Abstract 069: Methylation Of The Androgen Receptor In White Adipose Tissue Contributes To Female Obesity And Hypertension In BPH/5, A Model Of Superimposed Preeclampsia

Abstract

Preeclampsia (PE) is a hypertensive disorder of pregnancy that occurs in 10% of women with obesity. The effects of PE on offspring are chronic with increased incidence of cardiometabolic disease into adulthood. We hypothesize that a maternal obesogenic environment plays a role in pregnancy outcomes and offspring cardiometabolic disease in a sex-dependent manner through epigenetic modifications on the X chromosome. To test our hypothesis, we used the obese BPH/5 female mouse that spontaneously exhibits late-gestational hypertension, fetal growth restriction, and excessive gestational weight gain. BPH/5 offspring have sexually dimorphic cardiometabolic phenotypes with females being hyperphagic, obese, and hypertensive, while males are only hypertensive. BPH/5 dams were pair-fed (PF) to C57 control dams beginning at conception. Male and female BPH/5 offspring were fed an ad libitum (lib) diet until analyses. Whole genome bisulfite sequencing was performed to reveal differentially methylated regions between BPH/5 male and female genomic DNA. BPH/5 PF dams had attenuation of late gestational hypertension. BPH/5 offspring had improved fetal growth and significantly reduced adult female BPH/5 obesity, 14.7% BW and visceral white adipose tissue (WAT) from 1366 to 229.7 mg (n=7-32, p<0.05). Despite detectable levels of serum testosterone (2.04±0.6ng/dL, n=16), serum estrogen in BPH/5 adult females during proestrus is significantly lower than controls (3.3±1 v. 7.3±0.5 pg/mL, n=6, p<0.05). This is associated with hypermethylation of the androgen receptor on the X chromosome in adult BPH/5 females. Because androgen response elements are in the promoter region of the thermogenic marker, uncoupled protein 1 (Ucp1), an interaction has been proposed between sex steroid hormones and WAT energy homeostasis. Ucp1 mRNA expression is significantly increased in PF adult BPH/5 female mice compared to ad lib (n=3, p<0.05). Reduction in the maternal obesogenic environment may play a role in BPH/5 sex-dependent offspring differences via epigenetic modifications of the X chromosome. Future studies are needed to understand the transgenerational methylation of cardiometabolic genes in PE offspring to prevent the lifecycle of disease associated with obesity.