彰化地區民眾暴露鄰苯二甲酸二乙酯(DEP)對DNA甲基化變化的影響

Abstract

Introduction: Aging has become a global issue and in consequence, the prevalence of many chronic diseases has increased, especially metabolic syndrome (MS) and colorectal cancer (CRC). CRC was the top cancer prevalence in Changhua in the last decade, and the prevalence of MS also increased annually. Diethyl phthalate (DEP) is a common plasticizer frequently used in daily life. DEP may enter human body through inhalation, ingestion, and dermal contact. DEP has a weak estrogen effect. The hazard associated with DEP including skin sensitivity, reproductive hazard, metabolic disease, and cancer. Several studies indicated that DEP can cause MS and cancer through DNA methylation changes. DNA methylation may be able to explain the link between DEP exposure and the related health effects. In addition, epigenetic age can better access human aging. We investigated the effects of DEP on DNA methylation levels and epigenetic age acceleration in relation to MS and the development of CRC in Changhua. Materials and methods: Our study participants were from the participants of Changhua community-integrated screening (CIS), including 61 participants from 2006 to 2014. We used blood cell samples to measured DNA methylation levels by using Illumina Infinium® MethylationEPIC BeadChip. The qualitative and quantitative DEP exposure analyses were measured in serum by UHPLC Q-TOF MS and UPLC-MS/MS, respectively. The health screening results were collected in Changhua CIS. ChAMP package were used for DNA methylation related analyses. Both univariable and multivariable models were used. Epigenetic age was calculated in five methods, including Hannum, Horvath, ELOVL2, FHL2, and Weidner’s equation. The associations between DEP exposure and epigenetic age acceleration were estimated. Differential methylation analysis used two significant thresholds, false discovery rate (FDR) adjusted p-value < 0.05 and p-value < 5×10-5. The two-tailed test significant threshold was type I error < 0.05. Results: The mean age of our study participant was 59.27 years old, mean BMI was 26.38 kg/m2, and mean DEP exposure concentration was 7.71 ng/mL. When exposed to the higher concentrations of DEP, most of the MS-related indicators values changes had negative effects on health, particularly increased waistline, fasting blood glucose, and the risk of MS. Although we found the concentration of DEP exposure was higher in adenoma and CRC than control, but not statistically significant. We also observed that the genes affected by DEP exposure were mainly in the metabolic and carcinogenesis pathways. In addition, comparing to participants exposure to low concentrations of DEP, we found that DEP was associated with a decrease in CD8T cells, MS effector genes (POR, CNPY1, FTO, SH3RF3, and KRT32) and cancer-related effector genes (KNDC1, STK25, NFATC3, CCDC183, WDR74, SLC15A3, MPRIP, SNORA10B, and PLCL2) were hypomethylated among participants exposure high concentration of DEP. The hypomethylation of MS effector genes was related to BMI, waistline, blood pressure, fasting blood glucose, triglyceride, and high density lipoprotein. We did not find DEP exposure significantly related to accelerated aging of epigenetic age. Discussion and conclusion: In our results, higher concentration of DEP exposure was related to the increase of waistline and fasting blood glucose, which was the same as the results of previous studies. Additionally, DEP concentration was related to the decrease of CD8T cells, which may promote the development of cancer. POR, CNPY1, and FTO have been defined as MS-related genes in previous studies, while SH3RF3 and KRT32 were first to be discovered to have functions in the metabolic pathway. Previous studies showed that the methylation levels of KNDC1 and PLCL2 were related to cancer, while CCDC183 was the first time to link to cancer in our research. Although the half-life of DEP is short and DEP concentration of our participants was lower than other countries, we still found a positive relation between DEP exposure and MS and the development of CRC. Therefore, we must pay attention to chronic disease risks and hazards caused by DEP exposure and formulate relevant regulations. The further replications regarding the DEP exposure related effects in a larger sample size are still required.