Developmental Programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep.

Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health.

Persistence of Cardiac Malprogramming in Late Gestational Fetal Sheep by Early to Mid-Gestational Testosterone Excess.

Excess testosterone (T) exposure from early to mid-gestation (days 30-90) leads to sexually dimorphic adverse cardiac left ventricular (LV) programming at fetal day 90 (term 147 days). Whether this sexually dimorphic impact is a direct effect of T or reprogramming that persists beyond early fetal life is unknown. We hypothesized that adverse sex-specific cardiac outcomes seen in early fetal life will persist in late gestational fetuses.

Functional Integration of Different-Sex Gonad Transplants into the Adult Mouse Hypothalamic Pituitary Gonadal Axis.

Gender-affirming hormone therapy (GAHT) relies on exogenous hormones to produce hormonal milieus that achieve and/or maintain embodiment goals. Another potential route to these endpoints is transplantation of novel steroidogenic tissue. To develop a pre-clinical model, we asked whether different-sex gonad transplants can be functionally integrated into the adult mouse hypothalamic-pituitary-gonadal (HPG) axis.

POLYCYSTIC OVARY SYNDROME: ORIGINS AND IMPLICATIONS: Gestational anti-Müllerian hormone and testosterone excess combined with maternal adiposity program for polycystic ovary syndrome.

In Brief: A 'two hit' developmental origin involving testosterone and anti-Müllerian hormone is proposed to initiate PCOS pathogenesis during gestation. Epigenetic mechanisms amplify genetically heritable traits, while accompanying metabolic perturbations, including gestational hyperglycemia, hypertension and maternal obesity, exaggerate PCOS expression.

Abstract: Pre- or perinatal excess of anti-Müllerian hormone (AMH) or testosterone faithfully reproduce many polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in animal models.

Sexually dimorphic impact of prenatal hyperandrogenism on offspring growth trajectory in sheep.

In a translationally relevant ovine model of gestational hyperandrogenism we have previously reported cardiometabolic disruption in female offspring (males were not extensively studied). We hypothesized that gestational hyperandrogenism would lead to sex-specific disruption in offspring's growth, cytokine and metabolic milieu, potential mediators of cardiometabolic disease (CMD). 100 mg Testosterone propionate (T) or vehicle (C) was administered intramuscularly twice weekly between gestational days (GD) 30-90.

Prenatal per- and polyfluoroalkyl substance exposures and DNA methylation among newborns in the Environmental influences on Child Health Outcomes program.

Gestation is a vulnerable window when exposure to per- and polyfluoroalkyl substances (PFAS) may impact child development and health. Epigenetic modification, including DNA methylation (DNAm), may be one mechanism linking prenatal PFAS exposure to offspring outcomes. We tested associations between prenatal PFAS and newborn DNAm in 1017 participants from 6 cohorts in the US Environmental influences on Child Health Outcomes consortium.

Exploratory analysis of differences at the transcriptional interface between the maternal and fetal compartments of the sheep placenta and potential influence of fetal sex.

An understanding of the inner workings of the placenta is imperative to elucidate how the maternal and fetal compartments coordinate to mediate fetal development. The two compartments can be separated and studied before term in sheep, a feat not possible in humans, thus providing a valuable translational model. This study investigated differential expression of gene signaling networks in the maternal and fetal compartments of the placenta and explored the potential influence of fetal sex.

Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts.

Background: Phthalate exposure during pregnancy has been associated with preterm birth, but mechanisms of action may depend on the timing of exposure.

Objective: Investigate critical periods of susceptibility during pregnancy for associations between urinary phthalate metabolite concentrations and preterm birth.

Methods: Individual-level data were pooled from 16 US cohorts (N = 6045, n = 539 preterm births).

Developmental programming: mechanisms of early exposure to real-life chemicals in biosolids on offspring ovarian dynamics†.

Female reproductive capacity is shaped by ovarian reserve and patterns of follicle development. Ovarian reserve depletion occurs by follicle activation and atresia, which are affected by environmental chemicals (ECs). Because humans are simultaneously exposed to hundreds of ECs, real-life exposure models are essential to assess patterns of atresia after EC exposure.

Restoration of ovarian endocrine function with encapsulated immune isolated human ovarian xenograft in ovariectomized mice.

Anti-cancer treatments cause premature depletion of the non-renewable ovarian reserve of follicles, the source of key steroid hormones, leading to premature ovarian insufficiency (POI) in 50% of pediatric cancer survivors. Patients with POI, especially at the onset of pubertal development, experience significant endocrine complications, including delayed growth, elevated risks of obesity and diabetes, and accelerated cardiovascular, musculoskeletal and neurological disorders as adults. The only approved pharmacological treatment for POI is an off-label prescribed hormone replacement therapy, which does not replace physiologically functioning ovaries.

POLYCYSTIC OVARY SYNDROME: ORIGINS AND IMPLICATIONS: Polycystic ovary syndrome: an evolutionary metabolic adaptation.

In Brief: Polycystic ovary syndrome has ancient genetic origins that favored preferential abdominal fat accumulation, ovarian hyperandrogenism and insulin resistance. This review examines how endocrine-metabolic changes in normal-weight hyperandrogenic PCOS women originated as an evolutionary metabolic adaptation to balance enhanced fat storage with increased glucose and fatty acid availability for optimal energy use for survival and reproduction.

Abstract: Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance in combination with preferential abdominal fat accumulation.

Sexually dimorphic cardiovascular impacts of prenatal exposure to a real-life environmental chemical mixture in adult offspring.

Cardiovascular disease (CVD) is a leading cause of death that is sexually dimorphic. This study used an ovine model to investigate whether maternal exposure to an environmental chemical (EC) mixture (biosolids) prior to and throughout pregnancy, affected offspring cardiovascular (CV) structure and function in adulthood. CV function of male and female offspring from ewes grazed on either conventionally fertilised (control, C) or biosolids-treated pasture (B) was assessed.

Functional changes to Achilles tendon and enthesis in an adolescent mouse model of testosterone hormone therapy.

Purpose/aim: Some youth seek puberty suppression to prolong decision-making prior to starting hormone therapy to help align their physical sex characteristics with their gender identity. During peripubertal growth, connective tissues such as tendon rapidly adapt to applied mechanical loads (e.g.

Short and long duration testosterone treatments induce reversable subfertility in female mice using a gestational model of gender-affirming hormone therapy.

Study Question: How does testosterone gender-affirming hormone therapy (T-GAHT) impact breeding success in female mice?

Summary Answer: T-GAHT causes reversible subfertility in female mice and persistent changes to reproductive tract anatomy, gene expression, and hormone receptors.

What Is Known Already: Adult female mice implanted with capsules containing 10 mg of testosterone mimic many aspects of reproductive phenotypes of T-GAHT patients, who may desire future gestation while pausing T-GAHT. In mice, oocytes retrieved from T-GAHT mice had decreased IVF rates, and T cessation prior to stimulation improved these outcomes.

Weight-neutral approach and later sleep midpoint in adolescents with "emerging polycystic ovary syndrome phenotype" as vehicles for sustainable weight loss.

Objective: Incorporate sleep into a novel lifestyle intervention strategy in adolescents with Emerging symptoms of polycystic ovary syndrome (E-PCOS).

Design: A single-center cohort study.

Setting: University hospital-based clinic for adolescents with PCOS.

Placental and immune cell DNA methylation reference panel for bulk tissue cell composition estimation in epidemiological studies.

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental villous tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated new and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples ( = 36) with robust partial correlation based on the top 30 hyper- and hypomethylated sites identified per cell type.

Characterizing DNA Methylation and Hydroxymethylation in Cord Blood and Identifying Sex-Specific Differences using the Illumina EPIC Array.

DNA methylation, an epigenetic mark, has become a common outcome in epidemiological studies with the aid of affordable and reliable technologies. Yet the most widespread technique used to assess methylation, bisulfite conversion, does not allow for the differentiation of regular DNA methylation (5-mC) and other cytosine modifications, like that of hydroxymethylation (5-hmC). As both 5-mC and 5-hmC have distinct biological roles, sometimes with opposing effects, it is crucial to understand the difference between these marks.

Developmental programming: preconceptional and gestational exposure of sheep to biosolids on offspring ovarian dynamics†.

Developmental exposure to environmental chemicals perturbs establishment and maintenance of the ovarian reserve across the reproductive lifetime, leading to premature follicle depletion and ovarian aging. Considering humans are exposed to a complex mixture of environmental chemicals, real-life models assessing their cumulative impact on the ovarian reserve are needed. Biosolids are a source of a real-life mixture of environmental chemicals.

Protocol for a randomized comparative effectiveness trial comparing a very low-carbohydrate diet to DASH diet for polycystic ovary syndrome: the SUPER (Supporting Understanding of PCOS Education and Research) trial.

Background: Polycystic ovary syndrome (PCOS), the most common endocrine disorder for women of reproductive age, is associated with increased risk for insulin resistance and type 2 diabetes. Current PCOS treatments insufficiently address the spectrum and severity of the disorder, and there is little evidence-based guidance available for lifestyle management of PCOS, especially through nutritional approaches. Some evidence shows that a very low-carbohydrate diet can improve glucose control compared to low-fat or moderate-carbohydrate diets, leading to improved glucose control and insulin levels that may help to treat symptoms of PCOS.

In-utero exposure to real-life environmental chemicals disrupts gene expression within the hypothalamo-pituitary-gonadal axis of prepubertal and adult rams.

Environmental chemicals (ECs) have been associated with a broad range of disorders and diseases. Daily exposure to various ECs in the environment, or real-life exposure, has raised significant public health concerns. Utilizing the biosolids-treated pasture (BTP) sheep model, this study demonstrates that in-utero exposure to a real-life EC mixture disrupts hypothalamo-pituitary-gonadal (HPG) axis gene expression and reproductive traits in prepubertal (8-week-old, 8w) and adult (11-month-old) male sheep.

Early pregnancy serum PFAS are associated with alterations in the maternal lipidome.

Per- and polyfluoroalkyl substances (PFAS) have been detected in the blood of humans and animals worldwide. Exposure to some PFAS are associated with multiple adverse pregnancy outcomes. Existing literature has identified a strong association with PFAS exposure and metabolic dysfunction in humans, including modification of lipid metabolism.