Phenotypic Differences Exist between BPH/5 Offspring in a Sex‐Dependent Manner
Authors: Beckers Kalie F. , Gomes Viviane , Reijnders Dorien , Robillard Katherine , Liu Chin-Chi , Sones Jenny Liford 
Published: April 2020

The maternal obesogenic environment is known to play a role in offspring development and metabolism in a sex‐dependent manner. The impact of gestating in obese mothers, with superimposed preeclampsia (PE), on male and female development into adulthood is not completely understood. To investigate this, we utilized the obese BPH/5 female mouse which spontaneously develops hypertension in late gestation, fetal demise, and fetal growth restriction (FGR) while showing excessive gestational weight gain early in pregnancy. We have previously shown that calorie restricted pregnant BPH/5 females have reduction in adiposity and improved outcomes when pair‐feeding is imposed beginning at the time of conception, embryonic day (e) 0.5, including attenuation of inflammatory cytokines at the maternal‐fetal interface and in maternal circulation. We hypothesized that phenotypic differences exist between female and male BPH/5 offspring and that pair‐feeding BPH/5 dams during pregnancy would alter this.To test our hypothesis, we first phenotyped age‐matched juvenile and adult BPH/5 and control C57 mice that gestated in ad libitum fed dams. While adult BPH/5 females are obese compared to C57 female mice, adult BPH/5 males have decreased body weight compared to C57 male mice (n=20, p<0.005). Visceral adipose tissue depots (peri‐renal and peri‐gonadal) in BPH/5 adult females are increased as opposed to BPH/5 males that only show a significant increase in the peri‐renal depot versus controls (3‐fold; n=3, p<0.01). As expected in this genetically hypertensive mouse strain, both female and male BPH/5 adult mice have cardiomegaly compared to controls (6.7±0.3 vs 5.8±0.2 and 8±0.2 vs 5±0.5 heart:body weight ratio, respectively; n=3–13, p<0.05). Interestingly, BPH/5 adult females exhibit hepatomegaly as compared to C57 adult females (25% increase; n=3–9, p<0.05) and BPH/5 adult males do not (n=3, p>0.05).Next, we tested the influence of reducing the maternal obesogenic environment on sex‐dependent pregnancy outcomes in BPH/5. In polygynous litter bearing species, increased numbers of male offspring is advantageous for survival. Therefore, control C57 litters have significantly more male mice (60±5%) than female mice (40±5%) within a litter that survive to weaning age (n=29, p<0.005). BPH/5 show no difference in offspring sex ratios (n=71, p>0.05) and pair‐feeding BPH/5 dams beginning at e0.5 did not change the sex ratios in BPH/5 litters (n=6, p>0.05) nor the body weight in BPH/5 male and female offspring at 2 weeks of age (n=3–17, p>0.05). Pair‐feeding BPH/5 females beginning two weeks before pregnancy and throughout increased live birth weight and litter sizes compared to BPH/5 ad libitum fed pregnancies (n=5; p<0.05). This improvement in fetal demise and FGR was not shown when pair‐feeding began at e0.5 (n=6; p>0.05).Therefore, we believe that pre‐conception reduction in the maternal obesogenic environment may play a greater role in BPH/5 sex‐dependent pregnancy outcomes. Future investigations are necessary to understand the phenotypic differences observed in BPH/5 male versus female mice into adulthood as well as the transgenerational impact of attenuated maternal obesity in pregnancy.