DNA Methylation Biomarkers of IQ Reduction are Associated with Long-term Lead Exposure in School Aged Children in Southern China.

Although lead associated with intelligence decline in children has long been reported, studies combining intelligence determination, molecular mechanisms exploration, and biomarker screen are quite rare. In this study, based on 333 children aged 9-11, we determined the role of DNA methylation (DNAm) in the relationship of lead exposure with children's intelligence. DNAm was measured from children's blood DNA specimens, and mediation analysis was performed to identify DNAm biomarkers mediating the lead-intelligence relationship. We identified forty-three differentially methylated regions (DMRs), and two fragments (FAM50B1 and PTCHD3) significantly mediated the lead-intelligence relationship, with contribution rates of 30.36% (p = 0.010) and 60.36% (p < 0.001), respectively. In addition, blood lead levels (BLLs) lower than 100 µg/L still adversely affected children's IQs and DNAm of the two fragments. Our data suggests that DNAm mediates lead-associated cognitive delay in children and blood lead reference value for school-aged children (100 µg/L) should be revised, and the candidate biomarkers can be used in related neurological diseases in future.

Human Sex Hormone Disrupting Effects of New Flame Retardants and Their Interactions with Polychlorinated Biphenyls, Polybrominated Diphenyl Ethers, a Case Study in South China.

Even though sex hormone disrupting effects of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widely understood, similar effects associated with new flame retardants (NFRs) have not been so well studied. This study aimed to explore the sex hormone disruption of NFRs and their interactions with PCBs and PBDEs through the conduct of an ecological study in an e-waste dismantling and control region in South China. Questionnaires and blood samples were collected from local adult residents. Results of generalized additive model and linear regression analyses indicate that several species of NFRs showed similar disrupting effects with PBDE congeners on female follicle-stimulating hormone (FSH) and male testosterone. Judged by the curved shape and statistical significance, ΣNFR (sum of 8 species of NFRs) showed stronger disrupting effects on male testosterone and female FSH compared to ΣPBDE (sum of 13 congeners of PBDEs). The interactions induced by NFRs complicated the original sex hormone disruption led by PCBs and PBDEs. The disrupting effects and interactions induced by NFRs decreased female FSH levels in the exposed group. Comprehensive evaluation is needed to provide the evidence base for judging the health risks arising from the increased usage of NFRs.

Effects of lead, cadmium, arsenic, and mercury co-exposure on children's intelligence quotient in an industrialized area of southern China.

Exposure to metal(loid)s can lead to adverse effects on nervous system in children. However, little is known about the possible interaction effects of simultaneous exposure to multiple metal(loid)s on children's intelligence. In addition, relationship between blood lead concentrations (<100 µg/L) and the intelligence of children over 5 years needs further epidemiological evidence. We recruited 530 children aged 9-11 years, including 266 living in a town near an industrialized area and 264 from another town in the same city in South China as a reference. The levels of lead (Pb), cadmium (Cd), arsenic (As) and mercury (Hg) in blood (BPb, BCd, BAs, BHg) and urine (UPb, UCd, UAs, UHg) were assessed, as well as children's intelligence quotient (IQ). A significant decrease in IQ scores was identified in children from the industrialized town (p < .05), who had statistically higher geometric mean concentrations of BPb, BCd, UPb, UCd and UHg (65.89, 1.93, 4.04, 1.43 and 0.37 µg/L, respectively) compared with children from the reference town (37.21, 1.07, 2.14, 1.02 and 0.30 µg/L, respectively, p < .05). After adjusting confounders, only BPb had a significant negative association with IQ (B = -0.10, 95% confidence interval: -0.15 to -0.05, p < .001), which indicated that IQ decreased 0.10 points when BPb increased 1 µg/L. Significant negative interactions between BAs and BHg, positive interaction between UPb and UCd on IQ were observed (p < .10), and BPb <100 µg/L still negatively affected IQ (p < .05). Our findings suggest that although only BPb causes a decline in children's IQ when simultaneously exposed to these four metal(loid)s at relatively low levels, interactions between metal(loid)s on children's IQ should be paid special attention, and the reference standard in China of 100 µg/L BPb for children above 5 years old should be revised.

LINE-1 gene hypomethylation and p16 gene hypermethylation in HepG2 cells induced by low-dose and long-term triclosan exposure: The role of hydroxyl group.

Triclosan (TCS), a frequently used antimicrobial agent in pharmaceuticals and personal care products, exerts liver tumor promoter activities in mice. Previous work showed high-dose TCS (1.25-10µM) induced global DNA hypomethylation in HepG2 cells. However, whether or how tumor suppressor gene methylation changed in HepG2 cells after low-dose and long-term TCS exposure is still unknown. We investigate here the effects and mechanisms of DNA methylation of global DNA(GDM), repetitive genes, and liver tumor suppressor gene (p16) after exposing HepG2 cells to low-dose TCS (0.625-5nM)for two weeks using HPLC-MS/MS, Methylight, Q-MSP, Pyrosequencing, and Massarray methods. We found that low-dose TCS exposure decreased repetitive elements LINE-1 methylation levels, but not global DNA methylation, through down-regulating DNMT1 (DNA methyltransferase 1) and MeCP2 (methylated DNA binding domain) expression, and up-regulating 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. Interestingly, low-dose TCS elevated p16 gene methylation and inhibited p16 expression, which were not observed in high-dose (10µM) group. Meanwhile, methyl-triclosan could not induce these two types of DNA methylation changes, suggesting the involvement of hydroxyl in TCS-mediated DNA methylation changes. Collectively, our results suggested low concentrations of TCS adversely affected HepG2 cells through DNA methylation dysregulation, and hydroxyl group in TCS played an important role in the effects. This study provided a better understanding on hepatotoxicity of TCS at environmentally relevant concentrations through epigenetic pathway.

Triclosan reduces the levels of global DNA methylation in HepG2 cells.

Triclosan (TCS), an antibacterial agent, is widely used in a variety of personal care and industrial products. TCS is associated with the development of liver tumors in rodents and has become a concern to environmental and human health. This study is aimed at investigating whether TCS could modulate the levels of global DNA methylation (GDM) in human hepatocytes. We found that treatment with different doses (1.25-10 µM) of TCS did not affect HepG2 cell viability, but significantly reduced the levels of GDM in HepG2 cells, and inhibited DNMT1 activity. Furthermore, treatment with TCS significantly inhibited the methylated DNA-binding domain 2 (MBD2), MBD3, and MeCP2 mRNA transcription. In addition, treatment with TCS promoted the accumulation of 8-hydroxy-2-deoxyguanosine (8-OHdG) in a dose-dependent manner, which was abrogated by treatment with an antioxidant, N-acetylcysteine (NAC). Collectively, our data indicated that TCS reduced the levels of GDM and down-regulated the MBD2, MBD3, and MeCP2 gene expression by increasing 8-OHdG levels and inhibiting the DNMT1 activity in HepG2 cells.

Human GSTs polymorphisms in the Hakka population of south China and their associations with family history of several chronic diseases.

OBJECTIVE: To investigate the associations of genetic polymorphisms in GSTs genes of the Hakka population of south China with family histories of certain chronic diseases. METHODS: Five hundred and thirty-nine healthy Hakka natives of Meizhou city of Guangdong province in south China were involved. The genotypes of GSTM1, GSTT1, GSTP1, GSTM3, and GSTA1 were determined using PCR and restriction fragment length polymorphism analysis. The observed polymorphisms were analyzed by Chi-square and Hardy-Weinberg equilibrium tests. Logistic regression analysis was used to determine the associations of the distributions of GST genotypes with family history of certain chronic diseases. RESULTS: The distributions of polymorphisms in GSTP1, GSTM3, and GSTA1 conformed to the Hardy-Weinberg equilibrium. Compared to the Cantonese, the Hakka had a lower distribution of the GSTM3 deletion genotype (3.15% vs. 11.9%). A weak association was observed between the GSTM1 genetic polymorphism and family history of hypertension. Alcohol drinkers had a higher frequency of the null-GSTM1 genotype, while smokers had a higher frequency of a variant GSTP1 genotype. CONCLUSION: The results suggest that the Hakka is a special and distinctive Han Chinese ethnic group with different GSTs genetic polymorphisms. Smoking and drinking might be related to the distribution of GST genotypes.

Long-term heavy metal pollution and mortality in a Chinese population: an ecologic study.

The concentrations of heavy metals in both local environmental samples (water and crops) and in the whole blood of 1,152 local residents were determined by atomic absorption spectrometry. We calculated rate ratios and standardized mortality ratios based on age-, gender-, and cause-specific mortality for both the district and province. Multi-regression models were then used to evaluate the associations between the exposure to multiple heavy metals and cause-specific mortality in the studied population. Significant increases in the mean concentrations of cadmium, lead, and zinc in the blood samples were found to be associated with a substantially elevated all-cancer mortality rate in this high-exposure area (HEA). There were also significantly elevated mortality rates in the HEA for both sexes from a wide range of causes (all-cause), including cardiovascular disease (CVD), when compared with a low-exposure area (LEA). Further analysis showed positive correlations between exposure to both cadmium and lead and a higher risk of all-cancer mortality among women and for both sexes combined. In contrast, zinc exposure negatively correlated with the risk of cause-specific mortality, but this was not significant. These results of our current study thus reveal that long-term environmental exposure to both cadmium and lead is associated with an increased risk of all-cause, CVD, and all-cancer mortality, whereas zinc exposure showed a possible weak protection against death from CVD.

[Study on the genetic polymorphisms of human glutathione-S-transferase A1 in Hakka population in South China].

OBJECTIVE: Glutathione-S-transferase A1 (GSTA1) is one of the major phase II detoxification enzymes in the cytosol, which genetic polymorphisms distribution is different in different ethnic, national and regional population. Up to now, GSTA1 genetic polymorphisms has been rarely reported in China. The purpose of the study was to investigate the distribution of genetic polymorphisms of human GSTA1 in Hakka population in South China. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to identify the genotypes of GSTA1 gene and the data were analyzed with SPSS10.0 software. RESULTS: The GSTA1 genetic polymorphisms were detected in 480 samples. The frequency of GSTA1 * A/ * A,GSTA1 * A/ * B and GSTA1 * B/ * B were 77.1%, 21.7% and 1.2% respectively. And the GSTA1 genetic polymorphism distribution was in accordance with the Hardy-Weinberg equilibrium rule. There were no difference in the GSTA1 genetic polymorphisms among the different groups of age or gender. Logistic regression analysis showed that there were no association between the GSTA1 genetic polymorphism and family history of hypertension, coronary heart disease, stroke, lung cancer and nasopharyngeal cancer, et al. CONCLUSION: The GSTA1 gene existed polymorphism among Hakka in South China.