Chemical exposure, leukemia related DNA methylation changes and childhood acute leukemia

Abstract

To evaluate the association between chemical exposure, DNA methylation status and gene-environment interactions in the development of childhood acute leukemia (AL). From January 1st 2009 to December 31st 2010, an exploratory case-control study was conducted on childhood AL among children who were less than 15 years of age in Shanghai, China. A total of 131 patients with newly diagnosed AL were recruited from 3 Shanghai children hospitals. The controls selected from the same hospital were healthy children who attended the physical check-up held by the department of Children's Healthcare, or who visited the clinic of developmental pediatrics or orthopedics (excluding blood diseases and malignant tumors). 140 controls matched with cases in gender and age were included in this study. Chemical exposure were investigated by questionnaires, methylation specific polymerase chain reaction (MSP) was adopted to analyze the methylation or deletion status of 8 genes, and gene-environment interactions were analyzed by relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index (S). There were 131 and 140 subjects in case and control group, who were aged (6.9 ± 3.8) and (6.9 ± 3.9) years old (t = 0.01, P = 0.911), respectively. After adjusting age and other potential confounding factors, chemical substances' exposure of children/mother/father were all significantly higher in cases than that in controls (Children: OR = 3.90, 95% CI: 1.69-9.02; Mother: OR = 2.71, 95% CI: 1.12-6.52; Father: OR = 1.91, 95% CI: 1.05-3.47). For the 8 genes analyzed, the methylation status of DAPK and PTEN and P73 in case group were significantly higher than that in control group (cases: 3.1% (4 cases), 16.0% (21 cases), 7.6% (10 cases); controls: 0.7% (1 case), 2.9% (4 cases), 0.7% (1 case); χ²: 7.11, 16.90, 11.38; P value: 0.029, 0.000, 0.003). The methylation status of P16 in case group was significantly lower than that in control group (cases: 3.8% (5 cases); controls: 8.6% (12 cases), χ² = 10.33, P = 0.007). The interactions of children chemical substances' exposure and 3 genes' (PTEN, P16 and P73) methylation status were probably existed after adjusted for confounding factors (PTEN: RERI = -7.01, API = -2.14, S = 0.24; P16: RERI = 4.08, API = 0.53, S = 2.59; P73: RERI = 4.32, API = 0.48, S = 2.19), we also found the potential interaction between maternal chemical substances' exposure and PTEN, P16 gene methylation status (PTEN: RERI = -1.30, API = -0.38, S = 0.65; P16: RERI = 1.70, API = 0.38, S = 1.97). The study suggested the strong combined effects of chemical substances exposure of children and abnormal methylation status were risk factors of childhood AL, and there existed different interaction between them, which may indicate the important role in the pathogenesis process of childhood AL.