Genotypic analysis of the female BPH/5 mouse, a model of superimposed preeclampsia

Abstract

Animal models that recapitulate human diseases and disorders are widely used to investigate etiology, diagnosis, and treatment of those conditions in people. Disorders during pregnancy are particularly difficult to explore as interventions in pregnant women are not easily performed. Therefore, models that allow for pre-conception investigations are advantageous for elucidating the mechanisms involved in adverse pregnancy outcomes that are responsible for both maternal and fetal morbidity, such as preeclampsia. The Blood Pressure High (BPH)/5 mouse model has been used extensively to study the pathogenesis of preeclampsia. The female BPH/5 mouse is obese with increased adiposity and borderline hypertension, both of which are exacerbated with pregnancy making it a model of superimposed preeclampsia. Thus, the BPH/5 model shares traits with a large majority of women with pre-existing conditions that predisposes them to preeclampsia. We sought to explore the genome of the BPH/5 female mouse and determine the genetic underpinnings that may contribute to preeclampsia-associated phenotypes in this model. Using a whole genome sequencing approach, we are the first to characterize the genetic mutations in BPH/5 female mice that make it unique from the closely related BPH/2 model and the normotensive background strain, C57Bl/6. We found the BPH/5 female mouse to be uniquely different from BPH/2 and C57Bl/6 mice with a genetically complex landscape. The majority of non-synonymous consequences within the coding region of BPH/5 females were missense mutations found most abundant on chromosome X when comparing BPH/5 and BPH/2, and on chromosome 8 when comparing BPH/5 to C57Bl/6. Genetic mutations in BPH/5 females largely belong to immune system-related processes, with overlap between BPH/5 and BPH/2 models. Further studies examining each gene mutation during pregnancy are warranted to determine key contributors to the BPH/5 preeclamptic-like phenotype and to identify genetic similarities to women that develop preeclampsia.

Sex‐specific effects of maternal weight loss on offspring cardiometabolic outcomes in the obese preeclamptic‐like mouse model, BPH/5

“…Furthermore, little is known regarding the genetics and epigenetics in BPH/5 mice. A recent genome wide study in BPH/5 females (Sones et al, 2021) revealed several genetic mutations shared between BPH/2 and BPH/5 that could contribute to the hypertensive phenotype, but functional studies are lacking. Finally, epigenetic modifications may exist on the X chromosome that may contribute to sex differences in BPH/5.…”

Alternative pathway activation in pregnancy, a measured amount “complements” a successful pregnancy, too much results in adverse events

“…Interestingly, males are not obese and do not mirror the cardiometabolic phenotype of their female counterparts. 136 Following blastocyte implantation, and prior to decidualization and | 13 SMITH-JACKSON and placentation, BPH/5 mice have reduced macrophage but increased T lymphocyte infiltration within the maternal decidua, and reduced IL-10 levels, indicating an aberrant maternal immune response. 139 At 7.5 dpc complement gene upregulation (C3 and CFB) in BPH/5 mice corresponds to peak decidualization.…”

“…Complement activity is increased with obesity, positively correlating with BMI and decreasing with weight loss 84 . In mice, an increase in C3 is found in the adipose tissue before and during pregnancy as well as at the maternal fetal interface; this is reduced following calorie restriction, implying that dietary intervention could influence the propensity of immune dysregulation during pregnancy 84,136 . C3aR is highly expressed in adipose tissue and, in mice, with increased expression when they are placed onto a high fat diet 137 .…”

“…The female BPH/5 is obese with borderline hypertension but an absence of renal disease. Pregnancy exacerbates the model, female mice developing a superimposed pre‐eclampsia 136 . Adult females also show hyperphagia and hyperleptinaemia with signs of leptin (an appetite‐suppressing hormone) resistance.…”

The anti-inflammatory properties of the methanolic extract of Cucumis melo Linn. against prostate enlargement in Wistar rats

“…When the prostate is enlarged, the urethra may be compressed, resulting in a slight to severe obstruction of urine flow ( Dmochowski, 2005 , Calogero et al, 2019 ). Although the cause of this disease is unknown, obesity and lack of exercise predispose the condition ( Sones et al, 2021 , Cunto et al, 2019 ). In severe cases, there will be pain or burning when urinating and loss of control of the bladder, and sometimes hematuria ( Neuzillet et al, 2017 ).…”