1 Introduction
The concept of epigenetics was proposed by Dr. Waddington in 1942, who stated that epigenetics is a branch of biology involving a complex developmental process linking genotypes and phenotypes and this was coined as the epigenotype [
1]. All cells of the body have the same DNA but may perform vastly different functions in diverse organs and tissues with variable patterns and tissue-specific cellular identities. These genes are regulated by epigenetic information [
2]. Epigenetic modifications play an important role in maintaining cell identity, proliferation, and differentiation, together with the development and regulation of gene expression.
Changes in epigenetic thinking originate from the profound effects of the environment on developmental plasticity [
3]. The doctrines of Hippocrates put forward that the particular characteristics obtained in response to environmental exposure can be passed from parents to the next generation. Notably, epigenetic modifications are frequently activated when heritable cellular responses to environmental signals occur in the absence of DNA sequence alterations [
4]. Many studies published over the past few decades hypothesize that mechanical damage, chemical exposure, and the state of nutrients can alter the epigenetic state of cells. Potential heritability involves complex interactions between the environment and the genome [
5]. Increasing evidence highlights the influence of the environment on development, physiology, and pathology. Almost 80% of disease risk is associated with alterations in environmental factors that robustly influence gene expression and phenotype and increase the incidence rate of cancers and other diseases [
2]. Epigenetic modifications alter gene expression or function through crosstalk or by abnormally activating or inhibiting the response of transcription factors to environmental changes. The crosstalk between environmental alterations, epigenetic modifications, and genes determines how individuals respond to environmental variations. Epigenetic modifications are vulnerable and reversible to environmental exposure; therefore, this may provide a promising direction for clinical research and treatment of diseases.
This review comprehensively discussed how epigenetic alterations are involved in the process of various diseases initiation and progression. We highlight the essential role of environmental epigenetics in regulating the body’s health. Furthermore, we enumerated some potential epigenetic targets or drugs or diet regulation to prevent and treat abnormal epigenetic modifications that may be induced by environmental exposure. Furthermore, we highlight the link between environmental factors and epigenetics and show some phenotypic or functional changes owing to environmental epigenetic changes in an organism. These findings revealed that epigenetic modifications have considerable significance from clinical disease diagnosis to clinical treatment.
2 Epigenetic modification and diseases
Epigenetic modification represents heritable changes in gene function or phenotype that occur without changes in the DNA sequence that can be inherited by the next generation through gametes. Epigenetic modifications mainly include DNA methylation, histone modifications, chromatin remodeling, and RNA modifications (Fig.1). Epigenetic modification further complicates gene regulation and enriches hereditary diversity. Disruption of epigenetic regulation can profoundly impact growth development, aging, and various diseases including metabolic disorders, cardiovascular diseases, cancers, and so on. Identifying abnormal epigenetic alterations in physiologic or pathological processes may provide direction for diagnosis, prognosis, and therapy. Dissecting the interactions between epigenetic modifications and genes will benefit the development of new methods or combinatorial intervention approaches for various cancer and other diseases.
2.1 Epigenetics and cancers
Epigenetics mediates many biological processes that are important for tumor initiation and development. Here, we mainly present some of the evidence showing that their dysregulation can result in cancer. Furthermore, we show the promising clinical and preclinical value of epigenetic drugs and the central role of epigenetics in cancer.
2.1.1 DNA methylation and cancers
Gene regulation by 5mC usually occurs at CpG islands (CGIs) and is mostly associated with long-term, stable gene repression. Extensive epigenomic association studies show that 5mC signatures are associated with many diseases [
6]. CpG island methylation shows almost no dynamic changes in healthy tissues. Abnormal CpG island hypermethylation commonly occurs in cancers. Changes in methylation are observed in various pathologies, including tumor methylomes that are characterized by localized hypermethylation at specific CGIs, most of which are associated with tumor suppressor genes [
7]. Most tumors are associated with widespread losses or gains in DNA methylation in the genome [
8]. Beckwith–Wiedemann syndrome may cause embryonal tumors and persist after birth. It is induced by blocking the expression of insulin-like growth factor 2 (IGF-2), but usually activates the silent maternal allele and results in a twofold expression of IGF-2 protein [
9]. These observations suggest that epigenetic alterations raise the risk of tumorigenesis [
10]. In addition, DNA methylation variability is significantly increased in biopsy samples from patients with cervical and breast cancer. High methylation variability is also observed in chronic lymphocytic leukemia and is associated with poor prognosis [
11]. Increased methylation alterations are associated with more aggressive diseases, such as lymphoma and leukemia [
12,
13].
2.1.2 Histone modifications and cancers
The high mutation rate of histone-encoding genes or the alteration of histone modification patterns is extensively associated with cancers. For instance, mutation of the gene encoding histone H3 is found in brain and bone cancers [
14]. Mutation of the SET domain of EZH2 promotes H3K27me3 accumulation and increases the catalytic activity at H3K27me2 substrates. These oncogenic mutations strongly promote malignant transformation and drive tumorigenesis and development. However, diffuse large B cell lymphoma tumors that behave with these EZH2 mutations are extremely sensitive to EZH2 small molecule inhibitors [
15]. LSD1 overexpression usually occurs in many types of cancer, but LSD1 inhibitors can induce the differentiation of proliferative undifferentiated cancer cells [
16]. Epigenetic alteration affects the tumorigenesis and prognosis of lung cancer. For instance, increased acetylation of H4K5/H4K8 and decreased trimethylation of H4K20 are found in non-small cell lung cancer (NSCLC) and pre-invasive bronchial dysplastic lesions that are associated with the shortened survival of patients [
17]. Furthermore, epigenetic changes take place during the earliest stages of prostate cancer, which play an essential role in the initiation (and throughout disease progression and metastasis) of prostate cancer [
18].
2.1.3 RNA modifications and cancers
Numerous pieces of evidence point to the imbalance of RNA epigenetic modifications associated with the pathogenesis of human disease such as cancer. Furthermore, emerging evidence shows that m
6A modifications are closely associated with tumorigenesis, tumor proliferation, invasion, and metastasis [
19]. The methyltransferase-like protein (METTL3 and METTL14 complex) is associated with the spacious majority of m
6A on mRNA. However, the components of METTL3 and METTL14 complexes play different roles as tumor suppressors or oncoproteins depending on specific types of cancer [
20]. For instance, METTL3 expression plays an essential role in maintaining the undifferentiated state of AML cells, thus regulating the growth of myeloid leukemia cells
in vivo [
21]. Furthermore, METTL3 is usually upregulated in acute myeloid leukemia by methylating the mRNAs of BCL-2, PTEN, and c-MYC that further leads to the inhibition of cell apoptosis and differentiation, and promotes the progression of leukemia [
22]. Similarly, m
6A expression may promote or suppress tumorigenesis in hepatocellular carcinoma (HCC). METTL14 was used as a tumor suppressor in HCC. It can induce the upregulation of pri-miR-126 that further suppresses tumor metastases [
23]. m
6A levels are downregulated in 70% of endometrial cancers, mainly through METTL14 mutations or METTL3 reduction. These increased cell proliferation by upregulating the AKT pathway and promoting endometrial cancer [
24].
Furthermore, epigenetic modifications such as untranslated RNA participate in regulating tumor initiation and progression. Non-coding RNAs including short interfering RNA (siRNA), long non-coding RNA (lncRNA), and microRNAs (miRNAs) are functional RNA molecules that belong to another type of specific epigenetic marker that mediate various intracellular processes for normal development and physiology in animals [
25]. In HCC, the m
6A methylation level of circRNA-SORE increases by activating the Wnt/β-catenin pathway and inhibiting miR-130a-2-5p and miR-660-3p to maintain sorafenib resistance [
26]. miRNAs can be divided into suppressive miRNAs and oncogenic miRNAs in cancer-related processes. The miR-34a and miR-200 family is associated with various signaling pathways of cancer stemness and epithelial-mesenchymal transition (EMT). Let-7a, miR-200c, and miR-186 significantly inhibit stemness and reverse resistin-induced epithelial-mesenchymal transition in ovarian cancer [
27]. miR-5188 regulates forkhead box protein O1 and inhibits the level of nuclear β-catenin, which further activates Wnt and c-Jun signaling to promote EMT and cancer stemness of breast cancer and HCC. In turn, c-Jun can promote miR-5188, forming a positive feedback loop in HCC [
28,
29]. MicroRNAs can also interfere with other epigenetic events to regulate gene expression. For instance, they disrupt the expression of DNMT3a and DNMT3b and indirectly influence DNMT1 expression, thereby mediating DNA methylation and target gene expression. Recent studies also show that lncRNAs are specifically associated with cancer progression [
30]. Therefore, cancer is an epigenetic disease and a genetic disease. These findings reflect the relationship between cancer and epigenetic modifications. Diagnostic methods have greatly promoted the development of precision oncology based on epigenetics. Some epi-drugs and drugs targeting epigenetic modulators are currently already being used in clinical therapy or undergo clinical trials. Nine epigenetic drugs are already being approved by the US Food and Drug Administration (FDA) including EZH2 inhibitors, IDH inhibitors, histone deacetylases inhibitors (HDACis), DNA methyltransferases inhibitors, and so on. Among them, decitabine and azacytidine are two DNA demethylating agents that have potential efficacies in the therapy of hematological malignancies. Some of drugs targeting epigenetic modulators are undergoing clinical trials, such as trials (NCT01928576, NCT03179943) for treating solid tumors and trials (NCT03164057, NCT02717884) for hematologic tumors [
31].
2.2 Epigenetics and cardiovascular diseases
Senescence of different cardiac cell types is associated with a gradual decline in the structure and function of the cardiovascular system. It is a major risk factor for cardiovascular diseases including hypertension, heart failure, atherosclerosis, and myocardial infarction. Increasing evidence associates cardiovascular aging with epigenetic alterations, including DNA methylation, histone modifications, and numerous other epigenetic factors [
32,
33]. Changes in histone modification facilitate the development and progression of atherosclerosis. For example, the activities of histone acetyltransferases play a key role in the pathology of atherosclerosis. Increased H3K4 methylation and H3K9ac and H3K27ac are found in smooth muscle cells of atherosclerotic tissues [
34]. Sirtuins (SIRTs) belong to the histone deacetylase family dependent on nicotinamide adenine dinucleotide (NAD
+), and protect multiple cells against senescence. For example, SIRT1 can sustain the function of endothelial cells by regulating endothelial nitric oxide synthase (eNOS) to decrease oxidative damage. However, SIRT1 can inhibit the transcription of a SASP by deacetylating histone in cardiomyocytes [
35]. miR-126-5p plays an essential role in the regeneration of atheroprotective endothelial cells by inhibiting the Notch1 inhibitor delta-like 1 homolog (Dlk1) to prevent the formation of the atherosclerotic lesions, while the sister strand miR-126-3p (derived from apoptotic endothelial cells) reduces endothelial cell proliferation by derepressing Dlk1 [
36]. The crosstalk between various histone modifications also plays an important role in various diseases including cardiovascular diseases. For instance, in a transverse aortic constriction mouse model for cardiac hypertrophy, HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) can reduce left atrial diameter and cardiac fibrosis, but do not impact cardiac hypertrophy or systolic function. HDAC1 and HDAC2 present in the enhancer regions of miR-133a, and inhibit miR-133a downregulation in cardiomyocytes in this progress [
37].
2.3 Epigenetics and other diseases
Genomic instability, telomere attrition, deregulated nutrient sensing, epigenetic changes, mitochondrial dysfunction, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication are the hallmarks of aging [
38]. Epigenetic changes also influence aging and other physiological or pathological processes. Physiologic integrity is gradually lost during aging. Aging has become one of the most important health issues in current research. Epigenetic changes associated with aging include DNA methylation, histone modification, chromatin reconstruction, and non-coding RNA regulation [
39]. DNA methylation (specifically 5-methylcytosine levels) are altered during the aging process. The DNA methylation status of tissues (including blood, kidney, and liver) is known as the “epigenetic clock” and can be used to predict the actual age [
40,
41]. Significant changes occur in chromatin and nucleosome localization during aging [
42]. The environment induces chromosomes to accumulate large numbers of epigenetic changes in aging tissues resulting in heterogeneous gene expression between cells [
43]. This leads to functional dysfunction and an increased vulnerability to death. In mammals, SIRT1, SIRT3, and SIRT6 members of the sirtuin family help delay aging [
44]. Upregulated histone H3K4 trimethylation, H4K16 acetylation, H4K20 trimethylation, and downregulation of H3K27 trimethylation or H3K9 methylation are aging-associated epigenetic alterations [
45]. Hypermethylation of polycomb target and tumor suppressor genes is positively associated with aging; this partly reflects the association between DNA methylation and aging [
46]. Analysis of whole-genome methylomes suggests that DNA methylation is associated with partially methylated domains located in the late replicating parts of the genome. Partially methylated domain hypomethylation is rarely detectable in healthy tissues, but increases with aging. The loss of DNA methylation exhibited during aging may be owing to inadequate maintenance of DNA methylation during increased cell division [
41,
47]. Analysis of the microarray data of 5mC shows that there is a methylome-based clock that mainly manifests as the identification of a few CpG sites associated with age [
48]. Life expectancy can be extended, and healthy aging can be achieved through various means (including metabolic control, somatic cell reprogramming, and the removal of senescent cells) as tissue and organ functions decline and the risk of aging-related diseases increases [
39]. Some epigenetic inhibitors of histone deacetylases (HDACs, such as trichostatin A and β-hydroxybutyrate) are autophagy inducers with life-extending effects. Some compounds are used to maintain human health against aging. For instance, polyamine and spermidine have neuroprotective and cardioprotective effects in aging animal models and humans [
49].
A high risk of epigenetic changes also occurs in other diseases, including autoimmune diseases and diabetes. The treatment of autoimmune diseases is very difficult after a cytokine storm occurs; however, interference with epigenetic modification before the prodromal stages may be amenable to treatment [
50]. Ten-11 translocation (TET) protein regulates the levels of 5-hydroxymethylcytosine (5hmC), a DNA demethylation product. It becomes unstable in the hyperglycemic state of patients with diabetes; this results in a decrease in 5hmC levels that may contribute to tumor development [
51]. Research suggests that H3K27ac and H3K9ac dysregulate transcription and chromatin gene feedback loops and regulate the initiation and development of Alzheimer’s disease. H3K27ac and H3K9ac are the main enriched proteins in Alzheimer’s disease [
52]. Upregulation of histone deacetylase 2 is associated with decreased expression of genes important for learning and memory in patients with Alzheimer’s disease. Histone deacetylase 2 can block neurodegenerative memory disorders. Selective inhibitors of histone deacetylase 2 can recover the cognitive capacity of Alzheimer’s disease patients [
53]. These studies highlight that epigenetics has the greatest potential for the early diagnosis and treatment of Alzheimer’s disease.
Crosstalk between different epigenetic modifications or interactions between different epigenetic modification enzymes represent interesting mechanisms for a better understanding of gene regulation patterns in aging and cancer and other disease progression. For example, lncRNAs are involved in the maintenance of H2A ubiquitination in gliobastoma (GBM). At the same time, H2A ubiquitination is involved in EGFR-driven gliomas. Interference with lncEPAT expression leads to cell cycle arrest and cell senescence in glioma cells and inhibits GBM development. EGFR-lncEPAT-ubH2A coupling represents a novel mechanism for epigenetic gene regulation and anti-aging in GBM tumorigenesis [
54]. The mechanism by which epigenetic modifications regulate gene expression to further influence an organism during its whole lifetime is shown in Fig.2.
3 Epigenetics and environmental exposure
The genome inherited by an individual is unchangeable; however, epigenetic modifications can provide individuals with the ability to rapidly adapt to environmental changes without changing their genomes. Life gradually develops from a single fertilized egg into many types of cells and tissues. This involves delicate epigenetic regulation of genes and changes in response to exposure to the surrounding environment. Most human diseases are caused by genetic and environmental factors. The interaction between genes and the environment determines how living individuals with the same or different phenotypes respond to environmental variables. The epigenetic regulation of gene expression can be modulated by various environmental factors such as air pollution, diet, smoking, sugar, and alcohol consumption that is independent of the DNA sequence. Environmental exposure can cause epigenetic changes (such as chromatin remodeling, DNA methylation, histone modification, and miRNA modifications, and so on) that play important roles in various physiological and pathological processes during the lifetime of the human body. Here we highlight some of the evidence and the main mechanism of epigenetic modification change that may be regulated by environmental factors. The influence of environmental exposure on an organism during its whole lifetime through the regulation of epigenetic modifications and gene expression is shown in Fig.3.
3.1 Environmentally induced DNA methylation
Environmental factors drive global DNA methylation; however, the exact mechanism remains unclear. Transcription factor occupancy is a rational theory wherein the activation or inhibition of transcription factors by environmental factors affects DNA methyltransferases that lead to hypomethylation or hypermethylation and cause disease development [
4]. Environmental carcinogens include various types of air pollutants (such as bisphenol A and polycyclic aromatics), heavy metals (including cadmium, nickel, lead, and arsenic), and microorganisms producing mycotoxins and other bacterial toxins.
Short-term exposure to air pollution can affect mitochondrial DNA methylation. For example, short-term exposure to PM2.5 is significantly associated with mt12sRNA hypomethylation while long-term exposure to PM2.5 is prominently associated with hypomethylation of the D-loop region. Meanwhile, supplementation with L-arginine mitigates the effect of air pollution on platelet mtDNA methylation, especially in the D-loop region [
55]. PM2.5 exposure is associated with hypomethylation of the nitric oxide synthase (iNOS) gene and angiotensin-converting enzyme (ACE) gene [
56], and air pollution reduces methylation of the ADORA2B gene [
57]. Sodium arsenite exposure significantly induces activation of hepatic stellate cells and extracellular matrix deposition and phosphorylation of the EGFR/ERK signaling pathway. Inactivation of the EGFR negative feedback regulator gene (Mig-6) mitigates this process. DNA hypermethylation in the promoter region of Mig-6 caused by arsenic is the main cause of Mig-6 gene inactivation [
58]. Acute Cd exposure may reduce DNA methylation by the noncompetitive inhibition of DNA methyltransferase (DNMT) activity. In contrast, chronic Cd exposure may lead to an overall increase in DNA methylation owing to increased DNMT activity [
59–
61]. Some other metals can change the function of TET family proteins; for example, nickel binding to the Fe (II) chelating motif of TET proteins can replace the Fe (II) cofactor of TET dioxygenase and inhibit TET-mediated 5-methylcytosine oxidation [
62,
63]. Nickel compounds are not susceptible to gene mutations and their DNA damage capacity is weak. Therefore, Ni compounds may cause disease by modulating epigenetic modifications, particularly by altering the methylation status of genes. For example, nickel compounds can cause high methylation levels of p16, CDKN2A, and MGMT [
64,
65]. Microbiota-induced epigenetic remodeling is necessary to maintain gut homeostasis, and the microbiota leads to local DNA methylation changes in regulatory elements that are dependent on the demethylation enzyme, TET2/3. This ultimately activates a set of “early outpost-response genes” to maintain intestinal homeostasis. Most of the regions associated with altered gene expression are hypermethylated and highly enriched in the binding sites of three transcription factor families (FOXA, EKLF, and AP1). Exposure to commensal microbiota leads to the demethylation of gene regulation active regions and transcriptional activation of a set of early inflammatory genes (“sentinel inflammatory genes”: IFITM3, NOS2, and PLA2G2A) that are involved in antimicrobial and anti-inflammatory responses [
66]. Environmental exposure can regulate DNA methylation in an individual (Fig.4).
3.2 Environmentally induced histone modifications alteration
Environmental exposure can affect an individual by regulating histone modifications (Fig.5). For instance, acute persistent light exposure results in the suprachiasmatic nucleus maintaining basal levels of H3K27ac and regulating the expression levels of light-induced genes (such as Per1 and Per2) with the assistance of NPAS4. A loss of NPAS4 alters circadian rhythm behavior in mice [
67]. The levels of H3K27 acetylation in the
stat2 and
bcar1 promoter regions in the lung of mice significantly increase after 4 weeks of exposure to PM2.5 and cause lung dysfunction and inflammatory responses [
68]. Lead (Pb) exposure can cause dose-dependent attention deficit hyperactivity disorder in rats. Chronic lead exposure causes a significant increase in histone acetylation level in the rat hippocampus that may be related to the increase in histone acetyltransferase p300 transcription levels induced by lead exposure [
69]. Ni exposure increases H3K4me2/3 levels and inhibits H4 acetylation. Inorganic arsenic induces an increase in H3K4me2/3 and H3K9me1/2/3 levels in A549 cells, but inhibits H3K27me3. Low-dose exposure to perfluorooctanoic acid (PFOA) reduces the levels of H3K9ac, H3K18ac, and H3K27ac in rat testes, inhibits H3K9me1/3 near the SEAR promoter, activates SEAR transcription, and promotes steroid hormone synthesis [
70]. Intestinal microorganisms affect the acetylation and methylation of histones in various mouse tissues and organs via short-chain fatty acid metabolites. The acetylation levels of H3, H4, and H3.3 (and the levels of H3K27me2/3 and H3K36me2/3) significantly increase in the proximal colon, liver, and white adipose tissue (WAT) of mice that ingested a microbial community compared to sterile mice. Meanwhile, a high-fat/high sugar (HF/HS) diet inhibits histone acetylation levels in the liver and WAT of mice that ingested the microbial community. The composition of intestinal microorganisms and their metabolites can affect the chromatin state and epigenetic regulation of gene expression in the host [
71]. Oxidative stress can induce neurons to reduce methylation levels while mediating increased H3K9me3 levels in Alzheimer’s disease models [
72–
74].
3.3 Chromatin remodeling induced by environmental exposure
Environmental exposure-mediated epigenetic and chromatin structure changes result in alterations in DNA accessibility for polymerases, coactivators, and transcription factors that further lead to gene activation or repression at the transcriptional level (Fig.6). For instance, chromatin accessibility is significantly altered after PM2.5 exposure. The chromatin remodeler SWI/SNF complex regulates nucleosome situation near transcription start sites and restores chromatin accessibility in response to PM2.5 exposure [
75]. Formaldehyde (FA) exposure can increase chromatin accessibility and impair chromatin assembly, further altering the expression of many cancer-related genes [
76]. Acute alcohol exposure can promote DNA hypomethylation and transcriptional activation of chromatin by inhibiting DNMT. The upregulation of DNMT and HMT causes DNA hypermethylation and chromatin condensation after alcohol withdrawal [
10]. Cigarette smoke mediates oxidative stress-induced DNA damage that further evokes inflammation and senescence and is associated with HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications [
77]. Histone trimethylation of H3 lysine 4 (H3K4me3) and histone acetylation (H3/H4Kac) at gene promoters are connected with gene transcriptional activation in open euchromatin. Densely packed heterochromatin modified by H3K9me3 or H3K27me3 DNA methylation is usually associated with gene repression. HATs, HDACs, HMTs, HDMs, and DNMTs usually participate in the regulation of condensed and relaxed chromatin after environmental exposure. The paternal diet can influence H3K9me3 and H3K27me3 dependent silencing that further regulates sperm chromatin plasticity [
78]. Histone deacetylase inhibitors (HDACi) can influence the nuclear radial rearrangement of chromosomes by induced epigenetic changes (Fig.6).
3.4 Environmentally induced RNA modifications alteration
RNA chemical modifications have gained rising attention and emerging evidence shows its essential roles in various biological processes. RNA is methylated by methyltransferases, and demethylated by demethylases. We have limited knowledge about how environmental exposures influence the epi-transcriptome and further mediate disease. Emerging research suggests that the mostly common reversible mRNA modification is m6A modification.
3.4.1 Environmentally induced m6A modifications
m
6A methylation is the most obvious modification of mRNA, existing in the regulation of mRNA transcription, maturation, translation, and degradation. It can participate in the regulation of various physiologic and pathological processes, including cancer [
79]. The adenosine (A) base residue can be methylated to form N
6-methyladenosine (m
6A) by the core component of the METTL3–METTL14–WTAP complex or by METTL16 alone. S-adenosyl methionine (SAM) is a methyl donor in this process [
80]. External environmental exposure affects the m
6A modification of RNA (Fig.7). Multiple factors can regulate RNA modification, affect gene expression, and lead to diseases. Air pollution can induce respiratory diseases, and heavy metals are linked to neurological diseases. Environmental exposure disrupts the balance of m
6A levels that may be associated with disease occurrence and progression [
81]. For example, PM2.5 exposure induces m
6A modification of Sulf2, regulates Sulf2 expression through METTL16, and further induces microvascular injury [
82]. The decrease in SAM and increase in S-adenosylhomocysteine (SAH) methionine reduces METTL16 activity, which then methylates mRNA and promotes translation. However, the expression of WTAP and SAM synthesis promotes m
6A mRNA methylation and enhances mRNA translation to further stimulate tumor cell growth. Cd-exposure results in m
6A demethylation of phosphatase and tensin homolog (PTEN) mRNA and decreases protein expression that is mediated by ALKBH5. The m
6A demethylation of PTEN further promotes cell proliferation, invasion, and migration of BEAS-2B cells [
83]. ALKBH5 and FTO promote RNA m
6A demethylation in the presence of α-ketoglutarate, iron, and oxygen [
84]. Long-term exposure of human bronchial epithelial (HBE) cells to arsenite sodium (NaAsO
2) significantly upregulates m
6A modification and promotes malignant phenotypes, and this can be regulated by the METTL3–METTL14–WTAP complex and FTO. In addition, knocking down METTL3 dramatically reverses it [
85]. Exposure of human bronchial epithelial cells to CSE (cigarette smoke extract) enhances METTL3 levels and increases m
6A levels of ZBTB4 mRNA. This results in the downregulation of ZBTB4 protein by changing the mRNA stability of ZBTB4 in a YTHDF2-dependent manner. ZBTB4 downregulation leads to EMT in these cells [
86]. Different types of human epithelial cells chronically exposed to chemical carcinogens such as nickel (Ni), cadmium (Cd), and 3-methylcholanthrene show dynamic changes in m
6A abundance [
87]. YTHDF2 can convert m
6A-modified mRNAs to decay sites to trigger the deadenylation and degradation of transcripts by recruiting the CCR4-NOT deadenylase complex [
88]. Mutation of
TP53 pre-mRNA confers drug resistance in colon cancer cells in an m
6A-dependent manner. In addition, mRNA m
6A modifications of other genes (such as IFNB1, ANKLE1, and so on) influence their normal functions to promote the occurrence of various diseases [
80].
3.4.2 Environmentally induced miRNA and other RNA modifications alteration
miRNAs are non-coding single-stranded RNA molecules that possess approximately 22 nucleotides in length. MicroRNA base pairs with 3′-untranslated regions of mRNAs and translational inhibition of target mRNA molecules decrease protein production [
89]. The modification of miRNAs and lncRNAs regulates gene expression that further influences various physiologic and pathological processes (Fig.7). Exposure to cigarette smoke condensates causes hypomethylation of the METTL3 promoter and recruitment of transcription factor NFIC in human pancreatic cancer cells which increases METTL3 expression. High METTL3 expression prominently catalyzes the m
6A modification of primary microRNA-25 (miR-25) and results in the maturation of miRNA-25-3p. This further inhibits the expression of PHLPP2 and activates the AKT-p70S6K signaling pathway which promotes the aggressive phenotypes of pancreatic cancer cells [
90]. Gut microbiota
Fusobacterium nucleatum targets TLR4 and MYD88 orchestrates innate immune signaling, autophagy pathway, and specific microRNAs that further control colorectal cancer chemoresistance [
91]. m
6A methylation in lncRNAs is observed following m
6A mapping of poly(A) RNAs. Mutation or upregulation of conserved lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with tumor initiation and development. MALAT1 usually contains high levels of m
6A modifications at multiple m
6A sites [
92]. Moreover, lncRNAs interact with m
6A regulators to perform their functions. For instance, chromatin-bound lncRNA (FOXM1-AS) is transcribed in the antisense orientation of FOXM1 that accelerates the recruitment of ALKBH5 to the FOXM1 transcript. ALKBH5 demethylates the pre-mRNA of FOXM1 and promotes HuR binding. This further stabilizes the pre-mRNA of FOXM1 and increases FOXM1 expression in the tumorigenicity of glioblastoma stem-like cells [
93]. Additionally, exposure to Cd, MnCl
2, As, Paraquat (PQ), chronic constant light (CCL), carbon black nanoparticles (CB), mono-(2-ethylhexyl)phthalate (MEHP), di-(2-ethylhexyl) phthalate (DEHP), microplastics (MPs), and so on regulates the m
6A modification of genes through different targets or signaling pathways. Together, these studies suggest the effect of RNA modification dysregulation and its machinery of RNA methylation in transcript-specific aspects after environment exposure (Fig.7).
3.5 Interaction of epigenetics and the environment
The interaction of genetics and the environment is important in many diseases. Different environmental factors can affect epigenetic regulation, leading to various subtle changes in the human body as described in this article. Conversely, genetic mutations are key drivers of cancer, although regulating gene expression through epigenetic modifications to DNA, RNA, and histones can also promote tumor adaptation to the microenvironment. Dysregulated epigenetic modifications dynamically drive abnormal transcriptional processes and affect the tumor microenvironment, including promoting tumor progression, drug resistance, and metastasis [
94]. Epigenetic modifications can promote tumor adaptation to the hypoxic microenvironment. The DPY30-H3K4me3 axis is a necessary factor for glioblastoma stem cells (GSC) to maintain tumor growth and angiogenesis in the hypoxic microenvironment of mouse intracranial orthotopic tumor transplantation using the RNA interference (RNAi) epigenetic regulator screening system [
95]. Epigenetic therapy can inhibit tumor metastasis by disrupting the formation of the microenvironment before tumor metastasis, and myeloid derived suppressor cells (MDSCs) are involved in the process of tumor metastasis according to an animal model of the action of epigenetic regulators and identification of the immune cells that play a role in the animal model. In mouse models of lung metastasis, MDSCs can affect the microenvironment formed after tumor resection and stimulate local production of many cytokines, thus affecting tumor progression [
96]. Therefore, epigenetic regulation can also affect the tumor microenvironment and other environments.
4 Environmental exposure influences health through epigenetics
Abnormalities in gene expression may occur through genetic or epigenetic mechanisms during multistage pathologies induced by environmental pathogenic factors. Adverse factors such as environmental pollution can increase genomic instability and the risk of epigenetic diseases. This explains why some diseases only develop with age, whereas changing adverse habits and altering the living environment (combined with epigenetic drug therapy) greatly reduces the incidence of epigenetic diseases. Therefore, studying the relationship between the environment and epigenetics is important to prevent and treat human diseases. Environmental factors that cause human diseases are classified into major categories: physical, chemical, and biological. These factors (either alone or through complex interactions) regulate epigenetic modifications and affect physiologic functions and pathological processes.
4.1 Physical environmental exposure
4.1.1 Electromagnetic radiation
Physical environmental exposure includes electromagnetic radiation, temperature pollution, and light and noise pollution, and so on. Electromagnetic radiation is divided into ionizing radiation and non-ionizing radiation and mainly includes microwaves, radio waves, visible light, infrared, ultraviolet, gamma rays, and X-rays. Electromagnetic radiation can affect human health by causing DNA damage and gene mutations in cells that can induce leukemia and tumors. It can also cause chromosomal changes in embryos and lead to abnormalities in babies or spontaneous abortion in pregnant women [
97]. Ionizing radiation may affect methionine synthesis and/or inhibit the biological conversion of methionine to SAM, thereby depleting endogenous methyl donors and resulting in post-replication DNA hemimethylation, leading to DNA hypomethylation [
98]. Ionizing radiation induces upregulated intracellular reactive oxygen species (ROS) levels that induce cancer stem cell (CSC) properties (for example, dedifferentiation and self-renewal) and promotes carcinogenic metabolism by activating EMT-inducing pathways, and promoting tumor cell metastasis and invasion [
99]. Ultraviolet light induces Merkel cell carcinoma (an aggressive skin malignancy) through DNA damage, promotes the expression of inflammatory mediators, and affects the function of antigen-presenting dendritic cells [
100]. Radon is a colorless and odorless natural radioactive gas that is widely distributed in adipose tissue, the nervous system, reticuloendothelial system, and blood. It causes cell damage and eventually induces cancer. The alpha particles generated by radon decay can result in radiation damage to the human respiratory system, leading to genetic and epigenetic changes in the tumor genome and lung cancer; this is the second most common cause of cancer after smoking [
101].
4.1.2 Light or noise pollution
Light pollution is a new source of environmental pollution that are currently threatening human health; this mainly includes white light pollution, artificial day pollution, and color light pollution. Female ICR mice exposed to constant light significantly downregulated the expression of clock genes (Cry1, Nrld2, and Per2) in their offspring and altered the cytokine–cytokine receptor interaction, IL-17 signaling pathway, and the chemokine pathway. These mice exhibit obesity, abnormal lipid metabolism, early puberty, and other health problems [
102]. Long-term exposure to artificial light pollution disrupts circadian rhythm and glucose metabolism and raises the risk of coronary heart disease, diabetes, excess body weight, and obesity [
103]. Noise damages hearing and causes a variety of diseases, including cancer. Noise and air pollution cause changes in DNA methylation levels in blood cells [
104]. Munzelet
et al. reviewed the potential effects of noise on human health via epigenetic pathways [
105]. Noise induces vascular and mental stress, modulates coding and non-coding RNA expression patterns [
106–
108], and causes changes in the DNA methylation status in rat brains, ultimately leading to cardiovascular disease (CVD) [
109].
4.2 Chemical exposure
Chemical exposure includes industrial wastewater pollution, soil pollution, air particulate matter pollution, organic pollutants, heavy metals, smoking, alcohol, sugar, fat, and nutrition, and so on. Many studies over the past couple of decades show that chemical signal exposure or nutrient deficiency can alter cellular epigenetic states that can be passed onto the offspring in some cases [
110,
111]. Exposure to environmental factors such as smoking, drugs, nutrition, and so on during particularly sensitive periods (such as fetal development and early childhood) can lead to developmental abnormalities in children and even diseases in adulthood. Epigenetic changes may occur in metabolic syndromes and related disorders, various cancers, and other diseases. Changes in the external environment can impair normal growth by altering epigenetic modification patterns or crosstalk with genes that further interfere with gene expression. Targeting epigenetic alterations or gene expression may provide new directions to treat abnormal physiologic processes and diseases.
4.2.1 Heavy metals
Pb toxicity is a widespread environmental disease that has a devastating influence on the human body. Pb exposure can result in developmental disorders and various diseases by regulating different signal pathways and the crosstalk between epigenetics and genes (Fig.8). Lead exposure can increase blood pressure, infertility, and even cause death in adults. The World Health Organization (WHO) experts highlight the importance of mitigating Pb exposure to children, which may negatively affect the central nervous system and development [
112]. In addition, epigenetic aging is associated with various harmful health factors, such as oxidative stress caused by heavy metal exposure [
113]. Alzheimer’s disease is the main cause of dementia in elderly individuals. The risk factors for Alzheimer’s disease include genetic mutations, lifestyle, and environmental contamination. In particular, changes in DNA methylation and miRNA expression patterns are owing to Pb exposure [
114]. Mounting evidence indicates that environmental metal exposure (such as chronic exposure to arsenic, chromium, cadmium, and nickel) upregulates the incidence of cancer in individuals [
115]. Alterations in epigenetic markers may lead to associations between gene expression and disease occurrence and development. For instance, nickel exposure can lead to silencing of a DNA repair gene O
6-methylguanine DNA methyltransferase (MGMT) in lung cancer cells. MGMT gene silencing is associated with deacetylation of histone H3 and H3K9me2 that can be partially reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Nickel exposure can result in gene silencing by altering the levels of DNA methylation; however, pretreatment of cells with DNMT1 inhibitor (5-azacytidine) can reverse the phenomena [
116].
4.2.2 Organic pollutants
A growing body of research shows the toxicity and health effects caused by monofluoroalkyl and polyfluoroalkyl substances (PFAS), including epigenetic modifications [
117]. There is an association between perfluorooctane sulfonic acid (PFOS) or perfluorooctanoic acid (PFOA) exposure and epigenetic changes in adult populations and birth cohorts based on results from human epidemiology,
in vitro experiments, and animal studies. Perfluorooctanoic acid (PFOA) is a persistent organic pollutant with endocrine disrupting properties. It significantly reduces the levels of several histone modifications (H3K9me1/2 and H3K9/18/23ac) in rat testis. These results are expected to reveal epigenetic molecular mechanisms by which low doses of PFOA interfere with male reproductive endocrine, and may contribute to human health risk assessment of PFOA exposure in the environment [
70]. A growing number of studies report the effects of bisphenol A (BPA), phthalates, and polycyclic aromatic hydrocarbons on epigenetic regulation and their association with health outcomes [
118]. In addition, BPA significantly leads to abnormal histone-to-protamine replacement during spermiogenesis by increased histone variants-related to histone-to-PRM transition; the levels of histone H3 modification in the testes and DNA methylation in spermatozoa significantly increase [
119]. Allergic asthma and other diseases in children can be the result of prenatal exposure to environmental pollutants such as di-(2-ethylhexyl) phthalate (DEHP). Methylation EPIC Beadchip microarrays were used to examine global DNA methylation in the human placenta as a function of maternal exposure to DEHP during pregnancy. Bioinformatic analyses confirmed that DNA methylation effects are associated with neurological disorders such as autism and dementia. These results suggest that maternal exposure to DEHP may predispose offspring to neurological diseases. The potential role of DNA methylation as a biomarker to assess risk for these diseases warrants further investigation [
120].
4.2.3 Air pollution and nanomaterials
Atmospheric particulate matter is an overall term used for the variety of solid and liquid particulate matter existing in the atmosphere. Particulate pollutants from human sources are mainly dust, soot, fly ash, and particulate matter in tail gas produced during production, construction, and transportation processes, together with fuel combustion processes. Particles that are below 3.5 microns can be inhaled and deposited in the bronchi and alveoli of humans; this causes or aggravates respiratory diseases. Long-term exposure to Ottawa urban dust (EHC-93) promotes the secretion of pro-inflammatory factors (such as MCP-1 and IL-8) in A549 cells and alters the expression levels of proteins involved in the inflammatory response (TREM1, PDIA3, and ENO1) [
121]. Environmental pollution particles inhaled by the human body are phagocytosed by macrophages in lung-related lymph nodes and continuously accumulate; this affects the phagocytic function of macrophages and reduces the secretion of cytokines, resulting in impaired respiratory immune function [
122]. Long-term inhalation of nano-level (15–75 nm) carbon black particles can damage the mitochondrial function of lung macrophages, increase lactic acid secretion, form an immune-inhibitory microenvironment, and promote the occurrence and metastasis of lung cancer [
123]. Particulate matter (PM) pollutants of various aerodynamic diameters (PM2.5 and PM10) and gases (NO
2 and SO
2) are the dominant components of traffic-related air pollution (TRAP). These substances can increase the risk of several respiratory diseases (including lung cancer) by altering DNA methylation. Particulate matter decreases the methylation of LINE-1 and nitric oxide synthase (iNOS) and increases the methylation of the tumor suppressor genes (p16
CDNK2A and adenomatous polyposis coli (APC)) in a dose-dependent manner [
124].
Nanomaterials are prospective in various fields with the development of nanotechnology. Research on the toxicity of nanomaterials is increasing. The main exposure modes of nanomaterials include pulmonary inhalation, oral administration, skin contact, and so on. Carbon nanotube (CNT) respiratory exposure can significantly enhance the invasion and metastasis of mouse breast cancer cells, and promote tumor to lung metastasis and even multi-organ metastasis. Carbon nanotubes accumulate in the lung for a long time, stimulate the secretion of VEGFA by lung fibroblasts and macrophages, act on breast cancer cells through circulation, regulate the upregulation of endogenous VEGFA and COX2 expression in cancer cells, and strengthen angiogenesis in breast tissue through a positive feedback mechanism. Meanwhile, local lung inflammation and fibrosis caused by CNT provide a pre-metastatic tumor microenvironment conducive to lung metastasis of breast cancer cells [
125]. Nano-silver and graphene oxide can change the level of DNA methylation in cells, leading to abnormalities in various metabolic processes and signaling pathways, leading to cell damage [
126]. TiO
2 nanoparticles enhances the genotoxicity of arsenic through mitochondria-dependent ROS mediated physicochemical interactions [
127]. Cellular genotoxicity caused by nanoparticles is mainly caused by oxidative stress, gene expression changes, metabolic pathway disorders, and cell damage. Further studies are required to determine the in-depth molecular mechanisms such as whether nanoparticles affect gene expression through epigenetic modification.
4.2.4 Diets
Diet can cause epigenomic changes that lead to human diseases. For example, folate deficiency inhibits the biosynthesis of the active precursor for DNA methylation, S-adenosylmethionine. Additionally, deficiencies in folate and the essential amino acid methionine are associated with colon and liver tumorigenesis. Dietary fat composition influences DNA methylation in adipocytes [
128–
131]. A protein restricting diet can induce the repression of ribosomal DNA (rDNA) genes and DNA methylation [
132]. Maternal obesity impairs embryonic development and offspring health. For instance, Stella (also known as DPPA3 or PGC7) protein insufficiency in oocytes of HFD-fed mice mediates maternal developmental defects in early embryos and offspring growth. A high-fat diet (HFD) regulates epigenetic remodeling by accumulating modifications in maternal 5-hydroxymethylcytosine and DNA lesions and inducing global hypomethylation in the zygote genome [
133]. Gestational mice fed a high-fat diet exhibit heritable hypermethylation of PGC-1α promoters, leading to age-dependent metabolic dysfunction in the offspring [
134]. Dietary restriction partially prevents global changes in DNA methylation, histone modification, and chromatin remodeling associated with aging. Members of the sirtuin family are the first class of epigenetic enzymes associated with aging and dietary restriction. Therefore, good dietary habits are essential for normal human development and health.
4.2.5 Cigarette smoking and alcohol
Cigarette smoking is the main cause of lung cancer, but other etiologic factors such as radon, asbestos, second-hand smoking, or heavy metals also promote lung cancer initiation and development. Interestingly, exposure of lungs to these etiologic factors, such as cigarette smoking can influence epigenetic modifications. For instance, chromate, nickel, and arsenite can stimulate histone deacetylation and histone H3K9 dimethylation in tobacco [
17]. Chronic cigarette smoke-induced epigenetic alterations sensitize normal human bronchial epithelial cells in a time-dependent manner. Smoking can also induce chromatin changes, such as abnormal DNA methylation and suppression of the polycomb marking of genes. Meanwhile, cells transform from epithelial to mesenchymal cells to promote the development of non-small cell lung cancer [
135]. There are complex interactions between the environment and the genome in their potential heritability [
136]. Cigarette smoke condensate (CSC) mediates a decrease in H4K16Ac, H4K20Me3, and DNA methyltransferase 1 (DNMT1) in a dose- and time-dependent manner, while increasing the expression levels of H3K27Me3 and DNMT3b in human lung cancers [
137]. Furthermore, CSC induces excessive expression of miR-25-3p through m
6A modification catalyzed by METTL3. This triggers the malignant phenotype of pancreatic cancer cells and promotes the occurrence and progression of pancreatic cancer that is associated with poor prognosis [
90].
Alcohol is one of the main causes of death worldwide. Alcohol consumption can cause psychological, physiological, and pathophysiological problems. Recent studies show that ethanol may trigger epigenetic modifications (including histone modifications, DNA methylation, and RNA-related modifications) in individual and cellular responses to ethanol exposure. Importantly, these alcohol-induced epigenetic changes are detected in the blood. This allows for early diagnosis and clinical therapy of diseases related to alcohol abuse. Furthermore, some epigenetic drugs targeting alcohol abuse show efficacy, and targeting epigenetic modifications may be a promising treatment of alcoholic cardiomyopathy (ACM) and other diseases caused by alcohol abuse [
10].
5 Biology exposure
5.1 Viruses
Viral infections cause epigenetic diseases in humans. Epstein–Barr virus (EBV) is a human virus that is closely related to the occurrence of many types of tumors. This includes approximately 10% of gastric cancer and nasopharyngeal carcinoma occurrences, one of the most common head and neck malignant tumors in South-east Asia. An unintegrated viral genome can directly alter the epigenetic landscape of the host and promote the activation of proto-oncogenes and tumorigenesis. For example, an EBV infection reshapes chromatin topology and functions at the host genome sites where it interacts. This transforms H3K9me3
+ heterochromatin into H3K4me1
+/H3K27ac
+ and releases potential enhancers to bind and activate nearby gastric cancer-related genes [
138]. Nasopharyngeal carcinoma (NPC) is a tumor with poor differentiation and a high incidence of EBV. The EBV latent protein LMP1 increases STAT5A and recruits HDAC1/2 to the CEBPA site to downregulate its histone acetylation. This provides a new epigenetic mechanism for virus-induced cellular plasticity and offers the prospect of solid tumor therapy by targeting cellular plasticity using HDAC inhibitors [
139]. EBV also mediates the pathogenesis of other diseases (including infectious mononucleosis) by manipulating host epigenetic pathways, including DNA methylation, host histone modification, the Hippo pathway, m
6A RNA modification, and other pathways [
140]. Cervical cancer is one of the most common cancers affecting females. High-risk human papillomavirus (HPV) infection causes the HPV E6 oncoprotein to have typical carcinogenic functions such as p53 degradation and telomerase activation. HPV16 E6 interacts with the histone H3K4 demethylase KDM5C. This causes KDM5C to degrade in a proteasome-dependent manner and activates the super-enhancers EGFR and c-MET. This effect may be achieved by regulating the dynamics of H3K4me3/H3K4me1 and reducing the transcription of bidirectional enhancers [
141]. Chronic hepatitis B virus (HBV) infection is associated with liver cirrhosis and hepatocellular carcinoma. HBV covalently closed-loop DNA (cccDNA) exists in the form of small histone-bound chromosomes after hepatocyte infection. HMGA1 positively regulates HBV transcription; upregulation of its promoter II/core promoter (EII/Cp) is the key to enhancing viral gene expression and replication. The mechanism involves HMGA1 binding to conserved ATTGG sites in EII/Cp and recruiting transcription factors FOXO3α and PGC1α. In addition, HBV X protein (HBx) interacts with SP1 transcription factor to activate the HMGA1 promoter [
142]. Therefore, the HMGA1-HBV positive feedback loop is a potential therapeutic target for HBV-related diseases.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the global coronavirus pandemic (COVID-19) in 2019. SARS-CoV-2 significantly disrupts the epigenetic regulation of host cells [
143,
144]. The SARS-CoV-2 protein encoded by ORF8 acts as a histone mimic of the ARKS motif in histone H3, thus destroying the epigenetic regulation of host cells [
145]. In summary, several common viruses can cause various diseases. Epigenetic remodeling (especially the acetylation and methylation of histone proteins and DNA) is one of the main characteristics of diseases. Several studies show that epigenetic regulators improve antitumor efficacy with higher response rates. This provides a better molecular basis for the clinical treatment of tumors and other diseases.
5.1.1 Fungi
A dynamic fungal infection process requires rapid adaptation of fungal gene expression programs in response to altering host environments. Therefore, the transcriptional remodeling of fungal pathogens is essential to their development and pathogenicity. Histone modification is one of the major mechanisms of epigenetic regulation and is associated with fungal development and infection-related morphogenesis [
146]. Changes in microbiota composition or abundance are associated with chronic human diseases including metabolic disorders, inflammatory bowel disease (IBD), and cancer. Microbiota can synthesize many biological compounds, such as several regulatory factors that act as epigenetic substrates, cofactors, or epigenetic enzymes. For example, the intestinal microbiota can produce folic acid and other B vitamins (B2, B12) that contribute methyl groups to DNA or histone methylation [
147]. Folate is a crucial nutrient produced by many symbiotic microorganisms such as
Bifidobacterium and
Lactobacillus. It is involved in single-carbon metabolism to produce S-adenosylmethionine (SAM), a major substrate for DNA and histone methylation.
Clostridium, anaerobic rods, and eubacteria can produce butyric acid that induces histone acetylation and promotes intestinal development and immune homeostasis [
148]. Therefore, microbial metabolites might be involved in the development of epigenetic substrates and enzyme regulators.
Bacteria can evade host immune responses by epigenetic means, such as the DNA methyltransferase gene (modH) associated with the type III restrictive modification (R-M) system in some bacterial species. This includes
Helicobacter pylori (Hp), which protects bacterial hosts from invasion by foreign DNA [
149]. Methylation studies of several Hp strains show that each strain carries a different R-M system; therefore, the methyl group greatly varies [
150,
151]. Many bacteria such as
Mycobacterium tuberculosis epigenetically regulate the host [
152]. This results in the methylation of key genes during the host immune response [
153]. Intestinal flora alters chromatin accessibility in the enhancer region of intestinal epithelial lymphocytes to affect host physiologic functions [
154]. The intestinal flora can directly or indirectly regulate intestinal epigenetic modifications (DNA methylation, miRNA, histone acetylation, serotonin, and so on) that mediate the “dialogue” between the flora and the intestinal mucosal barrier. Different epigenetic modifications can promote the inflammatory response pathway and inflammatory cancer transformation. DNA methylation is an important factor in the development of colon cancer in patients with inflammatory bowel disease (IBD) owing to intestinal flora [
147]. The association between microbiota and DNA methylation under homeostatic and pathological conditions may predict intestinal inflammation-driven carcinogenesis. Many treatments can alter the gut immune system, prevent pathogen colonization, and change the activity and composition of gut microbiota, including prebiotics, probiotics, antibiotics, and fecal microbiome transplantation (FMT) [
155].
5.1.2 Parasites
Parasitic infections can involve a wide range of cells in the body and alter the function of host cells for survival. An infection that involves immune cells can be particularly damaging to the host. For example, the protozoan, leishmaniasis parasite, infects monocytes, causes severe immune-related diseases, and alters the chromatin landscape by modulating the DNA methylome. Histone modifications are essential for the regulation of macrophage expression, and
Leishmania amazonensis-infected macrophages reduce the expression of various pro-inflammatory genes associated with H3K9/14 hypoacetylation [
156]. The inhibition of HDAC activity of host cells in
L. donovani-infected THP1 cells reduces the intracellular parasite burden [
157].
Ascaris lumbricoides infections have a global prevalence of > 10% and can cause respiratory diseases.
Ascaris exposure is associated with 23 methylation sites in males and 3 methylation sites in females. We also identified a differentially methylated region in PRSS22 associated with nematode infection [
158]. Genetically identical cells exhibit different phenotypes associated with transcriptional stochasticity under identical environmental conditions. A study of the role of epigenetic factors in the intercellular transcriptional variation of human malarial parasites shows that msp1 and msp3 exhibit stochastic expression and are the main candidates for invasion-blocking vaccines [
159]. Furthermore, parasites can divert host epigenetic regulators and modifiers from their original functions and realign host gene expression to counteract innate immune responses. Therefore, it is possible to target host transcription factors and chromatin-modifying enzymes to regulate the fate of infected cells and improve the outcome of the infection [
160].
6 Prevention and therapy of diseases regulated by epigenetics and environmental exposure
Above all, environmental exposure may result in various diseases, especially cancers. However, the reversibility of epigenetic modifications is an attractive target for therapeutic intervention. For instance, combinations of sulforaphane (SFN), genistein (GE), and sodium butyrate (NaBt) can reduce the expression levels of epigenetic regulatory factors such as DNMT3A/3B, HDAC1/6/11, EZH2, GCN5, and P300, inducing that breast cancer cells MDA-MB-231 and MCF-7 were blocked in G2/M phase, cell proliferation was inhibited, and cell necrosis and apoptosis increased [
161]. Epigenetic-based drugs are widely investigated. Several epigenetic modifications targeting drugs are approved by the US FDA in cancer therapy, including HDAC inhibitors such as FK-228 (Romidepsin), SAHA (Vorinostat), PXD-101 (Belinostat), and LBH-589 (Panobinostat). Here, we focused on the mechanism and influence of epigenetic modifications induced by environmental exposure in human health. Some epigenetic drugs target commonly epigenetic changes that may be induced by environmental exposure (Tab.1).
Epigenetic remodeling depends on cofactors or substrates obtained from the diet, which is a fundamental feature of it. Therefore, changing epigenetic remodeling by modulating diet may be a more useful method to prevent or treat epigenome alteration-induced diseases. For instance, the activity of sirtuin histone deacetylase is decided by the ratio of oxidized nicotinamide adenine dinucleotide (NAD
+) and reduced nicotinamide adenine dinucleotide (NADH), which can be regulated by calorie restriction, fasting, or dietary supplementation of NAD
+ precursors [
162,
163]. Metabolic products are also used as raw materials for DNA and chromatin modification. For example, SAM is the methyl donor of DNA and histone methylation. Folate and vitamin B6 and B12 can induce the production of SAM. Acetyl-coenzyme A is the acetyl donor of histone acetylation. α-Ketoglutarate (α-KG) is a critical cofactor for histone demethylation (regulated by Jumonji domain-containing histone demethylase) and DNA demethylation (regulated by TET proteins) but also acts as an intermediate of the tricarboxylic acid cycle. α-KG is needed for DNA and histone demethylation, and succinate and fumarate restrict the demethylation of DNA and histone [
164,
165]. However, metabolic alterations can interfere with the epigenome. Growing evidence shows that some metabolites can interact with epigenetic processes and influence the physiologic or pathological process [
166]. Maternal dietary GE treatment can significantly reduce the fat accumulation in offspring mice, improve metabolic functions such as glucose intolerance, and delay the development of breast cancer induced by a high-fat diet in female offspring mice. Genistein can regulate intestinal microbiota, bacterial metabolites, and the epigenetic profile to potentially prevent the occurrence of obesity-related breast cancer in offspring mice by affecting the expression levels of genes related to metabolism, inflammation, and tumor development [
167]. Therefore, metabolic pathways may serve as potential therapeutic targets [
168,
169].
Exposure to PM2.5 results in susceptibility to adverse cardiac autonomic activity by upregulating TLR2 methylation in older individuals. Increasing the intake of flavonoids in the diet may decrease TLR2 methylation and relieve these effects [
170]. Multi-omics analysis found that the combination of broccoli sprouts (BSp) and green tea polyphenols (GTPs) can affect the HDAC and DNMTs enzymatic activities significantly in cells, regulate the methylation and expression levels of target genes, and further inhibit the tumor growth of transgenic breast cancer mouse models [
171]. An epigenetic diet may counteract or weaken the damage to the epigenome caused by environmental pollution. For example, dietary supplementation with folic acid partially protects against the adverse effects of environmental pollutants such as chromium and arsenic [
172]. Environmental exposure to ultraviolet light destroys folic acid, a co-vitamin essential for proliferation, methylation, and DNA repair mechanisms. Pigmentation protects folic acid from UV damage, screening for folic acid gene variants, and maintaining homeostasis in single-carbon metabolism [
173]. Dietary and nutritional supplements are closely related to the onset and progression of breast cancer, and inulin was marketed as a health supplement to improve intestinal health. Inulin supplementation significantly inhibited tumor growth and significantly delayed tumor latency. The plasma propionic acid concentration significantly increased in the inulin supplementation group. Epigenetic regulation of histone deacetylase 2 (Hdac2), Hdac8, and DNA methyltransferase 3b proteins decreased expression. In addition, sodium propionate prevents breast cancer
in vivo through epigenetic regulation. Regulating microbial composition through inulin intake may be a promising strategy for breast cancer prevention [
174].
7 Conclusions and perspectives
Epigenetic modifications play an important role in regulating gene expression and determining cell fate. Abnormal epigenetic modifications are associated with abnormal development, aging, cancer, and other disease-related physiologic and pathological changes. The epigenome is more unstable than the genome and can be altered even during the cell cycle or in response to different environmental stimulation, for instance, air pollution, heavy metals, or diet. Epigenetic modifications that regulate gene expression and function are susceptible to environmental factors, but they are reversible. Identifying genes and epigenetic changes mediated by environmental exposure may prevent the progression of various diseases. For instance, analyzing age-related diseases induced by environmental factors or epigenetic changes can help identify the physiologic and pathological mechanisms and develop new interventions using small-molecule drugs or gene therapy to inhibit or even reverse age-related diseases. Thus, reshaping or targeting aberrant epigenetic modifications in response to environmental exposure or induced epigenetic changes is an attractive approach for disease therapy. However, the influence of multifactorial exposure to genes and epigenetic variations is complex. Moreover, crosstalk networks between genes and epigenetic variations remain a big challenge. We summarized recent evidence associated with environmental exposure to epigenetic modifications and disease onset to formulate the mechanisms of various diseases induced by environmental exposure from the perspective of epigenetics. In addition, the influence of epigenetic modifications, environmental alterations on cancers, aging related diseases, and other diseases were elucidated, together with some of their crosstalk with genes. Further research should focus on the relationships and mechanisms among multi-environmental exposure, genes, and epigenetic modifications during the initiation and progression of various diseases to develop more useful therapeutic methods.
PDF
(3383KB)
