Placental cell type deconvolution reveals that cell proportions drive preeclampsia gene expression differences.

The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue (n = 9 biological replicates) at term (n = 40,494 cells).

Developmental programming: Adipose depot-specific regulation of non-coding RNAs and their relation to coding RNA expression in prenatal testosterone and prenatal bisphenol-A -treated female sheep.

Inappropriate developmental exposure to steroids is linked to metabolic disorders. Prenatal testosterone excess or bisphenol A (BPA, an environmental estrogen mimic) leads to insulin resistance and adipocyte disruptions in female lambs. Adipocytes are key regulators of insulin sensitivity.

Developmental programming: Impact of prenatal bisphenol-A exposure on liver and muscle transcriptome of female sheep.

Gestational Bisphenol A (BPA) exposure leads to peripheral insulin resistance, and hepatic and skeletal muscle oxidative stress and lipotoxicity during adulthood in the female sheep offspring. To investigate transcriptional changes underlying the metabolic outcomes, coding and non-coding (nc) RNA in liver and muscle from 21-month-old control and prenatal BPA-treated (0.5 mg/kg/day from days 30 to 90 of gestation; Term: 147 days) female sheep were sequenced.

Developmental Programming: Prenatal Testosterone Excess on Liver and Muscle Coding and Noncoding RNA in Female Sheep.

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance, ectopic lipid accumulation, and insulin signaling disruption in liver and muscle. This study investigated transcriptional changes and transcriptome signature of prenatal T excess-induced hepatic and muscle-specific metabolic disruptions. Genome-wide coding and noncoding (nc) RNA expression in liver and muscle from 21-month-old prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30-90 of gestation; term: 147 days) and control females were compared.

Impact of gestational exposure to endocrine disrupting chemicals on pregnancy and birth outcomes.

With the advent of industrialization, humans are exposed to a wide range of environmental chemicals, many with endocrine disrupting potential. As successful maintenance of pregnancy and fetal development are under tight hormonal control, the gestational exposure to environmental endocrine disrupting chemicals (EDC) have the potential to adversely affect the maternal milieu and support to the fetus, fetal developmental trajectory and birth outcomes. This chapter summarizes the impact of exposure to EDCs both individually and as mixtures during pregnancy, the immediate and long-term consequences of such exposures on the mother and fetus, the direct and indirect mechanisms through which they elicit their effects, factors that modify their action, and the research directions to focus future investigations.

Neurotensin: a neuropeptide induced by hCG in the human and rat ovary during the periovulatory period†.

Neurotensin (NTS) is a tridecapeptide that was first characterized as a neurotransmitter in neuronal cells. The present study examined ovarian NTS expression across the periovulatory period in the human and the rat. Women were recruited into this study and monitored by transvaginal ultrasound.

Developmental programming: Metabolic tissue-specific changes in endoplasmic reticulum stress, mitochondrial oxidative and telomere length status induced by prenatal testosterone excess in the female sheep.

Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver/muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial number, function, and oxidative phosphorylation (OxPhos), ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age.

Praegnatio Perturbatio-Impact of Endocrine-Disrupting Chemicals.

The burden of adverse pregnancy outcomes such as preterm birth and low birth weight is considerable across the world. Several risk factors for adverse pregnancy outcomes have been identified. One risk factor for adverse pregnancy outcomes receiving considerable attention in recent years is gestational exposure to endocrine-disrupting chemicals (EDCs).

Developmental programming: Adipose depot-specific transcriptional regulation by prenatal testosterone excess in a sheep model of PCOS.

Prenatal testosterone (T)-treated female sheep manifest adipose depot-specific disruptions in inflammatory/oxidative state, adipocyte differentiation and thermogenic adipocyte distribution. The objective of this study was to identify common and divergent gene pathways underlying prenatal T excess-induced adipose depot-specific disruptions. RNA sequencing and network analyses were undertaken with visceral (VAT), subcutaneous (SAT), epicardiac (ECAT) and perirenal (PRAT) adipose tissues from control and prenatal T-treated (100 mg T propionate twice a week from days 30-90 of gestation) female sheep at 21 months of age.

Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight.

Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads.

Developmental programming: Prenatal testosterone excess disrupts pancreatic islet developmental trajectory in female sheep.

Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30-90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age.

Developmental programming: Prenatal testosterone-induced changes in epigenetic modulators and gene expression in metabolic tissues of female sheep.

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance and tissue-specific changes in insulin sensitivity with liver and muscle manifesting insulin resistance accompanied by inflammatory, oxidative and lipotoxic state. In contrast, visceral (VAT) and subcutaneous (SAT) adipose tissues are insulin sensitive in spite of VAT manifesting changes in inflammatory and oxidative state. We hypothesized that prenatal T-induced changes in tissue-specific insulin resistance arise from disrupted lipid storage and metabolism gene expression driven by changes in DNA and histone modifying enzymes.

Developmental Programming: Sheep Granulosa and Theca Cell-Specific Transcriptional Regulation by Prenatal Testosterone.

Prenatal testosterone (T)-treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T-treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep.

Developmental programming: Transcriptional regulation of visceral and subcutaneous adipose by prenatal bisphenol-A in female sheep.

Background: Bisphenol-A (BPA) exposure is widespread and early life exposure is associated with metabolic syndrome. While visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are implicated in the development of metabolic syndrome, the adipose depot-specific effects of prenatal BPA treatment are poorly understood.

Objective: To determine the impact of prenatal BPA exposure on genome-wide gene expression of VAT and SAT depots.

Developmental programming of insulin resistance: are androgens the culprits?

Insulin resistance is a common feature of many metabolic disorders. The dramatic rise in the incidence of insulin resistance over the past decade has enhanced focus on its developmental origins. Since various developmental insults ranging from maternal disease, stress, over/undernutrition, and exposure to environmental chemicals can all program the development of insulin resistance, common mechanisms may be involved.

Developmental Programming: Prenatal Testosterone Excess on Ovarian SF1/DAX1/FOXO3.

Prenatal testosterone (T) excess, partly via androgenic programming, enhances follicular recruitment/persistence in sheep as in women with polycystic ovarian syndrome (PCOS). Decreased anti-Mullerian hormone (AMH) in early growing and increased AMH in antral follicles may underlie enhanced recruitment and persistence, respectively. Changes in AMH may be mediated by steroidogenic factor 1 (SF1), an enhancer of AMH, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), that antagonizes SF1.

Developmental programming: Adipose depot-specific changes and thermogenic adipocyte distribution in the female sheep.

Prenatal testosterone (T)-treated female sheep exhibit an enhanced inflammatory and oxidative stress state in the visceral adipose tissue (VAT) but not in the subcutaneous (SAT), while surprisingly maintaining insulin sensitivity in both depots. In adult sheep, adipose tissue is predominantly composed of white adipocytes which favor lipid storage. Brown/beige adipocytes that make up the brown adipose tissue (BAT) favor lipid utilization due to thermogenic uncoupled protein 1 expression and are interspersed amidst white adipocytes, more so in epicardiac (ECAT) and perirenal (PRAT) depots.

Developmental programming: Prenatal bisphenol A treatment disrupts mediators of placental function in sheep.

Gestational Bisphenol A (BPA) exposure is associated with low birth weight. We hypothesized that the low birth weight is the consequence of reduced placental efficiency and a function of BPA-induced inflammatory, oxidative, lipotoxic, angiogenic, steroidal and fibrotic changes involving epigenetic alterations. Placentomes were collected during early (day 65) and mid (day 90) gestation (term ∼147 days) from control and BPA (gestational day 30-90)-treated pregnant sheep.