The association between urine di-(2-ethylhexyl) phthalate metabolites, global DNA methylation, and subclinical atherosclerosis in a young Taiwanese population

doi:10.1016/j.envpol.2020.114912

Environmental Pollution

Volume 265, Part B, October 2020, 114912

https://doi.org/10.1016/j.envpol.2020.114912 Get rights and content

Highlights

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The association between urine DEHP metabolite, 5mdC/dG, and CIMT was studied in 793 young persons.
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Urine MEHP was positively associated with 5mdC/dG and CIMT after controlling for covariates.
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The correlation between DEHP and CIMT was more marked if concentrations of 5mdC/dG were elevated.
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5mdC/dG was a strong mediator for CIMT and MEHP in structural equation model.

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) has been utilized in many products for years. DEHP exposure has been linked to cardiovascular diseases (CVD) and its risk factors. Recent evidence has found a crucial role for epigenetics, including DNA methylation, in CVD. Moreover, DEHP exposure has proved to alter DNA methylation in epidemiological studies. However, the interplay between DEHP exposure, global DNA methylation, and atherosclerosis has never been reported. In this current study, we enrolled 793 participants (12–30 years) from a Taiwanese population to investigate the association between concentrations of DEHP metabolites, 5mdC/dG (global DNA methylation marker) and the carotid intima-media thickness (CIMT). The results showed urine mono-2-ethylhexyl phthalate (MEHP) level was positively correlated with 5mdC/dG and CIMT, respectively. In logistic regression models, the odds ratios (OR) of thicker CIMT (greater than 75^th percentile) with one unit increase in ln-MEHP level was higher when levels of 5mdC/dG were above 50%. In structural equation model, the result showed urine MEHP levels are directly associated with CIMT. Moreover, MEHP had an indirect association with CIMT through the 5mdC/dG after adjusting other confounding effects. In the current study, urine DEHP metabolite levels were positively correlated with 5mdC/dG, and CIMT. Our results showed DEHP had a direct and indirect association with CIMT through the 5mdC/dG. The finding implies that DNA methylation may mediate the association between DEHP exposures and subclinical atherosclerosis in this young population. Future effort is needed to elucidate the causal relationship between DEHP exposure, DNA methylation and CVD.

Graphical abstract

Introduction

Phthalates are the most common chemicals added into plastics to increase the flexibility. These chemicals are also widely used in cosmetics, building materials, medical devices, and other daily used products (Liao et al., 2018; Wang et al., 2018). Phthalate are hydrophobic and non-covalently bound to polymer and can easily leach into water, air and foodstuff. Among the phthalate easters, di-(2-ethylhexyl) phthalate (DEHP) is the main plasticizer used for decades and has been listed at the Annex XIV of REACH of the European Union since 2015 (Schaedlich et al., 2018). In May 2011, a food scandal occurred in Taiwan because DEHP were illegally used as clouding agents in products (Yen et al., 2011). This raises concerns about the impact of DEHP exposure on Taiwanese health (Bao et al., 2015).

Atherosclerosis is the primary cause of cardiovascular diseases (CVD) and accounts for about half of all deaths. Several environmental and genetic risk factors have been reported to be associated with atherosclerosis in epidemiological studies (Lusis, 2000). Recently, several cross-sectional epidemiological studies have linked DEHP exposure to several CVD risk factors (Huang et al., 2014; James-Todd et al., 2012; Stahlhut et al., 2007; Trasande et al., 2013). Since other phthalates have been found to associate with atherosclerosis and CVD (Shiue, 2013; Wiberg et al., 2014), few studies reported a significant correlation between DEHP, atherosclerosis, and CVD. Recently we found subjects with coronary heart disease have higher concentrations of urine DEHP metabolite, mono-2-ethylhexyl phthalate (MEHP), than controls in a case control study (Su et al., 2019a). In another study composed of adolescents and young adults, we reported that higher urine MEHP levels was associated with thicker carotid intima-media thickness (CIMT), suggesting DEHP might associate with subclinical arteriosclerosis (Su et al., 2019b).

The pathogenesis of atherosclerosis is not completely understood. Recent evidence has found a crucial role for epigenetics in CVD (Fernandez-Sanles et al., 2017). DNA methylation, one of the most studied epigenetic regulations, is a process by which methyl groups were added to the C5 position of cytosine rings within guanine residues (CpG dinucleotides) (Fernandez-Sanles et al., 2017). It accounts for 2–5% of all 2-deoxycytidine in mammals and can regulate gene expression without changing the sequence (Wachsman, 1997). Both global genomic DNA methylation and specific methylated specific loci have been reported to associate with CVD (Agha et al., 2019; Baccarelli et al., 2010; Kim et al., 2010; Movassagh et al., 2011; Talens et al., 2012).

DNA methylation is heritable and also influenced by environmental stimulants. Recently, epidemiological studies have linked DEHP exposure to altered DNA methylation. When linking DEHP exposure and DNA methylation to health outcomes, the published literature were focused primarily on reproductive and development health (Huang et al., 2018; LaRocca et al., 2014; Tian et al., 2019; Zhao et al., 2015). Some studies suggested the correlation between urine DEHP metabolites levels and adverse health outcome (sperm quality, infant growth) may mediate by changes in methylation (Tian et al., 2019; Zhao et al., 2015) but some studies did not show a significant effect of DNA methylation in the association between DEHP metabolites levels and birth outcomes (Huang et al., 2018; LaRocca et al., 2014).

Previous studies have linked DEHP exposure, as well as DNA methylation, to CVD and its risk factors. Moreover, DEHP exposure was also reported to altered DNA methylation. It is interesting whether DNA methylation mediate the association between DEHP exposure and atherosclerosis. Notably, previous reports have yet to provide an answer. In this current study, we planned a cross-sectional study in adolescents and young Taiwanese adults (the YOung TAiwanese Cohort (YOTA) study). We applied CIMT as a biomarker of subclinical arteriosclerosis and 5mdC/dG levels as biomarkers of global DNA methylation. The aim of this research was to study the correlation between urine levels of DEHP metabolites (MEHP, mono(ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethly-5-oxoheyl) phthalate (MEOHP)), CVD risk factors, CIMT, as well as DNA methylation marker 5mdC/dG.

Section snippets

Study population and data collection

From 2006 to 2008, we set up a cohort (YOTA, the YOung TAiwanese Cohort Study) according to these subjects had elevated blood pressure or not in childhood (Lin et al., 2019; Lin et al., 2018). Examinations were performed after signed informed consent and approved by the Research Ethics Committee of the National Taiwan University Hospital. Among 886 participants, urine samples for testing DEHP were unavailable in 17 subjects. 76 subjects were excluded if a urine sample is too dilute or too

Descriptive characteristics of DEHP metabolites, 5mdC/dG, CIMT, and CVD risk factors

The participants composed of 243 males and 550 females with mean age 21.3 years. Geometric means and 95% confidence intervals of the creatinine-adjusted urinary DEHP metabolites (μg/g creatinine) and 5mdC/dG in different subgroups are demonstrated in Table 1. Participants with age between 12 and 19 years old have a higher level of MEHP than subjects with age between 20 and 30 years old. Levels of MEHP and MEOHP were higher in females than males. Moreover, MEHHP and MEOHP levels were higher in

Discussion

In the current study, we are the first to report the associations and interplay among DEHP exposure, global DNA methylation, and atherosclerosis in a young Taiwanese population. We demonstrated that urine MEHP levels were positively correlated with 5mdc/dG and CIMT, respectively. Moreover, the OR between MEHP and CIMT is higher when levels of 5mdc/dG were elevated. The SEM showed MEHP had a direct and indirect association with CIMT through the 5mdC/dG. Our findings indicated that global DNA

Conclusions

In conclusion, urinary MEHP level was positively correlated with 5mdC/dG, and the CIMT in a young Taiwanese cohort. The positive correlation between MEHP and CIMT was more marked when concentrations of 5mdC/dG were elevated. The finding implies that DNA methylation may mediate the correlation between DEHP exposures and arteriosclerosis in this cohort. If a causal relationship exists, there could be a potentially health issue in general population. Our results provide new evidences and clues for

Author’s contributions

Chien-Yu Lin developed the theoretical concept and performed the analytic calculations and manuscript drafting. Hui-Ling Lee helped to analyze global DNA methylation and to write the analytic method. Yi-Ting Hwang helped to perform the analytic calculations. Chia-Jung Hsieh helped to analyze phthalate metabolites and to write the analytic method. Fung-Chang Sung contributed to study participants enrolled. Ta-Chen Su contributed to develop the theoretical concept, study participants enrolled,

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgements

We thanks all the people who helped to establish the cohort. This study was supported by grants from the National Health Research Institute of Taiwan (NHRI EX95-9531PI and NHRI-EX106-10629PI), the Ministry of Science and Technology of Taiwan (NSC 101-2314-B-002-184-NY3, NSC 99-2314-B-385-001-MY3, MOST 106-2314-B-385 -001, and MOST 107-2314-B-385-003).

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Di(2-ethylhexyl) phthalate (DEHP) a parent compound that is metabolized into 4 phthalate metabolites, which correlate to adverse cardio-metabolic risk factors. This study aimed to explore the links between urinary DEHP metabolites and serum lipids in the U.S. general adult population.
In this cross-sectional study, data on 11 urinary phthalate metabolites from the 2005–2018 National Health and Nutrition Examination Surveys (NHANES) were analyzed. Multivariate linear regression and restricted cubic spline (RCS) were used to examine the relationship between phthalate metabolites [specific DEHPs: mono-(2-ethyl-5-carboxy-pentyl) phthalate (MECPP), mono-(2-ethyl-5-hydroxy-hexyl) phthalate (MEHHP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP)] and serum lipids (triglycerides [TG], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]). To identify mixed exposure effects of phthalate metabolites, quantile g-computation (QG-C) and weighted quantile sum (WQS) regression were employed for the lipid profiles.
A total of 9141 adults were included in the analysis. MECPP, MEHHP, MEHP, and MEOHP in the highest quartile had a negative relationship with HDL-C compared to the lowest quartile (All P for trend <0.05). TG showed a significant positive relation with MECPP, MEHHP, and MEOHP (All P for trend <0.05), but there was no notable association with MEHP. RCS demonstrated a linear relationship of DEHP metabolites with HDL-C, TC, TG, and LDL-C (all P for nonlinearity >0.05). The WQS index of DEHP metabolites showed independent correlations with HDL-C [β = −0.26, 95%CI (−0.43, −0.09), P = 0.002], TC [β = 0.55, 95%CI (0.13, 0.98), P = 0.011], and TG [β = 2.40, 95%CI (0.85, 3.96), P = 0.003].
Our study suggests that environmental DEHP exposure may affect serum HDL-C and TG levels in the general adult population. Further research is warranted to confirm these findings and illuminate the underlying mechanisms of DEHP exposure on lipids.
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Being an essential component in the plastics industry, phthalates are ubiquitous in the environment and in everyday life. They are considered environmental contaminants that have been classified as endocrine-disrupting compounds. Despite di-2-ethylhexyl phthalate (DEHP) being the most common plasticizer and the most studied to date, there are many others that, in addition to being widely used in the plastic, are also applied in the medical and pharmaceutical industries and cosmetics. Due to their wide use, phthalates are easily absorbed by the human body where they can disrupt the endocrine system by binding to molecular targets and interfering with hormonal homeostasis. Thus, phthalates exposure has been implicated in the development of several diseases in different age groups. Collecting information from the most recent available literature, this review aims to relate human phthalates’ exposure with the development of cardiovascular diseases throughout all ages. Overall, most of the studies presented demonstrated an association between phthalates and several cardiovascular diseases, either from prenatal or postnatal exposure, affecting foetuses, infants, children, young and older adults. However, the mechanisms underlying these effects remain poorly explored. Thus, considering the cardiovascular diseases incidence worldwide and the constant human exposure to phthalates, this topic should be extensively studied to understand the mechanisms involved.
Phthalate promotes atherosclerosis through interacting with long-non coding RNA and induces macrophage foam cell formation and vascular smooth muscle damage
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Citation Excerpt :
Humans can be exposed to phthalates via eating or inhalation materials containing di (2-ethylhexyl) phthalate (DEHP) and mono (2-ehylhexyl) phthalate (MEHP). It has been well documented that phthalates exposure can cause reproductive toxicity, liver damage, and cancer (Liu et al., 2022; Lin et al., 2020). Due to its hydrophobic properties, DEHP may be leached from plasticizers directly or indirectly and subsequently transported to the liver, reproductive system, and kidneys (Shih et al., 2018; Wang et al., 2020; Kim, 2020).
Phthalates are commonly used in variety of plastic products. Previously it has been revealed that di (2-ethylhexyl) phthalate (DEHP), as the most common member of the class of phthalates, may disturb cholesterol homeostasis and deregulate the inflammatory response, and leading to accelerate the atherosclerosis process. In this regard, the aim of the current study is to explore the underlying mechanism of DEHP-induced atherosclerosis through the increasing of foam cell formation and Vascular Smooth Muscle Cells (VSMCs) damage via the interaction of long-non coding RNA (GAS5) and miR-145–5p.
ApoE^−/− mice were used to evaluate the in vivo study. RAW264.7 and VSMCs were used to evaluate the effect of DEHP on formation of foam cell, cell proliferation, and cell damage in vitro. Animals were treated with DEHP (5% w/w of food) orally and cells were treated with medium containing of 100 μM DEHP; qRT-PCR, Western blotting, flowcytometry, IHC, oil red O, BODIPY, and autophagic vacuoles assay were used to evaluate the effect of DEHP on formation of atherosclerosis.
DEHP significantly accelerated the formation of atherosclerosis in mice and alter the lipid profile in mice. In addition, after treating VSMCs with DEHP, GAS5 was significantly up-regulated and miR-145–5p was down-regulated. In VSMCs treated with DEHP, we observed that GAS5 could be used as the competing endogenous RNA (ceRNA) of miR-145–5p to regulate the proliferation and apoptosis of VSMCs; and the expression of GAS5 was correlated with the expression of miR-145–5p. DEHP increased the ox-LDL uptake by macrophage and increasing the formation of foam cells. Besides, GAS5 knocking down reversed the effect of DEHP on foam cell formation and ox-LDL uptake.
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Adverse cardiovascular effects and potential molecular mechanisms of DEHP and its metabolites—A review
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However, we describe several leading mechanistic frameworks: DNA methylation, PPAR-related pathways, oxidative stress and inflammation, Ca2+ homeostasis disturbance and defensive signaling pathways. DNAm induced by exposure to DEHP and its metabolites adversely affected signaling pathways and gene expression in cardiomyocytes, mainly resulting in cardiogenesis abnormalities and atherosclerosis of blood vessels (Lin et al., 2020; Lin et al., 2022; Mu et al., 2020; Schaedlich et al., 2015; Svoboda et al., 2020). In the context of DEHP exposure, the methylation percentages of specific CpGs within PPARγ1 and PPARα were both slightly but biologically increased, changing the metabolic programming and functional characteristics of embryonic cardiomyocytes (Schaedlich et al., 2015).
Currently, cardiovascular disease (CVD) is a health hazard that is associated with progressive deterioration upon exposure to environmental pollutants. Di(2-ethylhexyl) phthalate (DEHP) has been one of the focuses of emerging concern due to its ubiquitous nature and its toxicity to the cardiovascular (CV) system. DEHP has been noted as a causative risk factor or a risk indicator for the initiation and augment of CVDs. DEHP represents a precursor that contributes to the pathogenesis of CVDs through its active metabolites, which mainly include mono (2-ethylhexyl) phthalate (MEHP). Herein, we systematically presented the association between DEHP and its metabolites and adverse CV outcomes and discussed the corresponding effects, underlying mechanisms and possibly interventions. Epidemiological and experimental evidence has suggested that DEHP and its metabolites have significant impacts on processes and factors involved in CVD, such as cardiac developmental toxicity, cardiac injury and apoptosis, cardiac arrhythmogenesis, cardiac metabolic disorders, vascular structural damage, atherogenesis, coronary heart disease and hypertension. DNA methylation, PPAR-related pathways, oxidative stress and inflammation, Ca²⁺ homeostasis disturbance may pinpoint the relevant mechanisms. The preventive and therapeutic measures are potentially related with P-glycoprotein, heat-shock proteins, some antioxidants, curcumin, apigenin, β-thujaplicin, glucagon-like peptide-1 receptor agonists and Ang-converting enzyme inhibitors and so on. Promisingly, future investigations should aid in thoroughly assessing the causal relationship and molecular interactions between CVD and DEHP and its metabolites and explore feasible prevention and treatment measures accordingly.
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There is growing evidence that phthalate exposure results in a deteriorated effect on human health, while very few studies directly investigate the relationship of phthalate metabolites with mortality among people with hypertension. We aimed to explore whether exposure to phthalates is associated with all-cause and cause-specific mortality among people with hypertension. This study included 4012 people with hypertension from the National Health and Nutrition Examination Survey from 2003 to 2014. Death information was obtained from the National Death Index until 2015. A total of 577 deaths including 196 deaths due to cardiovascular disease (CVD) and 119 deaths due to cancer were documented. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). After adjustment for potential covariates, participants exposed to mono-ethyl phthalate (MEP) had a higher risk of cancer mortality (HR, 2.06; 95% CI, 1.07–3.95). Participants exposed to mono-n-butyl phthalate (MnBP) had higher risks of all-cause (HR, 1.83; 95% CI, 1.28–2.60), CVD (HR, 2.19; 95% CI, 1.21–3.95), and cancer (HR, 2.35; 95% CI, 1.07–5.17) mortality. Participants exposed to mono-benzyl phthalate (MBzP) had higher risks of all-cause (HR, 2.19; 95% CI, 1.58–3.05) and CVD (HR, 2.36; 95% CI, 1.35–4.13) mortality. Participants exposed to di-2-ethylhexylphthalate (DEHP) had a higher risk of all-cause mortality (HR, 1.69; 95% CI, 1.19–2.39). Our findings suggested that higher levels of specific phthalates were significantly associated with increased risks of all-cause, CVD, and cancer mortality among people with hypertension. Further studies are needed to confirm these findings and identify the underlying mechanisms.
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Phthalates exposure has been reported to be linked with arterial stiffness. However, the biological mechanisms underlying this association remain unclear. We conducted a panel study using 338 paired urine-blood samples by repeated measurements of 123 adults across 3 seasons to assess the potential mediating role of plasma microRNAs (miRNAs) in the association of phthalates exposure with arterial stiffness. We measured 10 urinary phthalate metabolites by gas chromatography-tandem mass spectrometry (GC-MS/MS) and 5 candidate arterial stiffness-related miRNAs (miR-146a, miR-222, miR-125b, miR-126, and miR-21) in plasma by real-time PCR. Arterial stiffness parameters including brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) were determined in health examinations during each visit. Linear mixed-effect (LME) models revealed that mono-methyl phthalate (MMP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MBP), mono-n-octyl phthalate (MOP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were significantly associated with one or more of the 5 plasma miRNAs (all P _FDR < 0.05). Based on weighted quantile sum (WQS) regression, we found positive associations of phthalate metabolites mixture with miR-146a, miR-125b, and miR-222, and individual MMP and MBP were the major contributors. Additionally, miR-146a was inversely related to ABI. Mediation analysis further indicated that miR-146a mediated 31.6% and 21.3% of the relationships of MMP and MiBP with ABI, respectively. Our findings suggested that certain phthalates exposure was related to plasma miRNAs alterations in a dose-response manner and miR-146a might partly mediate phthalate-associated ABI reduction.

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The association between urine di-(2-ethylhexyl) phthalate metabolites, global DNA methylation, and subclinical atherosclerosis in a young Taiwanese population☆

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Study population and data collection

Descriptive characteristics of DEHP metabolites, 5mdC/dG, CIMT, and CVD risk factors

Discussion

Conclusions

Author’s contributions

Declaration of competing interest

Acknowledgements

Environ. Toxicol. Pharmacol.

Methods Enzymol.

J. Hazard Mater.

Atherosclerosis

Sci. Total Environ.

Chemosphere

Environ. Res.

Environ. Pollut.

Environ. Int.

Int. J. Hyg Environ. Health

Environ. Pollut.

Environ. Pollut.

Int. J. Cardiol.

J. Hazard Mater.

J. Biol. Chem.

Environ. Res.

Toxicology

Ecotoxicol. Environ. Saf.

Environ. Pollut.

Chemosphere

Mutat. Res.

Environ. Pollut.

Environ. Res.

Food Chem. Toxicol.

J. Formos. Med. Assoc.

Blood leukocyte DNA methylation predicts risk of future myocardial infarction and coronary heart disease

Circulation

Ischemic heart disease and stroke in relation to blood DNA methylation

Epidemiology

DNA methylation and its role in the pathogenesis of diabetes

Pediatr. Diabetes

Phthalate metabolites in urine samples from school children in taipei, taiwan

Arch. Environ. Contam. Toxicol.

Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements

Environ. Health Perspect.

Carotid intima-media thickness as a biomarker of subclinical atherosclerosis

Swiss Med. Wkly.

Levels of seven urinary phthalate metabolites in a human reference population

Environ. Health Perspect.