Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight

Abstract

Prenatal smoke exposure, maternal obesity, aberrant fetal growth, and preterm birth are all risk factors for offspring metabolic syndrome. Cord blood aryl-hydrocarbon receptor repressor (AHRR) DNA methylation is responsive to maternal smoking during pregnancy. AHRR serves not only to inhibit aryl-hydrocarbon receptor (AHR) transcription, which is involved in mediating xenobiotic metabolism, but it is also involved in cell growth and differentiation. Other than maternal smoking, other predictors of offspring AHRR DNA methylation status remain unknown; we sought to identify them among newborns. We enrolled pregnant women in the PROGRESS birth cohort in Mexico City. Using pyrosequencing, we analyzed DNA methylation of 3 CpG sites within the AHRR gene promoter from the umbilical cord blood of 531 infants. We used generalized estimating equations to account for the correlation of DNA methylation between CpG sites. Multivariable models were used to adjust for maternal age, BMI, education, parity, smoke-exposure, infant sex, gestational age, and birth weight-for-gestational age. AHRR DNA methylation was positively associated with maternal BMI (P = 0.0009) and negatively associated with the length of gestation (P < 0.0001) and birth weight-for-gestational age (P < 0.0001). AHRR DNA methylation was 2.1% higher in offspring of obese vs. normal weight mothers and 3.1% higher in preterm vs. term infants, representing a third and a half standard deviation differences in methylation, respectively. In conclusion, offspring AHRR DNA methylation was associated with maternal obesity during pregnancy as well as infant gestational age and birth weight-for-gestational age. Further work to discover the health impacts of altered AHRR DNA methylation is warranted.

Keywords: AHRR; BMI; DNA methylation; aryl-hydrocarbon receptor repressor; epigenetics; pregnancy; preterm birth.

Figures

Figure 1.

Aryl-hydrocarbon receptor repressor (AHRR) DNA methylation (%5-methylcytocines) at 3 CpG sites in cord blood DNA and their correlations, PROGRESS birth cohort, Mexico City, n = 512.

Figure 2.

Aryl-hydrocarbon receptor repressor (AHRR) DNA methylation (%5-methylcytocine) and (A) maternal BMI; (B) infant gestational age; and (C) birth weight-for gestational age, PROGRESS birth cohort, Mexico City, n = 512.

Figure 3.

Distributions of aryl-hydrocarbon receptor repressor (AHRR) CpG 1 DNA methylation (%5-methylcytocines) among categories of (A) maternal BMI; (B) full-term vs. preterm births; and (C) birth weight-for-gestational age, PROGRESS birth cohort, Mexico City, n = 512. SGA, small-for-gestational age; AGA, appropriate-for-gestational age; LGA, large-for-gestational age.