Why do toxins affect methylation

Mercury is found in mercury thermometers, amalgam dental fillings and large sea fish like tuna and swordfish. Mercury poisoning can lead to irritability, fatigue, memory loss, tremors, and sleep disturbances. The main exposure to cadmium is from cigarette smoke, although it is also in some industrial fumes. Symptoms of toxicity include lung inflammation, shortness of breath, cough, headache, dizziness and chest pain.

It is possible to test for both toxins and metals in urine, including levels of glyphosate, parabens, phthalates, and many other toxins, including benzene and perchlorates.

Metal levels are also often checked with a hair analysis, oligioscan and other specific GPL Tox testing. We offer all of these testing methods at Advanced Functional Medicine. For the removal of heavy metals, it is important to work with an experienced practitioner with relevant training. It is important to follow a protocol that includes nutrient and antioxidant support for the liver to detoxify metals, and individualized dosing of a chelating agent based on your unique body weight, genetic profile and sensitivities.

Current evidence supports the notion that environmental exposures are associated with DNA-methylation and expression changes that can impact human health.

To help eliminate toxins and metals from your body, we need to maximize the methylation process and assist with chelation of metals. That means avoiding the things that cause your methylation process to break down, testing to find out how well your methylation is working and what toxins and metals are present. We will then work with you to return to proper methylation and optimal health with dietary, supplement and lifestyle advice.

He is a Naturopathic Doctor with extensive functional medicine training from leading practitioners in the USA and worldwide. He is leading the way with advancements of functional medicine, clinically implementing worldwide best practices in Functional Medicine throughout Australia. Jarrod consults in person from Perth, Western Australia and also online via Telehealth throughout Australia and worldwide. Get functional medicine information and tips on how to manage your health delivered to your inbox.

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What is methylation? Factors that affect your methylation process Damaging toxins and metals that affect methylation Treatments for the removal of toxins and metals Tips for avoiding toxins and metals Many toxins and metals can adversely affect your health, and many are damaging to DNA methylation, particularly if you have a MTHFR mutation. A methyl group is one carbon and three hydrogens.

Factors that affect your methylation process There are a number of factors, including toxicity in the body, that affect the methylation process. These include: Genetics — 20 percent of us are genetically predisposed to high homocysteine Poor diet — you need to get adequate levels of vitamins B6 and B12, betaine and folate.

How do toxins affect methylation? Damaging toxins and metals that affect methylation Environmental toxicants such as toxic metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression. Glyphosate Glyphosate is weed killer that is used on many crops including corn, soy and wheat. Parabens Parabens are a preservative, frequently used to prevent bacteria from growing in personal care products like toothpaste, shampoo, soaps, skin lotion and lipstick.

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Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between environmental chemicals with DNA methylation levels in adults. After excluding arsenic, recently evaluated in a systematic review, we identified a total of 17 articles 6 on cadmium, 4 on lead, 2 on mercury, 1 on nickel, 1 on antimony, 1 on tungsten, 5 on persistent organic pollutants and perfluorinated compounds, 1 on bisphenol A, and 3 on polycyclic aromatic hydrocarbons.

Considering consistency, temporality, strength, dose-response relationship, and biological plausibility, we concluded that the current evidence is not sufficient to provide inference because differences across studies and limited samples sizes make it difficult to compare across studies and to evaluate sources of heterogeneity. Important questions for future research include the need for larger and longitudinal studies, the validation of findings, and the systematic evaluation of the dose-response relationships.

Future studies should also consider the evaluation of epigenetic marks recently in the research spotlight such as DNA hydroxymethylation and the role of underlying genetic variants. Beyond lifestyle determinants, the role of environmental chemicals as determinants of DNA methylation has gained considerable attention. Changes in DNA methylation add biological plausibility to the increasingly recognized contribution of environmental chemicals to disease burden [ 1 ] as DNA methylation is involved in regulating many cellular processes, including X-chromosome inactivation, genomic imprinting, chromosome stability, and gene transcription.

Environmental chemicals can interfere with the one-carbon and citric acid metabolism pathways, resulting in anomalous DNA-methylation status throughout the genome [ 2 , 3 ]. Environmental chemicals can also directly interact with enzymes involved not only in one-carbon metabolism and citric acid metabolism pathways but also in histone modifications [ 4 - 6 ]. A summary of suggested mechanisms of action of environmental chemicals on DNA methylation machinery is shown in Figure 1. In turn, these epigenetic mechanisms may modify potential toxicity pathways specific to the environmental chemicals in the organism.

Overview of possible mechanisms of action for environmental chemicals on DNA methylation based on reviews of experimental studies [ 2 , 3 , 5 , , ]. Under chronic consumption of glutathione GSH for conjugation with ROS, chemicals, and their metabolites, homocysteine is employed into GSH rather than methionine synthesis pathways, leading to a reduced synthesis of S-adenosylmethionine SAM, a substrate for DNA methyltransferases DNMT which catalyzes the addition of the methyl group onto the 5-carbon cytosine 5C to become 5-methylcytosine 5mC.

Exposures to specific environmental chemicals such as short-term cadmium, PAH, lead, and mercury exposures can directly reduce the enzymatic activity and concentrations of DNMT [ ]. Overall, it facilitates DNA hypomethylation. Conversely, it has been suggested that long-term cadmium exposure induces compensatory DNMT overexpression [ 4 ] that could lead to increased DNA methylation. On the other hand, environmental chemicals can modulate the enzymes involved in covalent modifications acetylation Ac , methylation Me , phosphorylation P and ubiquitination Ub at the histone tails that can interact with the DNA methylation or demethylation machinery.

Lead has been related with transcription-active histone modifications associated to DNA hypomethylation , while methylmercury and nickel have been related with transcription-repressive histone modifications associated to DNA hypermethylation [ 5 , ]. Finally, while other environmental toxicants have been related to DNA hypomethylation BPA, PFCs and hypermethylation tungsten, antimony in epidemiologic studies, their mechanism of action in epigenetic regulation of gene transcription is unknown.

Environmental chemicals have been linked to aberrant changes in epigenetic pathways both in experimental and epidemiological studies. In animal studies, maternal diet during pregnancy was associated with the pattern of DNA methylation of specific genes, which resulted in permanent phenotypic changes including body weight and blood pressure levels [ 7 , 8 ].

In humans, populations exposed to famine during the prenatal period showed increased prevalence of cardiometabolic factors and ischemic heart disease mortality [ 9 ], with evidence supporting a mediating role of epigenetic mechanisms in disease pathogenesis [ 10 ].

Deleterious effects of epigenetic changes are not restricted to the prenatal period. Monozygotic twins experienced an epigenetic drift in relation to one another with advancing age, time shared together, and behavioral factors such as smoking [ 11 ].

There is, however, a need to undertake a systematic appraisal of the epidemiologic evidence evaluating the potential role of environmental chemicals as determinants of DNA methylation in adults. Our objective was to conduct a systematic review and synthesis of results from epidemiologic studies evaluating the association of environmental chemicals including cadmium, lead, mercury, nickel, persistent organic pollutants POPs , bisphenol A BPA , polycyclic aromatic hydrocarbons PAHs , and phthalates, with DNA methylation levels in adults.

We did not include arsenic studies in our search because there is a recently published systematic review published by Bailey et al. Other environmental exposures, which have been related to DNA methylation, such as exposure to tobacco smoke [ 13 - 17 ] and air pollution [ 18 ], are out of the focus of the present review, as tobacco smoke and air pollution are mixtures of different types of chemicals rather than individual groups of compounds.

We searched PubMed for relevant studies published through 10 April using the search strategy described in Additional file 1 : Table S1 Supplemental Material. The search strategy retrieved a total of citations including duplicates. We included all articles assessing environmental chemical exposures using biomarkers. The search had no language restrictions.

We also included two relevant studies published after 10 April and identified by hand search [ 19 , 20 ]. Two investigators A. In this systematic review, the focus was on the role of environmental chemicals exposure in DNA methylation changes in adults.

Therefore, as a second layer of exclusion, we additionally excluded one study focusing on prepubescent girls [ 21 ], and five studies that focused on the association of maternal exposure biomarkers and DNA methylation in cord blood or the offspring and did not provide corresponding measures of DNA methylation in the mothers [ 22 - 26 ].

We additionally, excluded two studies with semi-quantitative assessment of DNA methylation [ 27 , 28 ] as the comparison of results with quantitative DNA methylation assessment methods is unclear.

Any discrepancies were resolved by consensus, and if necessary, a third reviewer was involved. A native speaker reviewed the full text of any non-English article that could not be included or excluded based on the initial abstract review.

We included in the final review 17 papers, some of them measuring multiple environmental toxicants evaluated in unique study populations [ 19 , 29 , 30 ] Figure 2. Our review identified no publications investigating the association between phthalates and DNA methylation. After retrieval of articles from the search, the reference lists of selected articles were checked for other potentially relevant articles, identifying no additional studies. For studies modeling exposures both as continuous and as categorical, we reported continuous measures of association due to space constraints in the tables.

However, we evaluated flexible dose-response relationships when reported. For polychlorinated biphenyls PCBs , when multiple congeners were reported, we selected the congener with the weakest, highest, and median association. We also reported all the statistically significant POPs.

Flow diagram of the study selection process. Summary of inclusion and exclusion criteria used in this systematic review of studies investigating the association between environmental chemicals and DNA methylation levels, 10 April Tajuddin et al.

Tellez-Plaza et al. To assess study quality, we adapted the criteria used by Longnecker et al. We followed the criteria proposed by the US Surgeon General Report on the health consequences of smoking [ 32 ], which include the evaluation of consistency, temporality, strength, dose-response relationship, and biological plausibility including confounding.

As a result, the evidence for each environmental chemical and DNA methylation was classified into four groups as modified from the Surgeon General Report [ 32 ]: sufficient evidence, suggestive but not sufficient evidence, insufficient evidence to infer a relationship, and suggestive of no relationship.

We organized the presentation of the results by environmental chemical. Cadmium exposure from tobacco smoke, air pollution, occupation, and diet leafy and root vegetables, grains, and offal is widespread in general populations [ 33 ].

In the US, cadmium exposure has substantially decreased during the last decades, in part related to reductions in smoking [ 34 ]. Cadmium exposure, however, remains an important concern, because even at the currently reduced levels of exposure, cadmium has been related to cardiovascular, bone, and kidney disease in studies of the US National Health and Nutrition Examination Survey NHANES to data [ 35 - 41 ].

In epidemiologic studies, cadmium concentrations in blood and urine are established biomarkers of cadmium exposure and internal dose [ 33 , 42 ]. Both biomarkers can reflect cumulative exposure, although blood cadmium also reflects short-term fluctuations in exposure [ 33 , 42 ].

Experimental ex vivo evidence showed that cadmium was an effective, noncompetitive inhibitor of M. In rat liver cells, short-term cadmium exposure induced DNA global hypomethylation [ 4 ].

Prolonged exposure, however, resulted in global DNA hypermethylation [ 4 , 43 - 45 ]. In general, most in vitro and in vivo studies showed increased gene-specific DNA methylation after exposure to cadmium [ 46 - 52 ]. We identified six publications investigating the association between cadmium and DNA methylation Table 1. These studies were conducted in the US [ 19 , 29 , 53 ], Argentina [ 54 ], Spain [ 30 ], and China [ 55 ].

Cadmium exposure was measured in urine only [ 19 , 29 ], blood only [ 53 ], both in urine and blood [ 54 , 55 ], and in toenail [ 30 ]. CpG site-specific DNA methylation was measured in candidate genes by pyrosequencing in one study [ 55 ] and in an exploratory genome-wide manner using microarray technologies in two studies [ 53 , 54 ]. In general, studies mostly showed a trend towards positive associations of cadmium exposure and DNA methylation. Among five studies evaluating global or candidate gene methylation, three studies reported significant or marginally significant associations with cadmium biomarkers [ 19 , 54 , 55 ].

In US American Indians, the multi-adjusted odds ratio of percent 5-mC comparing participants with urine cadmium levels above and below 0. Both epigenome-wide association studies [ 29 , 53 ] evaluated general patterns in the association of DNA methylation in specific CpG sites and cadmium biomarkers in CpG sites with an effect size considered relevant, consistently finding a trend towards increased methylation with elevated cadmium exposure.

None of the genome-wide studies reported statistically significant regions after controlling for a false discovery rate, although the study sample sizes were relatively small [ 29 , 53 ].

Confounding by sex, age, and smoking status was generally addressed, with exceptions [ 29 ]. Only two studies [ 19 , 30 ] addressed the potential confounding effect of tissue cell heterogeneity. Lead in the environment has decreased over the last decades when regulations banning the use of lead in gasoline, paint, and solders were implemented [ 56 , 57 ]. The general population is exposed through ambient air, alcohol consumption, and tobacco smoke [ 58 , 59 ].

Patella and tibia lead are biomarkers of cumulative lead exposure and body burden, while blood lead is a biomarker of recent exposure including endogenous exposure from bone [ 60 ]. Patella lead is biologically more active than tibia lead [ 61 ], having a role in internal exposure dose from redistribution of accumulated lead in the body.

Studies have shown associations between low-exposure to lead and increased risk of neurocognitive outcomes, high blood pressure, chronic kidney disease, hyperuricemia, gout, cardiovascular disease, cancer, and other health effects [ 60 , 62 , 63 ].

In in vivo and in vitro studies, lead exposure was associated with changes in DNA methylation and expression of specific genes [ 64 - 67 ], although experimental studies evaluating the molecular mechanisms of lead-induced changes in DNA methylation are needed. We identified four publications investigating the association between lead and DNA methylation Table 2. These studies were conducted in the US [ 29 , 68 ], China [ 69 ], and Spain [ 30 ]. Lead exposure was measured in blood [ 29 , 68 , 69 ], patella and tibia [ 68 ], or toenail [ 30 ].

CpG site-specific DNA methylation was measured in an exploratory genome-wide manner using microarray technologies in one study [ 29 ], with validation of significant regions by quantitative pyrosequencing.

In general, all the studies reported a trend towards inverse associations of lead exposure and global DNA methylation. Two studies reported statistically significant associations of DNA methylation with lead biomarkers [ 19 , 55 ]. Blood and tibia lead biomarkers, however, did not show statistically significant associations with LINE-1 methylation in this study population, although the direction of the association was similar as compared to patella.

The authors interpreted that the redistribution of accumulated lead from bone over time is associated with DNA methylation in circulating leukocytes.

Among CpG sites with an effect size considered relevant by the authors, a general trend towards hypomethylation with increasing blood lead levels was observed. There were not reported statistically significant regions after controlling for a false discovery rate [ 29 ]. Two out of four studies addressed potential confounding by sex, age, smoking status, and tissue cell heterogeneity in DNA methylation status [ 30 , 68 ].

While one of the studies was a cohort study with repeated measurements of lead biomarkers and DNA methylation [ 68 ], all the studies reported cross-sectional associations. Mercury is a highly reactive metal with unknown physiological activity, which is persistent in the food chain [ 70 ]. While the main source of inorganic mercury is occupation dentistry, mining, artisans manipulating mercury-containing materials and dental amalgams, the general population is mainly exposed to organic mercury through consumption of fish specially large predatory fish and in a lesser degree shellfish and other marine animals [ 70 ].

Blood and hair mercury reflects exposure to methylmercury. Urine mercury, however, mainly reflects exposure to inorganic mercury [ 70 ]. Methylmercury is especially toxic for the neurologic system, especially during infancy [ 71 ]. Both methylmercury and inorganic mercury have immunotoxic effects, although the immunotoxicity is higher for inorganic mercury [ 71 ].

Other mercury-related health outcomes include cardiovascular disease, cancer, alterations of the reproductive system, and kidney disease [ 71 - 74 ]. There is evidence from experimental studies that mercury can change DNA methylation patterns. In rat embryonic neural stem cells and prenatally exposed adult rats, methylmercury reduced neural cell proliferation and was associated with global DNA hypomethylation [ 75 ]. In mouse stem cells, mercury exposure induced aberrant DNA methylation at specific gene loci [ 76 ].

The molecular mechanisms for potential epigenetic effects of mercury, however, are unknown. Other nonessential metals are also of concern because they have been related to diverse health outcome in human studies. Tungsten has been related to cancer mortality [ 77 ], lung cancer, respiratory alterations, electrocardiograph abnormalities, and sudden death [ 78 ], and with prevalent cardiovascular disease and peripheral arterial disease [ 38 , 79 ].

Antimony was associated with peripheral arterial disease [ 38 ]. Nickel is an established carcinogen in occupational settings respiratory cancers , especially insoluble nickel subsulfide and nickel oxide [ 80 ]. Other chronic health effects associated to nickel include rhinitis, sinusitis, nasal septum perforations, asthma, skin allergies, and reproductive effects [ 80 ].

However, experimental evidence indicating a potential role in altering DNA methylation for these metals is scarce, except for nickel. In vitro studies treatment with nickel resulted in both promoter hypermethylation and increased global DNA methylation [ 81 , 82 ]. Nickel may also influence DNA methylation by deregulating epigenetic enzymes involved in post-translational histone modifications [ 83 , 84 ].

For mercury, we identified two publications investigating the association between mercury and DNA methylation Table 3. Both studies were conducted in the USA [ 29 , 85 ]. Mercury exposure was measured in blood [ 29 ] or urine and hair [ 85 ]. For other metals, we only identified one publication investigating the association of DNA methylation with toenail nickel in a population from Spain [ 30 ] and urine tungsten and antimony in US American Indians [ 19 ].

Among all the retrieved studies evaluating mercury and other metals, global DNA methylation was assessed by pyrosequencing of LINE-1 elements in three studies [ 29 , 30 , 85 ] and by and ELISA-like method in one study [ 19 ]. Site-specific DNA methylation was measured in candidate genes by pyrosequencing in one study [ 85 ] and in an exploratory genome-wide manner using microarray technologies in one study [ 29 ].

In the only study reporting both cross-sectional and prospective associations, conducted in US American Indians [ 19 ], the odds ratio of global DNA methylation after 10 years of follow-up was 2.

The cross-sectional association, however, was not statistically significant [ 19 ]. In this study, no statistically significant positions were reported after controlling for a false discovery rate [ 29 ].

The nickel, antimony, and tungsten [ 19 , 30 ], but not mercury [ 29 , 85 ], studies reported fully adjusted models including sex, age, and smoking status. For mercury, since the major source of exposure in humans is methylmercury from seafood consumption [ 86 ], adjustments for nutrients for example, selenium, magnesium, n-3 fatty acids , lifestyle seafood as a proxy for healthy diet , and other toxicants POPs in seafood should be considered.

Only nickel, antimony, and tungsten studies [ 19 , 30 ] addressed the potential confounding effect of tissue cell heterogeneity.

POPs are industrial chemicals that persist in the environment for decades even after production has been stopped [ 87 ]. Human exposure begins prenatally as many POPs can cross the placenta [ 88 ]. After birth, exposure occurs through breast milk [ 88 ] and also through inhalation dust , ingestion dairy and animal products , and skin contact [ 88 , 89 ].

POPs are lipophilic and accumulate in the adipose tissue. The potential effects of POPs include skin rashes to endocrine disruption, developmental delays, metabolic syndrome and diabetes, and cancer, depending on the type of compound and exposure [ 88 ].

Drinking water is the primary route of PFCs exposure in some populations [ 91 ], but exposure sources are not well understood. While PFCs are persistent in the environment and in the body half-life in humans is 3 to 5 years depending on the compound , they are not metabolized in humans and they are not lipophilic [ 91 ]. Animal data indicate that PFCs can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems.

Data on the human health effects include reported positive associations with cholesterol levels, hepatic enzymes, and adverse reproductive outcomes [ 91 ]. BPA is a compound with a shorter half-life compared to POPs, but it is frequently grouped together with POPs given its ubiquity and endocrine disruptor functions [ 88 ]. While humans are exposed through the placenta and ingestion canned food , BPA is also present in dust and ambient air [ 88 , 92 ].

There are some studies evaluating the effect of POPs and other endocrine disruptors on DNA methylation in experimental settings.

Rats treated in utero and postnatally with organochlorine pesticides and PCBs also showed decreased methylation of CpG sites in the promoter of the tumor suppressor gene p16 INK4a compared to controls [ 94 ].

Perfluorooctanoic acid induced gene promoter hypermethylation of GSTP1 in human liver L02 cells [ 95 ]. Maternal BPA exposure disrupted genomic imprinting in the mouse embryos and placenta [ 96 ]. In studies assessing POPs, exposure was measured in plasma [ ] or serum [ 20 , 98 , 99 ]. CpG site-specific DNA methylation was measured in an exploratory genome-wide manner using microarray technologies in one study [ 29 ].

For most POPs, studies evaluating DNA methylation globally showed a trend towards hypomethylation with increasing levels of exposure [ 20 , 98 , ]. Other PFCs did not show statistically significant associations.

In this study, no statistically significant regions were reported after controlling for a false discovery rate [ 29 ]. All studies tested at least five POPs, but only one study [ ] reported addressing multiple testing due to the elevated number of compounds. Most studies addressed potential confounding by sex, age, and smoking status [ 20 , 98 , 99 , ].

One study did not adjust for sex, although the proportion of women was low [ ]. One study presented unadjusted results [ 29 ]. POPs are highly lipophilic and their serum concentrations are closely related to serum lipid levels. Therefore, it is common practice to correct POP levels by lipid levels that is, divide POP concentrations by total lipid concentrations.

Alternatively, some authors argue that lipid correction may be problematic under certain assumptions [ ]. In addition to lipid correction, it is advisable to conduct sensitivity analyses to evaluate robustness of findings using different approaches of handling lipid adjustment, such as conducting separate adjustment for total lipid levels with lipid-uncorrected POPs in regression settings.

All retrieved studies evaluating POPs only conducted analyses with lipid-corrected concentrations. Both standardization of summary POP measurements TEQ versus measured values or sum of POPs functional subgroups and adjustment for lipid levels are ongoing challenges that require consensus in order to facilitate data comparison and meta-analysis.