Preeclampsia (PE) is a hypertensive disorder that impacts 2–8% of pregnant women worldwide. It is characterized by new onset hypertension during the second half of gestation and is a leading cause of maternal and fetal morbidity/mortality. Maternal obesity increases the risk of PE and is a key predictor of childhood obesity and potentially offspring cardiometabolic complications in a sex‐dependent manner. The influence of the maternal obesogenic environment, with superimposed PE, on offspring development into adulthood is unknown. Obese BPH/5 mice spontaneously exhibit late‐gestational hypertension, fetal demise and growth restriction, and excessive gestational weight gain. BPH/5 females have improved pregnancy outcomes when maternal weight loss via pair‐feeding is imposed beginning at conception. We hypothesized that phenotypic differences between female and male BPH/5 offspring can be influenced by pair feeding BPH/5 dams during pregnancy. BPH/5 pair‐fed dams have improved litter sizes and increased fetal body weights. BPH/5 offspring born to ad libitum dams have similar sex ratios, body weights, and fecal microbiome as well as increased blood pressure that is reduced in the dam pair‐fed offspring. Both BPH/5 male and female offspring born to pair‐fed dams have a reduction in adiposity and an altered gut microbiome, while only female offspring born to pair‐fed dams have decreased circulating leptin and white adipose tissue inflammatory cytokines. These sexually dimorphic results suggest that reduction in the maternal obesogenic environment in early pregnancy may play a greater role in female BPH/5 sex‐dependent cardiometabolic outcomes than males. Reprograming females may mitigate the transgenerational progression of cardiometabolic disease.

Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy closely linked to obesity. Long-term adverse outcomes may occur in offspring from preeclamptic pregnancies. Accordingly, sex-specific changes in pubertal development have been described in children from preeclamptic women, but the underlying mechanisms remain vastly unexplored. Features of PE are spontaneously recapitulated by the blood pressure high subline 5 (BPH/5) mouse model, including obesity and dyslipidemia in females before and throughout pregnancy, superimposed hypertension from late gestation to parturition and fetal growth restriction. A sexually dimorphic cardiometabolic phenotype has been described in BPH/5 offspring: while females are hyperphagic, hyperleptinemic, and overweight, with increased reproductive white adipose tissue (rWAT), males have similar food intake, serum leptin concentration, body weight and rWAT mass as controls. Herein, pubertal development and adiposity were further investigated in BPH/5 progeny. Precocious onset of puberty occurs in BPH/5 females, but not in male offspring. When reaching adulthood, the obese BPH/5 females display hypoestrogenism and hyperandrogenism. Kisspeptins, a family of peptides closely linked to reproduction and metabolism, have been previously shown to induce lipolysis and inhibit adipogenesis. Interestingly, expression of kisspeptins (Kiss1) and their cognate receptor (Kiss1r) in the adipose tissue seem to be modulated by the sex steroid hormone milieu. To further understand the metabolic-reproductive crosstalk in the BPH/5 offspring, Kiss1/Kiss1r expression in male and female rWAT were investigated. Downregulation of Kiss1/Kiss1r occurs in BPH/5 females when compared to males. Interestingly, dietary weight loss attenuated circulating testosterone concentration and rWAT Kiss1 downregulation in BPH/5 females. Altogether, the studies demonstrate reproductive abnormalities in offspring gestated in a PE-like uterus, which appear to be closely associated to the sexually dimorphic metabolic phenotype of the BPH/5 mouse model.

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. It occurs in ~10% of pregnant women worldwide and the etiology is still unknown. Obesity increases the risk of developing PE by three-fold and has been associated with adverse fetal outcomes. Short chain fatty acids (SFCAs) are gut microbiome derived metabolites that fuel the host metabolism and have been found to be key mediators between dysbiosis and disease signaling through G protein coupled receptors (GPRs) that regulate appetite and glucose metabolism. We hypothesize that obese mice with a gut dysbiosis have perturbed GPR pathways and increased local inflammatory response. To better understand the relationship of maternal PE risk and outcomes, the obese hypertensive BPH/5 mouse model of superimposed PE was utilized. Previous research demonstrated that adult BPH/5 female mice have an adverse cardiometabolic phenotype: hyperphagia, hypertension, obesity with increased white adipose tissue (WAT), and dyslipidemia that is exaggerated by pregnancy. Fecal samples were collected from pregnant and non-pregnant BPH5 and C57 female controls for Illumina sequencing of 16S v4 rRNA amplicon libraries to examine the PE-like maternal fecal microbiome. SCFAs, GPR41, and IL-15 were measured in the colon of the pregnant dams. Microbial community composition of the pregnant BPH/5 compared to the lean normotensive C57 controls were significantly different using PERMANOVA with Bray-Curtis dissimilarity of 16S Amplicon Sequence Variant’s relative abundance (p<0.05, n=8-15). Alpha diversity was increased in pregnant BPH/5 dams compared to lean C57 dams (p<0.05, n=8-15). Significant differences were also found in the BPH5 model after the onset of pregnancy such as a decrease in Muribaculum spp., Muribaculaceae unclassified, Parabacteroides spp, and Lachnospiraceae_NK4A136 unclassified. SCFAs were not different between groups (p>0.05). BPH5 demonstrate an altered GPR41 pathway with decreased GPR 41 expression in the colon (p<0.05, n=5-9) and increased IL-15 to represent local colonic inflammation (p<0.05, n=3). In conclusion, the maternal fecal microbiome demonstrates microbial dysbiosis characterized by diversity changes in a model of PE and after the onset of pregnancy. The gut dysbiosis may be a key mechanism that affects GPR41 signaling, inflammation, and contributes to the BPH5 phenotype and poor pregnancy outcomes. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Preeclampsia (PE) is a hypertensive disorder of pregnancy and a leading cause of maternal and fetal mortality with maternal obesity as a risk factor. Decreasing white adipose tissue (WAT) via calorie restriction during the first half of pregnancy may alter the maternal-fetal environment to improve offspring outcomes. We hypothesized that pair-feeding BPH/5 dams during pregnancy will improve cardiometabolic risk and WAT pro-inflammatory cytokine expression in BPH/5 offspring in a sex-dependent manner. Previously, we showed that BPH/5 males, unlike females, have similar body weights, daily food intake, and circulating leptin levels as compared to age-matched control mice. Although, adult BPH/5 females and males have cardiomegaly and increased subcutaneous and peri-renal WAT mass compared to lean control mice. To investigate the prevention of maternal obesity on offspring outcomes, BPH/5 dams were pair-fed (PF) beginning at embryonic day (e)0.5 to C57 pregnant mice. Offspring cardiometabolic risk and WAT pro-inflammatory cytokine mRNA were measured using real time PCR in adult ad libitum fed offspring. Compared to controls, peri-renal WAT from BPH/5 males showed a 5-fold increase while females had a 15-fold increase in TNFa (n=3-6; p<0.05), 6-fold increase in PTGS-2 for males and 5-fold increase for females (n=3-6; p<0.05), and 3-fold increase in IL-6 for males and 1.25-fold increase for females (n=3-6; p<0.05) in subcutaneous WAT. Adult offspring born to PF BPH/5 dams had decreased expression in TNFa (male: 4-fold and female: 7-fold), PTGS-2 (male: 5-fold and female: 4-fold), and IL-6 (male: 10-fold; n=3-6; p<0.05). In conclusion, prevention of maternal obesity in BPH/5 dams attenuates cardiometabolic risks and reduces the pro-inflammatory WAT milieu in male and female offspring. The transgenerational effects during pregnancy is believed to be caused by an alteration in the maternal-fetal environment due to WAT pro-inflammatory adipokines. Future investigations are necessary to understand the differences observed in BPH/5 male versus female mice into adulthood as well as the transgenerational impact of attenuated maternal obesity in pregnancy.