Phthalate Exposures, DNA Methylation and Adiposity in Mexican Children Through Adolescence

Abstract

Phthalates are a class of endocrine disrupting chemicals with near ubiquitous exposure to populations around the world. Phthalates have been associated with children's adiposity in previous studies, though discrepancies exist across studies that may be due to timing of exposure or outcome assessment and population differences (i.e., genetics, other confounders). DNA methylation, an epigenetic modification involved in gene regulation, may mediate the effects of early life phthalate exposures on health outcomes. This study aims to evaluate the mediating effect of DNA methylation at growth-related genes on the association between phthalate exposure and repeat measures of adiposity (BMI-for-age z-score, waist circumference, and skinfolds thickness) in Mexican children. Urinary phthalate metabolite concentrations were quantified in mothers at each of the three trimesters of pregnancy and in children at the first peri-adolescent study visit. Blood leukocyte DNA methylation at H19 and HSD11B2 was quantified during the first peri-adolescent visit, and adiposity was measured at the first visit and again ~3 years later among participants ( n = 109 boys, 114 girls) from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) project. Associations between phthalates or DNA methylation and repeat outcome measures were assessed separately in boys and girls using generalized estimating equation models including covariates (urinary specific gravity, maternal education, and child's age). Sobel tests were used to assess DNA methylation as a mediator in models adjusting for the same covariates. Associations between phthalates and adiposity varied by phthalate and timing of exposure. Early gestation MBP, MIBP, and MBzP were associated with adiposity among girls. For example, among girls first trimester maternal urine concentrations of MIBP were associated with increases in skinfold thickness, BMI-for-age, and waist circumference ( p < 0.01). Second trimester and adolescent MBzP were associated with adiposity among boys in opposite directions. In girls, H19 methylation was positively associated with skinfold thickness. No significant mediation of phthalate exposure on adiposity by DNA methylation of H19 or HSD11B2 was observed (Sobel p > 0.05). However, the mediation analysis was underpowered to detect small to medium effect sizes, and the role of DNA methylation as a mediator between phthalates and outcomes merits further study.

Integrative Analysis of Gene-Specific DNA Methylation and Untargeted Metabolomics Data from the ELEMENT Cohort

“…Examined separately, lower levels of dicarboxylic fatty acids have been previously associated with obesity in children 5,9 and H19 methylation is positively associated with adiposity including among 17-year old children. 34,35 Our findings suggest DNA methylation and subsequently expression of H19 may influence the formation of dicarboxylic fatty acids and development of adiposity and metabolic risk, especially among children who have initiated puberty. The biological pathway by which H19 may affect fatty acid oxidation is currently unknown and an area of interest for future research.…”

“…33,57 There is evidence that epigenetic alteration at these DMRs from the early life environment is persistent-even into late adulthood 58 -and contributes to adverse health outcomes including low birth weight, adolescent adiposity, and adiposity in post-menopausal women. [34][35][36]57 While epigenetic regulation of IGF2 and H19 seem to play a role in obesity and metabolic conditions later in life, how or whether this starts to develop in childhood or adolescence is unknown. Examined separately, lower levels of dicarboxylic fatty acids have been previously associated with obesity in children 5,9 and H19 methylation is positively associated with adiposity including among 17-year old children.…”

“…These genes and the LINE-1 biomarker were selected due to evidence for environmental-lability by various exposures in early development 15,[31][32][33] and for evidence of associations with adiposity-related outcomes in childhood or beyond. [34][35][36] Percent DNA methylation was quantified via the pyrosequencing platform 37 using assays previously developed by us for LINE-1 38 and HSD11B2 15 and by others for H19. 33 Details on each region are included in Supplemental Table S1.…”

Phthalate Exposure and Long-Term Epigenomic Consequences: A Review

“…H19 methylation was positively associated with skinfold thickness in girls. There were sex-specific differences in exposure outcomes-among boys, adiposity was inversely associated with second trimester and adolescent MBzP (Bowman et al, 2019).…”

“…In a longitudinal study involving 250 Mexican American children, the relationship between perinatal exposure to phthalates and adiposity during the peri-adolescence (between ages 8 and 14 years) was evaluated (Bowman et al, 2019). Among girls, adiposity was associated with exposure to MBP, MiBP, and MBzP.…”