucose processes, and erythropoiesis. These findings provide insight into how short-term environmental hypoxia may influence the human epigenome, highlighting DNA methylation as a dynamic marker of environmental exposure.
The role of intragenic cytosine methylation in shaping phenotypes has been contentious. Recent studies show association between stress and alternative splicing of transcripts, but without functional genome-wide or single-position analysis. We utilized the msh1 experimental system in Arabidopsis as a model of reproducible epigenetic states with stress-responsive phenotypes, including commitment to heritable memory for at least seven generations. We mapped the methylome to single-cytosine resolution with signal-detection, verified by machine learning. Differentially methylated genes were overlapped with msh1 -derived transcript isoforms to show that different patterns of exonic methylation led to different levels of isoform expression. Alternatively spliced and differentially methylated genes were enriched in key regulators of growth and development and spliceosome components. Genes targeted for differential methylation also contained a known CTT motif. These results demonstrate a direct relationship in plants between environmentally responsive differential methylation and alternative splicing behavior leading to phenotype changes.
Background and objective:Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy, which is impacted by genetic, epigenetic, and environmental variables. Aberrant methylation of genes, such as O6-methylguanine-DNA-methyltransferase (MGMT), is one of the key mechanisms in carcinogenesis. The aim of the present study was to examine the association of exposure to diazinon with MGMT gene methylation and expression levels in children with ALL. Methods:This case-control research was performed on 136 children with ALL and 136 healthy children as the control group. Demographic data were gathered using a questionnaire and blood sampling. Serum concentrations of diazinon were determined using gas chromatography (GC). DNA was extracted from nucleated cells, followed by bisulfite treatment and examination of MGMT gene promoter methylation using methylation-specific polymerase chain reaction (MSP). Gene expression levels were also determined using real-time Polymerase chain reaction (PCR). Acetylcholinesterase (AChE) activity and malondialdehyde (MDA) concentrations were evaluated as indicators of pesticide toxicity and oxidative stress. Results:Diazinon levels were significantly increased in ALL patients compared to controls (P < .001) and were positively associated with elevated methylation levels of MGMT gene promoter. The odds ratio of ALL development was significantly higher in children with both increased diazinon concentrations and elevated MGMT methylation levels. Moreover, patients exhibited reduced AChE activity and higher MDA concentrations, suggesting the induction of neurotoxicity and oxidative stress triggered by diazinon. Conclusion:Exposure to diazinon might contribute to the development and progression of ALL by triggering aberrant methylation of the MGMT gene, decreasing DNA repair capacity, and promoting oxidative damage. This study highlights the importance of minimizing pesticide exposure and suggests the use of MGMT methylation as a biomarker for the diagnosis and prognosis of ALL.
Household air pollution (HAP) has been associated with adverse pregnancy and birth outcomes, but the underlying mechanisms remain unclear. Pollutants can cross the placenta, potentially causing dysregulation of the crucial organ. Placental microRNAs (miRNAs) may serve as biomarkers of placental health, but studies of prenatal air pollutant exposure and placental miRNAs using non-targeted approaches have been scarce. We leveraged personal air monitoring data from mothers enrolled in the Ghana Randomized Air Pollution and Health Study to estimate prenatal exposure levels to carbon monoxide (CO) and particulate matter <2.5 µm (PM2.5). Placental tissue small RNA was sequenced and aligned to miRbase v22. We used sparse principal components analyses (sPCAs) to identify candidate placental miRNAs associated with prenatal CO (N = 133) and PM2.5 (N = 85) exposure. Associations between candidate miRNAs and prenatal exposures were assessed using linear regressions. We identified four placental miRNAs upregulated with prenatal CO exposure (miR-128-3p, miR-423-3p, miR-671-3p, and miR-744-5p) and five downregulated miRNAs (miR-29b-3p, miR-30e-5p, miR-101-3p, miR-130a-3p, and miR-376b-3p) at P < 0.1. Among female infants only, five miRNAs were downregulated (miR-101-3p, miR-130a-3p, miR-19b-3p, miR-106b-5p, and miR-301a-3p) and one upregulated (miR-22-3) with CO exposure (P < 0.1). We did not identify any associations between placental miRNAs and prenatal PM2.5 exposure. Our results support associations of prenatal CO exposure with differential expressions of critical placental miRNAs that have been implicated in placental disorders by previous studies. This is the first study to examine associations of these exposures with placental miRNAs using a non-candidate approach and lays the groundwork for targeted studies of placental miRNAs associated with prenatal HAP exposure.
Preeclampsia (PE) remains a major contributor of maternal and fetal morbidity and mortality worldwide, affecting 2%-8% of pregnancies. While genetic predisposition, placental dysfunction, and angiogenic imbalance remain central to PE pathophysiology, emerging observational evidence suggests potential associations between environmental factors, epigenetic modifications, and PE development. This review consolidates available research linking environmental exposures, particularly air pollution, maternal gut microbiome composition, and dietary habits, with changes in epigenetic markers during pregnancy that may influence PE susceptibility. We synthesize findings from epidemiological studies, mechanistic research, and biomarker studies across this research area. However, definitive causal evidence linking specific environmental exposures to PE through epigenetic mechanisms remains limited. The majority of existing studies employ observational designs or focus on biological mechanisms; well-designed prospective cohorts incorporating direct environmental measurements and randomized intervention trials are lacking. Circulating biomarkers, including microRNAs and DNA methylation patterns, show associations with both PE status and prior environmental exposure, providing biological support for the concept that environmental factors may influence PE development. The maternal gut microbiome demonstrates dysbiosis in PE patients, and mechanistic studies in animal models suggest that microbiota-derived metabolites may influence placental development through epigenetic pathways; however, clinical evidence in humans remains preliminary. Integration of environmental exposure assessment with multi-omics profiling in large prospective studies is necessary to establish whether environmental factors causally contribute to PE pathogenesis. Future research combining detailed environmental characterization, longitudinal epigenomic profiling, and rigorous causal inference methods will be essential to translate these mechanistic insights into prevention and therapeutic strategies.
