(2015) Offspring DNA methylation of the arylhydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight, Epigenetics, 10:10, 913-921, DOI: 10.1080/15592294.2015 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 D 0.0009) and negatively associated with the length of gestation (P < 0.0001) and birth weight-forgestational 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.

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E 2 (PGE 2 ), which elicits antiproliferative effects mediated through the E prostanoid (EP) 2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE 2 and a selective EP 2 agonist (P , 0.0001 at 1 mM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP 2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P , 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP 2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP 4 , and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP 2 promoter correlated strongly with baseline EP 2 mRNA (r = 0.80; P , 0.01). These studies suggest that the EP 2 promotor is under epigenetic control, and one explanation for PGE 2 resistance in AERD is an epigenetically mediated reduction of EP 2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Aim:To investigate childhood abuse victimization in relation to adult DNA methylation levels in a novel region of NR3C1, with emotional support as a possible modifier. Materials & methods: 295 participants from the Black Women's Health Study. Multivariable linear regression models were used to compute differences in mean percent methylation levels. Results: Women reporting childhood abuse victimization exhibited higher mean NR3C1 methylation levels than nonabused women, with a clear dose-response relationship. Childhood emotional support appeared to attenuate associations only among women with the highest levels of physical and sexual abuse. Conclusion: NR3C1 mean methylation was higher among women who reported childhood abuse. Further research is warranted to clarify whether or the extent to which childhood emotional support buffers the association.