Biology subjects

Jazwiec, P. A.

Publications and source records attributed to Jazwiec, P. A..

6 recordsLinked to original sources

bioRxiv2025

Obesogenic diet alters decidual differentiation and cell-cell communication in the mouse uterus

Maternal obesity is associated with increased risk of infertility, implantation failure, miscarriage, and other pregnancy complications. While prior studies have linked obesity to uterine dysfunction and impaired endometrial biology, how obesity alters the cellular and molecular landscape of the early pregnant endometrium remains poorly understood. Here, we perform single-cell RNA sequencing of embryonic day 5.5 uterus from control and obesogenic mice to generate a cellular atlas of the early decidualizing endometrium. We identify obesity-associated transcriptional changes across multiple Endometrial Stromal Cell (ESC) states and innate immune populations, including uterine natural killer cells and macrophages. Computational modeling reveals that maternal obesity disrupts distinct routes of ESC differentiation during decidualization and leads to shifts in ESC-derived cues known to impact innate immune responses. These findings provide a comprehensive single-cell resource of the post-implantation mouse endometrium while simultaneously generating critical insight into how maternal obesity reprograms the maternal-fetal interface in early pregnancy.

developmental biology↗

bioRxiv2024

Maternal high-fat, high-sucrose diet-induced excess adiposity is linked to placental hypoxia and disruption of fetoplacental immune homeostasis in late gestation

Maternal excess adiposity (i.e., overweight and obesity) at conception is linked to numerous signs of malperfusion and inflammatory injury in the placenta. Previous reports have suggested that obesity-associated placental malperfusion may trigger a state of fetoplacental hypoxia, contributing to adverse health outcomes within and beyond the perinatal period. However, many previous studies have relied on indirect measures of tissue oxygen saturation, including readouts influenced by external inflammatory stressors. Direct comparisons of tissue oxygen saturation at the uteroplacental interface in pregnancies complicated by excess adiposity are lacking. Here, we used a mouse model of chronic preconception high-fat, high-sucrose (HFHS) diet feeding to model the impacts of an obesogenic milieu on placental oxygenation near term gestation (E17.5). We found that both placental junctional and labyrinth zone tissues were relatively hypoxic in HFHS pregnancies compared to chow-fed controls (CON). However, this was not associated with enhanced HIF-1 expression in labyrinth tissues. Similarly, placentas from CON and HFHS dams did not exhibit gross differences in morphology or vessel density and pericyte coverage. However, HFHS placentas have a greater burden of histopathological lesions, including tissue calcification and fibrinoid deposition within the labyrinth zone. Calcified placental tissue coincided with the destruction of vasculosyncytial membranes and macrophage-dense foci, alongside altered expression of immunomodulatory and chemotactic cytokines within the labyrinth zone proteome, which differed in magnitude with fetal sex. While fetal growth was not markedly affected, fetuses from HFHS pregnancies exhibited higher levels of circulating IL-6, prolactin, CXCL1, and CCL2. Collectively, these data confirm that diet-induced maternal excess adiposity leads to a relative state of placental hypoxia, even in the absence of marked growth restriction or fetal demise. While this hypoxic state is not linked to gross morphological abnormalities, it is associated with a greater histopathological burden indicative of local malperfusion and inflammation, and an altered fetal inflammatory and endocrine milieu in late gestation. These findings provide new insight into mechanisms by which an obesogenic environment during pregnancy compromises placental function and contributes to the long-term programming of chronic disease susceptibility.

developmental biology↗

bioRxiv2024

Maternal obesogenic diet disrupts mid-gestation decidual immune and vascular homeostasis without impairing spiral artery remodelling

Excess maternal adiposity (i.e., overweight and obesity) during pregnancy has been linked to impaired uteroplacental perfusion, compromised placental development, and a higher risk of adverse pregnancy outcomes. Owing to the nature of chronic inflammation and immune dysregulation accompanying excess adiposity, disruption of leukocyte-mediated tissue remodelling and immunoregulation within the decidua have emerged as likely drivers contributing to suboptimal placental function in pregnancies impacted by maternal overweight or obesity. However, the impacts of excess adiposity on major populations of innate lymphoid cells (ILCs) and macrophages which orchestrate these processes and the environment that these cells occupy remain vastly understudied. Here, we used a mouse model of chronic high-fat, high-sucrose (HFHS) diet-feeding to characterize the impacts of an obesogenic milieu on decidual immune dynamics during placental development at mid-gestation (E10.5). HFHS pregnancies exhibited marked increases in total decidual leukocyte abundance, driven by population-level increases in tissue-resident and conventional NK cells, and MHC-II+ macrophages. This was not associated with abnormalities in implantation site morphology or decidual spiral artery remodelling but was coincident with histological patterns of local inflammation. In line with this, expression of canonical proinflammatory cytokines and chemokines were moderately upregulated in bulk decidual tissue of HFHS dams. This was accompanied by more potent elevations in multiple mediators of angiogenesis, endothelial activation, and coagulation in HFHS decidual tissue. Collectively, these findings point towards pathological vascular inflammation and possibly dysregulated decidual angiogenesis in the first half of pregnancy as factors predisposing to reduced placental efficiency, malperfusion, and inflammation seen in pregnancies affected by maternal overweight and obesity.

developmental biology↗

bioRxiv2022

Paternal obesity alters the sperm epigenome and is associated with changes in the placental transcriptome and cellular composition

Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally driven gene expression in placenta function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm epigenetic signatures, the placenta transcriptome and cellular composition. C57BL6/J males were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 enrichment at imprinted genes, and at promoters of genes involved in metabolism and development. Notably, sperm altered H3K4me3 was localized at placental enhancers and genes implicated in placental development and function. Bulk RNA-sequencing on placentas detected paternal obesity-induced sex-specific changes in gene expression associated with hypoxic processes such as angiogenesis, nutrient transport and imprinted genes. Paternal obesity was also linked to placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity-effects on placenta development and function as one mechanism underlying offspring metabolic disease. Summary sentencePaternal obesity impacts the sperm epigenome at genes implicated in placenta development and is associated with an altered placenta transcriptome and trophoblast cell lineage specification.

developmental biology↗

bioRxiv2022

Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse

It is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. In this study, we investigated the impacts of pregnancy and adiposity on maternal intestinal epithelium morphology, in vivo intestinal permeability, and peripheral blood immunophenotype, using control (CTL) and high-fat (HF) fed non-pregnant female mice and pregnant mice at mid-(embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF-fed mice had reduced small intestine length, ileum crypt depth and villus length. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid-versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid but not late-gestation. The impaired maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity.

developmental biology↗

bioRxiv2021

Paternal obesity results in placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolic function

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether paternal obesity-induced offspring metabolic dysfunction is associated with placental endoplasmic reticulum (ER) stress and impaired vascular development. We determined whether offspring glucose intolerance is fueled by ER stress-mediated changes in fetal hepatic development. Furthermore, we also determined whether paternal obesity may indirectly affect in utero development by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow diet (CON; 17% kcal fat) or high fat diet (PHF; 60% kcal fat) for 8-10 weeks were time-mated with control female mice to generate pregnancies and offspring. Glucose tolerance in pregnant females was evaluated at mid-gestation (embryonic day (E) 14.5) and term gestation (E18.5). At E14.5 and E18.5, fetal liver and placentae were collected, and markers of hypoxia, angiogenesis, endocrine function, and macronutrient transport, and unfolded protein response (UPR) regulators were evaluated to assess ER stress. Young adult offspring glucose tolerance and metabolic parameters were assessed at [~]60 days of age. Paternal obesity did not alter maternal glucose tolerance or placental lactogen in pregnancy but did induce placental hypoxia, ER stress, and altered placental angiogenesis. This effect was most pronounced in placentae associated with female fetuses. Consistent with this, paternal obesity also activated the ATF6 and PERK branches of the UPR in fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Adult offspring of obese fathers showed glucose intolerance and impaired whole-body energy metabolism, particularly in female offspring. Thus, paternal obesity programs sex-specific adverse placental structural and functional adaptations and alters fetal hepatic development via ER stress-induced pathways. These changes likely underpin metabolic deficits in adult offspring. Summary SentencePaternal obesity alters placental vascular structures and is associated with sex-specific compromises in glucose tolerance and metabolism in young offspring

physiology↗