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Environmental exposures influence multigenerational epigenetic transmission

Clinical Epigenetics volume 16, Article number: 145 (2024) Cite this article

Abstract

Epigenetic modifications control gene expression and are essential for turning genes on and off to regulate and maintain differentiated cell types. Epigenetics are also modified by a multitude of environmental exposures, including diet and pollutants, allowing an individual’s environment to influence gene expression and resultant phenotypes and clinical outcomes. These epigenetic modifications due to gene–environment interactions can also be transmitted across generations, raising the possibility that environmental influences that occurred in one generation may be transmitted beyond the second generation, exerting a long-lasting effect. In this review, we cover the known mechanisms of epigenetic modification acquisition, reprogramming and persistence, animal models and human studies used to understand multigenerational epigenetic transmission, and examples of environmentally induced epigenetic change and its transmission across generations. We highlight the importance of environmental health not only on the current population but also on future generations that will experience health outcomes transmitted through epigenetic inheritance.

Background

Posttranscriptional epigenetic modifications serve as a biological mechanism to control tissue-specific gene expression and promote normal organ development and function. However, environmental influences, such as diet and toxic pollutant exposures, can alter the epigenome and allow the environment to influence gene expression and cell function. Exposure-acquired epigenetic patterns can persist and be inherited to subsequent generations. For this reason, epigenetic alterations are a mechanism for lifelong health and disease prevention.

The field of epigenetics began at the end of the twentieth century, although the concept of epigenetics was developed earlier [1]. Conrad Waddington, an embryologist, first coined the term “epigenetic landscape” in 1957. He described that genes and the environment interact to form a unique landscape that determines cell differentiation fate, similar to how a rolling ball’s direction changes based on the bumps and turns it encounters [2]. This was based on his earlier observations in 1942 that, early in life, cells undergo a series of differentiation stages and disturbances that give rise to tissues and organs [3]. DNA methylation was discovered around the same time [4], but the realization that methylation can alter gene expression only occurred in 1975 [5, 6]. In more recent years, the specific molecular mechanisms underpinning epigenetic processes have been better established.

This narrative review summarizes our current understanding of epigenetic mechanisms, including types of epigenetic modifications, epigenetic inheritance (transmission through mitosis and meiosis), the long-term health impacts of epigenetic reprogramming (especially during the fetal period), model systems to study epigenetics, and the influence of the exposome on epigenetics. Such information offers critical insights into how the environment influences health and disease throughout the life course and across generations, with important clinical and public health impacts.

Types of epigenetic changes

Epigenetic modifications include DNA methylation, histone modification, 3D genome organization, and RNA-mediated gene regulation [7]. Through these mechanisms, an individual’s exposome directly influences gene expression and other processes throughout their life. The exposome is a measure of all the exposures, including diet, behaviors, stress, pathogens, air pollution, and other environmental chemical exposures, experienced by an individual in their lifetime and how these exposures relate to their biology and health [8].

Fetuses, infants, and children are especially susceptible to the exposome-induced epigenetic changes as their bodies undergo rapid growth (cell division and proliferation) and development (increasing level and complexity of functions). For example, increasing evidence supports an epigenetic mechanism underlying the connection between folic acid and the prevention of neural tube defects [9]. Indeed, a recent multiomics study identified over 900 associations between the exposome and measures of biological responses that could influence the child’s health [10]. To understand how in utero and early life exposures may cause epigenetic changes, we first review the major types of epigenetic modifications.

DNA methylation occurs when a methyl group is added to a cytosine residue by a family of enzymes called DNA methyltransferases (Dnmts) [11]. Dnmts transfer a methyl group, from S-adenyl methionine, onto the fifth carbon of a cytosine residue in a CpG dinucleotide (forming 5-methylcytosine). DNA methylation is well characterized across tissues and species. CpG islands are typically localized to transcription start sites, and CpG methylation in promoter regions is a mechanism to confer a gene silencing effect. CpG methylation therefore specifically acts as a determinant of tissue specificity [12,13,14,15]. DNA methylation arrays can be used to deconvolute cell proportions in a given sample [16, 17]. There is also evidence for non-CpG localized DNA methylation [12, 18] and for DNA methylation to promote gene expression [13, 14]. Within somatic cells, epigenetic patterns can be maintained or modified throughout a lifetime. During mitosis, Dnmts establish methylation patterns [11]. DNMT1 catalyzes the persistence of existing DNA methylation patterns by replicating the methylation marks of parental DNA onto daughter DNA, converting hemi-methylated sites back to symmetrical methylation [15]. In parallel, DNMT3A and DNMT3B, known as de novo methyltransferases, establish new methylation patterns to promote the normal developmental process and based on nutrition, environmental exposures, aging, stress, and other behavioral and lifestyle factors [19,20,21].

Histone proteins provide structural support for a chromosome, and histone modifications affect gene expression by changing the DNA–histone interaction, therefore modifying DNA accessibility for transcription [22, 23]. Histones can be modified by methylation, acetylation, and phosphorylation, which are added either to the core histone proteins or to the histone tails, together forming a landscape that enables or restricts gene expression. While most histone modifications are widely conserved, the epigenetic mechanisms of histone modifications are also subject to modification by environmental factors [20]. Histone methyltransferases (HMTase) catalyze the methylation of histones, and the methylation process can be reversed by histone demethylases. Histone acetyl transferases (HAT) and histone deacetylases (HDAC) contribute to the relaxation of chromatin, as acetylation removes the positive charge of a histone, decreasing its interaction with negatively charged DNA [24].

The overall 3D structure of the genome also has a direct influence on which genes are expressed within a cell, due to the proximity of multiple genes and accessibility of transcriptional machinery [25]. DNA methylation and histone modifications both influence 3D genome organization, highlighting its importance in epigenetic gene regulation [26]. Finally, RNA molecules, such as long noncoding RNA [27] and small nucleolar RNA [28], regulate gene expression through binding of the genome and mRNA transcripts. Specific miRNAs also regulate expression of Dnmts and histone deacetylases through directly binding to the gene transcripts encoding these epigenetic modifying proteins [29]. This results in a downstream change in the epigenetic modification capabilities of the cell. Conversely, miRNA expression itself is epigenetically regulated. The interplay of Dnmts, histone-modifying proteins, and miRNAs together create a complex epigenetic modifying network. Disruption of this network has large negative impacts. For example, epigenetically dysregulated miRNA expression has been linked to many human diseases, including multiple cancer types, cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung's disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, and pulmonary fibrosis [30].

Epigenetic reprogramming during development

An important mechanism of epigenetic transmission across generations is epigenetic reprogramming. Upon fertilization, the global dynamic change in the epigenome is critical for embryonic and fetal development. Early efforts to track epigenetic changes during preimplantation embryo development focused mostly on miRNAs [31, 32]. With recent technological advancements and availability of discarded human preimplantation embryos [33], it is more feasible to integrate single-cell multiomics analyses to comprehensively reveal the stage-dependent epigenetic changes, including DNA methylation and histone modifications, in human preimplantation embryos [34, 35]. We will therefore highlight the dynamic epigenetic reprogramming that occurs in human embryos and emphasize the implications in proper embryonic and fetal development (Fig. 1).

Fig. 1
figure 1

Epigenetic patterns observed across the life span. Epigenetic modifications change over time and increase with age as exposures accumulate. This epigenetic change occurs for both histone modifications (green line) and DNA methylation (orange line). Epigenetic regulation is retained from the parental sperm and egg and undergoes multiple rounds of reprogramming to assume a baseline epigenetic profile in the developing fetus. Some epigenetic marks persist through these reprogramming stages, allowing epigenetic transmission from earlier generation(s). Some epigenetic marks are acquired de novo due to the environment during pregnancy and during organ development in utero. After birth, epigenetic patterns continue to change most rapidly during growth and development in childhood and adolescence. Epigenetic modifications are continually acquired throughout life. The resultant epigenetic state in adulthood is then passed on to the next generation through the germ cells, and the cycle repeats. Figure was designed using biorender.com

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Methylation reprogramming

The first wave of demethylation occurs in both sperm and oocyte genomes, which are highly methylated but become demethylated upon fertilization. This demethylation wave differs between the male and female genome [36]. Single-cell reduced representation bisulfite sequencing analysis showed a stronger hydroxy-methylation signal in male pronuclei of human embryos, compared to female [37], supporting increased demethylation. This occurs rapidly and as early as 10–12 h post-fertilization, and DNA methylation in the early male pronucleus decreases from about 80 to 50% of the sperm genome [36]. DNA demethylation of the parental genome is necessary for acquiring cell pluripotency [38]. The resultant demethylated regions from this first wave of reprogramming are located at enhancer sites and gene body regions that are critical for transcription activation and embryogenesis [39].

The second and third waves of demethylation occur as the zygote develops [36]. At the two-cell stage, the global methylation level decreases to about 40% (second wave). From the eight-cell stage to morula, the global DNA methylation further decreases to about 35% (third wave). At this point, the demethylated regions are mostly introns and short interspersed nuclear elements (SINE), especially the Alu elements, which regulate gene expression by modulating polyadenylation, splicing, and editing by adenosine deaminase [40]. Since zygotic genome activation of human embryos occurs at the eight-cell stage, the coincidental demethylation of SINEs implies active transcription, which is crucial for blastomere cleavage [41]. The global DNA methylation level reaches its lowest (about 25–30%) when the blastocysts are ready for implantation [36, 42, 43].

Coinciding with global demethylation, new methylation marks are established through de novo DNA methylation [36]. In human embryos, the first wave of de novo methylation occurs from the early male pronucleus to mid-pronucleus stage, and the second wave occurs from the four-cell to eight-cell stage. These hypermethylated sites are mostly active repeat elements including the SINEs, long interspersed nuclear elements (LINEs), and long terminal repeats (LTRs). Suppression of these regulatory elements before zygotic genome activation (ZGA) at the eight-cell stage is postulated to reduce gene integration and thus maintain genome integrity of the developing embryos.

Histone modification reprogramming

Changes in the methylome coincide with chromatin accessibility of the embryo genome. Histone modifications facilitate the dynamic change in the chromatin state of preimplantation embryos to allow incorporation of paternal and maternal genomes [38, 44, 45]. These histone modification changes also occur asymmetrically between paternal and maternal genomes. For example, the paternal genome has lower levels of repressive histone marks H3K9me2, H3K9me3, H3K27me2, and H3K27me3, while the maternal genome is enriched with the same histone marks [38], which have implications for transcription initiation and gene expression (45). To facilitate this asymmetry, the maternal genome undergoes passive demethylation in a stage-dependent manner and is transiently protected from Tet3-mediated hydroxy-methylation. Developmental pluripotency-associated protein 3 (DPPA3/PGC7/STELLA) binds to Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) and negatively regulates the repressive histone mark H3K9me3 to downregulate repeated elements [45, 46].

At the mid-zygote stage, while half of the open promoters remain hypermethylated, the nucleosome-depleted regions (NDR) are enriched in the exons and intragenic regions of genes functionally linked to cellular metabolism, RNA processing, and biosynthesis [34]. As such, histone modifications during the maternal–zygotic transition serve to transiently open the chromatin of the demethylated embryo genome. This fine-tunes expression of the repeated elements for embryonic stage-specific transcription activation and metabolism. At the four-cell and eight-cell stages, H3K9me3 marks are enriched in the LTRs and LINE regions. As the methylome is mostly demethylated, the establishment of H3K9me3 marks ensures the stability of the embryonic genome. Eventually H3K9me3 marks are enriched at the genic and distal regions of the inner cell mass (ICM) and trophectoderm (TE) upon lineage segregation [47].

Enrichment of specific histone marks at the morula stage then increases the global chromatin accessibility upon ZGA [34]. For example, after ZGA, previously depleted H3K27ac domains become enriched around the TSS. In addition, establishment of H3K4me3 and H3K27me3 marks help maintain pluripotency of the developing embryos. Broad domains of H3K4me3, which mark transcriptionally active chromatin, are detectable in the embryo and increase following the two-cell stage [48, 49]. The enrichment of H3K4me3 marks may also induce an open chromatin structure, which coincides with the increase in chromatin accessibility from the four-cell stage and subsequent transcription activation [34]. This increase in accessibility via proximal NDRs occurs near transcription factor binding sites that promote pluripotency and early embryonic regulation. In contrast, distal NDRs are enriched for stage-specific enhancers and insulators that promote differentiation and cell fate determination.

Reprogramming within fetal organs

Unlike preimplantation embryos, DNA methylation patterns of somatic cells are organ-specific. Human fetal organs begin expressing a set of organ-specific genes at 9 weeks of gestation [50]. As these organ-specific genes are actively transcribed through DNA hypomethylation from 9 to 22 weeks of gestation, development-associated genes are simultaneously hypermethylated and downregulated. Two studies using human induced pluripotent stem cells (iPSCs) found that the epigenetic memory of the stem cells is preserved in their derived mature cells [51, 52]. Successful differentiation of iPSC-derived mature cells was more likely to occur when the iPSCs were derived from the same organ as the target mature cell. However, little else is known about chromatin remodeling during fetal development. Similarly, aberrant chromatin regulation is suggested to underlie abnormal tissue development, heightening risk of adult disease [53,54,55].

Gene imprinting

Imprinted genes are the exception to dynamic epigenetic reprogramming. Parent-specific DNA methylation marks are established in the parental germ line and regulate monoallelic expression of the imprinted genes [55]. Imprinted genes, including Igf2-H19, Dlk1-Dio3, Igfr2, Snrpn, and Kcnq1, are often clustered and co-regulated by a cis-acting imprinting control region (ICR) that features a differentially methylated region at the CpG site [56]. Upon fertilization, maternal DPPA3 interacts with H3K9me2 to maintain DNA methylation patterns of the imprinted genes [57]. Trans-acting factors also specifically recognize cis-acting sequences and protect the imprinted genes from epigenetic reprogramming. An example of one of these factors is the zinc finger protein homolog 57 (ZFP57). In mice, loss of functional maternal and zygotic ZFP57 leads to embryonic lethality associated with hypomethylation of specific imprinted genes [58]. However, a similar mechanism has yet to be confirmed in human embryos.

Importantly, DNA methylation marks of imprinted genes are initially erased during post-implantation development. This minimizes the transfer of imprinting from prior generations to future generations. As primordial germ cells (PGCs) are specified and migrate to the genital ridge, there is a loss of repressive and activating histone modifications, loss of DNA methylation, and reactivation of the silent allele of the imprinted genes [59]. In mice, PGCs lack expression of many Dnmts, facilitating demethylation of ICRs [60]. However, how the established epigenetic marks of the imprinted genes are erased in humans remains unclear.

Notably, most imprinted genes are growth factors or regulators for gene expression that modulate growth and development [61]. Aberrant methylation of imprinted genes at the ICR has been associated with genetic disorders that are characterized by disrupted growth and development, abnormal neurological behavior, and other clinical phenotypes [57]. For example, Silver–Russell syndrome, responsible for undergrowth and dwarfism, is associated with the imprinted domains H19-IGF2, GRB10, PEG1, and PEG3 [62]. Conversely, Beckwith–Wiedemann syndrome, responsible for overgrowth, is also associated with the imprinted domain CDKN1C [63]. Thus, disrupted epigenetic reprogramming of the imprinted genes has postnatal health consequences and risks inheritance by the next generation upon gametogenesis.

Epigenetic transmission across generations

Intergenerational transmission occurs over two generations where the impacts of an exposure in the parent are directly inherited by the child. Transgenerational inheritance occurs over three, or more, generations where a parent has an exposure and the biological effects are seen in the unexposed grandchild or subsequent generations [7]. Due to challenges inherent in human population studies, there is limited research on epigenetic inheritance in humans. As a result, studies in model organisms provide valuable insights into the mechanisms and implications of epigenetic inheritance [64].

Model organisms to study epigenetic inheritance

Model systems used to study epigenetic inheritance include mammals, insects, nematodes, and plants [65]. In mouse embryonic stem cells, DNA methylation can be induced at specific loci through integration of CpG-free DNA using a Cas9 system. The modified embryonic stem cells can then be microinjected into a parent mouse, and the specific methylation pattern, and resultant phenotype, can be observed over multiple generations. In one example of targeted DNA methylation at two metabolism genes, Ankd26 and Ldlr, epigenetic signatures at CpG islands exhibit inter- and transgenerational conservation to both the F1 and F2 generations [66]. Similarly, research in fruit flies has shown that environmental stressors, such as heat stress, alter the heterochromatin structure at specific genes, such as dATF-2. When heterochromatin was disrupted in embryos through heat stress exposure, the defective heterochromatin pattern persisted for at least five generations [67]. Furthermore, a study in the roundworm Caenorhabditis elegans determined that transgenerational inheritance of longer life span was dependent on the H3K4me3 complex, demonstrating the importance of epigenetic modifications for specific inherited phenotypes [68]. In plants, research in the mustard family plant Arabidopsis thaliana determined that temperature stress can lead to changes in DNA methylation patterns at the flowering time gene locus, which is subsequently inherited across multiple generations [69]. These findings collectively identify specific epigenetic patterns that are conserved inter- and trans-generationally. While these model studies do not perfectly recapitulate human epigenetic mechanisms, they offer support for epigenetic transfer across generations.

Model systems also provide evidence that harmful environmental exposures induce epigenetic modifications inherited into future generations. For example, this has been recently demonstrated in the freshwater flea Daphnia pulex, where exposure to polyethylene microplastics [70], cadmium, glyphosphate, or 4-nonylphenol [71] each led to specific methylation patterns that persisted at least three generations beyond the removal of pollutant exposure. This supports the hypothesis that the epigenome plays a significant role in transmitting the effects of environmental experiences across generations. Yet, there is the need to validate the exposure-induced epigenetic inheritance mechanisms in human cohorts.

Human studies to understand epigenetic inheritance

Understanding epigenetic inheritance in humans presents several new challenges compared to model systems. The complexity of human genetics and the ethical, practical, and temporal constraints of research add layers of difficulty to controlled, multigenerational studies, which are necessary to understand epigenetic mechanisms. A key challenge in epigenetic research is establishing clear causality to understand the direct inheritance of epigenetic traits [72, 73]. Challenges to drawing conclusions about the inheritance of epigenetic traits have been discussed in broader reviews of epigenetic inheritance [74, 75]. For example, investigations into allergic diseases reveal that environmental exposures during critical developmental periods can induce epigenetic changes with potential long-term health implications [76]. However, the interplay of genetics, environment, and lifestyle can make it difficult to disentangle the impact of environmental exposures.

Despite these challenges, a growing body of evidence suggests that paternal and maternal exposures influence epigenetic transmission to subsequent generations. In one study, paternal smoking prior to conception was associated with offspring DNA methylation patterns [77]. However, it was difficult to distinguish between the epigenetic effects of the biological father’s smoking prior to conception with that of the secondhand smoke exposure experienced by the child if the father was a current smoker. Nonetheless, some of the fathers had been smokers only as teenagers, supporting the potential for the inherited epigenetic pattern of their child. Clinical evidence of paternal epigenetic transmission of exposures is a study from Sweden, which found that limited access to food during crop failures in prepubescent Swedish grandfathers predicted cancer mortality in their grandsons [78]. Maternal diet and intake of specific food groups, vitamins, and micronutrients are associated with asthma, allergy, and infection occurrence in offspring [79, 80]. For example, folic acid supplementation is associated with an elevated risk of asthma [81]. Mechanistically, allergy and asthma loci are under specific epigenetic regulation that are specifically modifiable by vitamins, food, and other exposures [82]. Together, these findings provide evidence that the exposome during both preconception and during pregnancy can induce epigenetic change that may be transferred to offspring.

The challenge to tease apart the role of shared genes, exposures, and behaviors is exemplified by findings on epigenetic changes that are associated with risk of asthma across multiple generations, which has been well studied in humans [83]. In a subset of the Panel Study of Income Dynamics cohort, children with asthmatic parents or grandparents had four times the odds of developing asthma [84], supporting the transgenerational impact of health outcomes. Similarly, hospitalization records in Sweden found a high familial risk of asthma [85]. The observed increased asthma risk, regardless of singleton, same-sex twins, or different-sex twins, suggests that there may be epigenetic modifications that enhance the heritable genetic risk of asthma.

In addition, there is growing evidence that epigenetic reprogramming underlies the pathogenesis of clinical outcomes such as asthma and allergic rhinitis. For example, asthmatic patients have altered histone deacetylase activity which leads to impaired bronchial epithelial barrier integrity and worse asthma [86]. Conversely, early life exposure to dietary butyrate, a histone deacetylase inhibitor, may protect against allergy [87] and inhibition of histone deacetylase activity restores the epithelial barrier tight junctions to promote airway repair [88]. Inhibition of CpG methylation similarly improved epithelial barrier integrity which prevents asthma progression [89]. The direct role of epigenetic modification machinery in the pathogenesis and prevention of asthma supports that epigenetic inheritance may be a mechanism underlying the high familial risk of asthma. We highlight asthma and allergy as an example and hypothesize that similar mechanisms may exist for other diseases.

Human studies of epigenetic inheritance, despite inherent challenges, are important in advancing our understanding of the relationship between genetics, the environment, and epigenetic mechanisms. Reviews of non-genetic inheritance of human phenotypes and diseases through germline cells have emphasized the need for more intricate research to disentangle the contributions of genetic and epigenetic factors. Recent studies echo this sentiment by advocating for a more integrative approach to studying complex traits [90,91,92]. These studies underscore the importance of developing advanced research methodologies and interdisciplinary collaboration to understand how epigenetic patterns are established, inherited, and modified across generations.

Epigenetic effects of environmental exposures in offspring

Epigenetic reprogramming works to eliminate epigenetic modifications acquired through infections, diseases, and exposures in the parents. However, as described above, there is evidence that specific parental epigenetic modifications survive epigenetic reprogramming during fetal development and are maintained in future generations. This allows the exposome of the pregnant individual to translate into altered epigenetic patterns in subsequent generations (Fig. 2). The specific molecular mechanism of exposure-mediated epigenetic conservation or divergence across generations is a central focus of current research. It is well documented that maternal exposures during pregnancy can affect a range of offspring health outcomes. These exposures include cigarette and e-cigarette smoke [93], heavy metals and trace elements [94, 95], air pollutants such as particulate matter under 2.5 microns in diameter (PM2.5) [96], and micronutrients such as folate [95, 97]. Here we will present the current mechanistic evidence, complemented by animal studies, for the acquisition and persistence of exposome-mediated epigenetic modifications across multiple generations.

Fig. 2
figure 2

Preconception and prenatal exposures confer multigenerational inheritance of clinical outcomes through epigenetic modifications. Exposures, shown in the outer green circle, with known associations to altered epigenetic modifications include environmental pollutants from industrial plants, traffic fuel combustion, and fire smoke, diet and nutrition, exercise, stress from mental health, physical health and environmental health such as climate change, and behavioral and lifestyle factors such as smoking. These exposures induce changes in the epigenetic landscape of an individual, shown in the inner yellow circle, through DNA methylation, histone modifications, miRNA gene regulation, and 3D genome reorganization, that can be transmitted across one or more generations. Specific clinical outcomes, in the inner blue circle, are associated with these preconception and prenatal exposure-induced epigenetic modifications. Figure was designed using biorender.com

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The Agouti Yellow mouse model, where maternal diet alters offspring gene expression and resultant clinical phenotypes [98], offers mechanistic insight into this connection between the maternal exposome and offspring phenotype. In the model, the female Agouti Yellow dam has an altered version of the agouti gene, leading to a yellow hair, obese, and disease-prone phenotype. When fed a normal diet, most offspring will have this phenotype, but when fed a diet rich in methyl groups, the agouti gene is turned off through increased genome methylation, leading to a brown hair, lean, less disease-prone phenotype. The methyl group-rich diet induces epigenetic silencing of the agouti gene to alter the offspring phenotype. While this is an example of in utero epigenetic modifications from exposures, it demonstrates that environmental exposures penetrate across the placenta to alter the epigenetic state of the fetus.

Consistent with these animal studies, an epidemiological human study with participants from the Boston Birth Cohort found that adequate maternal plasma folate levels during pregnancy reduced the intergenerational association of overweight/obesity by half [97]. Other studies also provide evidence of various maternal exposures leading to DNA methylation alterations in offspring [99,100,101]. For example, maternal smoking is consistently found to alter DNA methylation patterns, in the placenta and cord blood, at genes involved in oxidative stress and hypoxia pathways [93, 102]. In contrast, higher maternal folate levels counteract the demethylation effects of cigarette smoking, most notably on the AHRR gene, which is known to affect multiple health outcomes [100]. In fact, in a pilot human intervention trial, maternal B vitamin supplementation, including folic acid, prevented PM2.5-induced methylation changes at mitochondrial oxidative energy metabolism genes [103]. These studies not only found that maternal smoking altered fetal DNA methylation, but more importantly, showed that the intergenerational link between maternal smoking and lower birthweight in offspring was substantially mediated by altered DNA methylation in multiple genes [93]. Another study found an association between lead exposure during pregnancy and changes in cord blood methylation near the PREX1 gene, which is activated in several cancers [104]. Finally, as described above, maternal diet similarly influences in utero epigenetics and neural tube formation, to protect against defects that lead to conditions such as spina bifida [10, 11]. These studies, and others [105], highlight the impact of maternal diet and environmental exposures on fetal epigenetics. If exposures can epigenetically modify somatic cells of the fetus in utero, resulting in phenotypic changes, then they likely also can modify epigenetic patterns in the fetal germline, setting the stage for future transgenerational inheritance.

Epigenetic influence of preconception and prenatal exposures

Preconception exposures are defined as those that occur in one or both parents before conception, do not directly expose the fetus, but may result in inherited epigenetic patterns and phenotypes. These phenotypes can be either beneficial, from nutrients, or harmful, from toxic exposures. Maternal preconception folic acid supplementation, obese body mass index, and physical inactivity were associated with both positive and negative health outcomes for the mother or child, depending on the exposure [106]. Similarly, preconception paternal environmental exposures can shape the sperm epigenome, and in turn influence reproductive success and offspring health [107]. Paternal exposure to smoke and metal fumes years before conception are associated with an increased risk for child asthma [108]. These preconception studies provide strong evidence that environmental exposures penetrate germline cell nuclei and allow epigenetic transmission, or memory, across generations.

Prenatal exposures are defined as those occurring during gestation, from conception until birth. As the fetus is directly exposed, and there is more available data from birth cohorts to study this, there is a wide range of mechanisms by which prenatal exposures lead to adverse outcomes. Exposures can occur via inhalation, ingestion, and dermal absorption [109], enter the bloodstream, and pass from the maternal blood circulation to the placenta. The placenta acts as a barrier for many exposures, but also serves to actively transport nutrients to the fetus [110]. As a result, the transfer rate of exposures across the placenta depends on size, chemical properties, such as water solubility, and transport proteins [111]. Finally, the metabolic ability of the placenta works to maintain its protective barrier. Through a wide diversity of enzymes, such as cytochrome P450 enzymes, the placenta has high metabolic activity to metabolize and eliminate harmful exposures [112]. Despite the barrier function, many environmental exposures still pass through the placenta and alter the epigenome of the fetus.

Environmental exposures in the prenatal period

Environmental chemicals in the air and water are an important source of prenatal exposure associated with epigenetic modifications. One of the most researched is maternal smoking and tobacco exposure. Several studies have found hundreds to thousands of CpG sites in the placenta and newborn blood that are associated with maternal smoking during pregnancy [102, 113,114,115]. These differentially methylated areas in the placenta are also associated with asthma, immune disorders, and fetal growth restriction. For example, one study of 6,685 newborns with prenatal smoking exposure found 6,000 differentially methylated CpGs that were associated with genes related to orofacial clefts, asthma, and histone methylation [113].

Inhaled airborne pollution is another known harmful prenatal exposure. In one study, exposure to larger particulate matter under 10 microns in diameter (PM10) during pregnancy was associated with 10 differentially methylated regions and 5 genes in cord blood [116]. These genes were most vulnerable to epigenetic changes in the first 4 weeks of pregnancy and functioned in apoptosis, cell cycle progression, and postnatal development. Prenatal exposure to smaller PM2.5 has been linked to decreased methylation of the genes encoding leptin and polyADP-ribose polymerase 1 (PARP1) [117,118,119]. Prenatal ozone exposure has been associated with sex-specific methylation in the placenta, but not cord blood, for genes related to asthma, inflammatory processes, and metabolism [120]. Polycyclic aromatic hydrocarbons (PAHs) have also been shown to cause lasting changes to the fetal epigenome, particularly of acyl-CoA synthetase long-chain family member 3 (ACSL3) [121]. Increases in ACSL3 methylation are associated with childhood asthma [122, 123].

Toxic chemicals, such as and phthalates, are additional pollutants with adverse effects during prenatal exposure. Prenatal exposure of BPA decreases methylation of both the IGF2 gene and the PPARA gene in female children [124,125,126]. Both genes are related to metabolic and adipogenesis pathways associated with fatty liver disease and metabolic disorders. Prenatal BPA exposure is also associated with childhood obesity through hypomethylation of mesoderm-specific transcript (MEST) and promotion of mesenchymal cell differentiation into adipocytes [127, 128]. Prenatal phthalate exposure is associated with hypomethylation of the global methylator genes LINE1, IGF2, and PPARA in a dose-dependent manner in cord blood[124]. Animal models also suggest that prenatal BPA and phthalate exposures influence transcription factor expression in sperm, mediated through DNA methylation and histone modifications [129], suggesting a mechanism for inter- and trans-generational inheritance of toxic chemical-induced epigenetic patterns.

Metal exposures, like lead, are yet another wide class of prenatal environmental exposures that are linked to epigenetic modifications in utero. Lead (Pb)-induced epigenetic changes are dependent on the stage of gestation and have transgenerational effects through genetic imprinting [130, 131]. Pb-associated CpG methylation sites in infants and children are positively associated with the timing of exposure in utero; earlier Pb exposure during pregnancy has a stronger epigenetic effect on the child. The Pb-associated CpG methylation sites were associated with genes related to neurodevelopment, neurological signaling, and autism spectrum disorder [104, 131].

Prenatal arsenic (As) exposure, a toxic metalloid, is associated with specific epigenetic changes in human cord blood. Activation of the NFkB gene in cord blood following arsenic exposure during pregnancy has been reported [132]. The NFkB pathway mediates inflammation, apoptosis, and carcinogenesis. Exposure to As is also associated with decreased total histone 3 levels in plasma in a folate-dependent manner, suggesting that diet and toxic exposures interact with and modify the epigenome [133]. This study also found an association between maternal As-associated histone levels and risk of myelomeningocele in the child, supporting an epigenetic mechanism for intergenerational inheritance of toxic As-induced health effects. Another study found an association between prenatal As exposure and CD8 + T lymphocyte concentrations in cord blood [134, 135]. Other toxic and essential elements, including mercury, manganese, copper, and zinc, have shown similar hypermethylation effects to LINE1, antioxidant gene NRF2, DNA repair gene OGG1, and PARP1, which was associated with a decrease in respective protein expression (136). Water disinfection by-product exposure during pregnancy is associated with birth outcomes and may act via an epigenetic mechanism [137]. Due to the direct epigenetic effect on both mother and child, these toxic environmental exposures are important concerns for maternal and child health throughout pregnancy.

Psychosocial exposures

Psychosocial stressors, including maternal mental health, may alter the fetal epigenome. One study of 1,018 mother–infant pairs analyzed the epigenome of umbilical cord blood and corresponding maternal. Maternal ACEs were used as an indicator of preconception stress and resulted in five differentially methylated CpG sites in male infants [138]. The genes associated with these CpG sites are involved in cellular signaling, mitochondria function, and neuronal development. The genes encoding BDNF and NR3C1 are highly associated with prenatal maternal stress, anxiety, and depression. BDNF is a neurotrophic factor that is vital for neuron survival and growth, and NR3C1 is a glucocorticoid receptor involved in cortisol regulation. Subjective maternal stress and the presence of stressful events in pregnancy have been found to be associated with increased methylation at both gene sites for NR3C1 in placenta and BDNF in maternal blood [139]. Similarly, studies in infant cord blood and newborns associated maternal depressive symptoms with increased methylation of the NR3C1 gene [140,141,142] and decreased methylation of BDNF [140]. Epigenetic changes to these genes were associated with delayed preterm birth and delayed neurodevelopment [140, 143]. Elevated NR3C1 methylation was also associated with increased cortisol levels in 3-month-old newborns [142]. Finally, prenatal anxiety was associated with hypomethylation of the IGF2/H19 gene in cord blood and with low birth weight [144]. Overall, maternal stress, anxiety, and depression can be either preconception or prenatal exposures that may influence the fetal epigenome and infant health, and have the potential to cause heritable epigenetic changes.

Clinical and public health relevance

There is growing evidence that the exposomic and epigenetic modifications that occur earlier in life play a critical role in the development of adult-manifesting diseases. The “developmental origins of health and diseases,” or DoHaD, hypothesis [145] posited that sensitive developmental periods in early life are especially important for establishing disease risk. Another hypothesis, the cumulative multihit risk model, describes that chronic diseases are the result of cumulative exposures over the life course, starting in the fetal period. Numerous longitudinal birth cohorts and animal studies provide strong support for the fetal-to-adult connection between exposures and health [146, 147].

As reviewed in earlier sections, the epigenome is an interface to link environmental exposures with short- and long-term health outcomes. Epigenetic modifications can regulate gene expression in response to environmental cues, leading to altered subclinical and clinical phenotypes. The epigenome is largely established in utero, which is the most sensitive and susceptible period to environmental insults. On the other hand, the epigenome can be altered throughout the life span, and thus, the health effects of many early life exposures are potentially reversible. As such, epigenome and epigenetic modifications can inform primary and primordial prevention strategies. In this context, epigenetic modifications could serve as biomarkers of environmental exposure, early biological effect, early risk prediction, and novel targets for early interventions.

Conclusion

Here we review the current literature addressing how epigenetic modifications are reprogrammed in utero to prevent the inheritance of harmful epigenetic modifications, and how some environmental exposures can escape this reprogramming and are inherited by the child. While most of the original work to understand epigenetic inheritance was performed in plant and animal models, the mechanisms of epigenetic inheritance are becoming better understood in humans through longitudinal cohort studies. Environmental exposures during pregnancy, and even before conception, can directly affect epigenetic modifications in the fetus and may result in altered offspring health—good and bad. Future work in epigenetic inheritance and environmental health is needed. In particular, combined use of laboratory organisms, animal models, stem cell and organoid cultures, and ongoing multigenerational prospective birth cohorts will be valuable. Studies using these techniques will improve our understanding of the effects of single exposures and the exposome, the critical and sensitive developmental periods to environmental insults, the corresponding epigenetic modifications in the fetus and over the life course, and the resultant whole spectrum of subclinical and clinical phenotypes. Together, these will identify the initial onset/manifestation and longitudinal trajectories of epigenetic regulation throughout the life course and across generations.

Availability of data and materials

No datasets were generated or analyzed during the current study.

Abbreviations

Dnmts:

DNA methyltransferases

HMTase:

Histone methyltransferases

HAT:

Histone acetyl transferases

HDAC:

Histone deacetylases

SINE:

Short interspersed nuclear elements

LINEs:

Long interspersed nuclear elements

LTRs:

Long terminal repeats

NDR:

Nucleosome-depleted regions

iPSCs:

Induced pluripotent stem cells

ICR:

Imprinting control region

PGCs:

Primordial germ cells

PM2.5 :

Particulate matter under 2.5 microns in diameter

BPA:

Bisphenol A

Pb:

Lead

As:

Arsenic

ACEs:

Adverse childhood experiences

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  1. Eleanor Klibaner-Schiff and Elisabeth M. Simonin: First authors.

Authors and Affiliations

  1. Department of Environmental Health, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Eleanor Klibaner-Schiff, Elisabeth M. Simonin, Ana Cheong, Mary M. Johnson, Sarah Kirsh, Olivia Kline, Maitreyi Mazumdar, Vanitha Sampath, Nicholas Vogler & Kari C. Nadeau

  2. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland

    Cezmi A. Akdis

  3. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03756, USA

    Margaret R. Karagas

  4. Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA, USA

    Emily Oken

  5. Department of Population, Family and Reproductive Health, Center On the Early Life Origins of Disease, Johns Hopkins Bloomberg School of Public Health, Baltimore, MA, USA

    Xiaobin Wang

  6. Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Xiaobin Wang

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Contributions

EKS, EMS, MMJ, and KCN designed and outlined the review. All authors (EKS, EMS, CAA, AC, MMJ, MRK, SK, OK, MM, EO, VS, NV, XW, and KCN) contributed to the literature search review, and drafted and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kari C. Nadeau.

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KCN is an associate editor for the "allergy, immunology and pathogen epigenetics" section of Clinical Epigenetics.

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Klibaner-Schiff, E., Simonin, E.M., Akdis, C.A. et al. Environmental exposures influence multigenerational epigenetic transmission. Clin Epigenet 16, 145 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13148-024-01762-3

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Keywords

Clinical Epigenetics

ISSN: 1868-7083

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