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Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring’s risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR)

Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance and dyslipidemia along with tissue-specific increases in ectopic lipid accumulation, oxidative stress and insulin resistance in liver and muscle of the early adult female sheep. Prenatal T increased inflammation and oxidative stress in the visceral (VAT) but not subcutaneous (SAT) adipose tissue, with no effect on insulin sensitivity in both depots. These systemic and tissue-specific metabolic changes are reminiscent of defects such as non-alcoholic fatty liver disease (NFLAD) common among aged individuals. Because it is known that gestational insults can program premature aging of reproductive organs and chronic cardiovascular abnormalities, we hypothesized that programming of premature cellular senescence is one of the ways through which gestational T induces premature aging of metabolic systems during early adulthood. To test this hypothesis, mitochondrial oxidative phosphorylation (OXPHOS) and telomere length, as measure of cellular senescence, were assessed in liver, muscle, VAT and SAT collected from control and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation) -treated female sheep at 21 months of age. Genomic DNA was subjected to TeloTAGG Telomere Length Assay (Sigma-Aldrich, St Louis, MO) and whole tissue protein lysates analyzed by immunoblot using Total OXPHOS Human WB Antibody Cocktail (ab110411, Abcam, Cambridge, MA). Data were analyzed by Student’s t test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) a trend (p = 0.09) towards a large magnitude increase in shorter telomere fragments (0.08 -3.6 KB) in the liver and 2) a non-significant large magnitude decrease in shorter telomere fragments in muscle and SAT without having any effect in the VAT. Prenatal T also induced a large magnitude increase in mitochondrial OXPHOS protein complexes II and IV in liver, without having an effect at the level of the muscle, VAT and SAT. These findings are suggestive that prenatal T-treatment induced hepatic defects may involve premature cellular senescence. The relevance of parallel increase in mitochondrial OXPHOS in the liver is unclear and remains to be explored. The defects observed in the muscle and SAT may occur independent of cellular senescence or alterations in mitochondrial function. The lack of change in telomere length and mitochondrial OXPHOS in spite of increased inflammation and oxidative stress in the VAT is suggestive of a potential protective function in play, consistent with maintenance of the insulin sensitivity in this tissue. This study, therefore, raises the possibility that metabolic defects programmed by gestational insults may involve premature aging of metabolic organs in a tissue-specific manner and have translational bearing in conditions associated with hyperandrogenic states.

The impact and reversibility of long-term gender-affirming testosterone (T) therapy on the reproductive axis of transgender men has not been well-established. Little is known about outcomes for transgender men interested in pausing T therapy to harvest oocytes or get pregnant. We previously established a translational mouse model to investigate T-induced acyclicity and ovarian perturbations. We hypothesized that the duration of T-induced acyclicity would impact the reversibility of cyclic and ovarian changes. To test this hypothesis, T-treated mice were assigned to two groups: (SHORT) 6 weeks of T therapy with immediate reversibility (1.5 mg T propionate pellet implant/removal, n = 5) and (LONG) 6 weeks of T therapy with a prolonged T washout phase (subcutaneous oil injections of T enanthate at 0.9 mg once weekly, n = 5). Control groups (placebo pellets n = 5, sesame oil vehicle injections n = 5) were run in parallel. Estrous cycles were monitored using daily vaginal cytology. Following cessation of T therapy, mice were sacrificed in diestrus after resumption of cyclicity for 4 cycles and ovarian histology examined. Data were analyzed in GraphPad Prism using Welch’s t-test or Mann-Whitney where appropriate. T therapy led to persistent diestrus within a week after T administration for all T-treated mice and none of the controls. The total duration of acyclicity was 6±1 weeks for the SHORT group, which was significantly shorter than the 11±2 weeks for the LONG group (mean ± s.d., p = 0.0079). With resumption of cyclicity, both the SHORT and LONG groups had a significantly lower percentage of days in estrus and higher percentage of days in metestrus as compared to their parallel age-matched controls. Ovarian histology for the SHORT group all showed regular corpora lutea and minimal stromal changes, however, 3/5 mice in the LONG group lacked corpora lutea and 4/5 revealed marked stromal cell hypertrophy. Similar stromal cell changes were not seen in control mice. In conclusion, the length of time of T-induced acyclicity appears to impact the development of stromal cell hypertrophy and formation of corpora lutea even after resumption of cyclicity with similar alterations to the estrous cycles. These findings may have clinical relevance for transgender men interested in fertility, based on duration of gender-affirming T therapy. Future work will aim to separate out the respective contributions of T exposure and acyclicity to the stromal phenotype.

Studies show that a subset of transgender men desire children; however, there is a paucity of literature on the effect of gender-affirming testosterone therapy on reproductive function. In this manuscript, we will review the process of gender-affirming hormone therapy for transgender men and what is known about ovarian and uterine consequences of testosterone exposure in transgender men; draw parallels with existing animal models of androgen exposure; summarize the existing literature on parenting experiences and desires in transgender people; discuss considerations for assisted reproductive technologies and fertility preservation; and identify gaps in the literature and opportunities for further research.

Steroids are important for fetal development and parturition, and aberrant exposure during gestation can lead to abnormal fetal outcome. Gestational exposures to endocrine disrupting chemicals (EDCs) have the potential to alter pregnancy steroidal milieu. Most studies to date have focused on individual EDCs, when in real life humans are exposed to a host of EDCs in parallel, emphasizing the need to consider cumulative impact. To meet this goal, 121 pregnant women (18-42 years of age) were recruited between 8 and 14 weeks of gestation from Southeastern Michigan, and maternal samples at recruitment and delivery were collected, as well as neonatal cord blood. Maternal and neonatal steroids were measured by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in blood samples collected from 121 mother-infant dyads of spontaneously conceived singleton pregnancies. A total of 41 EDCs encompassing commonly encountered environmental EDCs (phenols and phthalates), metals and metalloids were quantified in early pregnancy maternal urine from a subset (56 dyads) via LC-MS/MS. Maternal and neonatal steroid levels from all 121 subjects were related to pregnancy outcomes and, in the subset, individual and uniquely weighted EDC mixtures were related to steroid milieu. Additionally, the influence of BMI, maternal age, and offspring sex in modulating the EDC associations with steroids were determined. To determine the association of steroids at each time point with pregnancy outcomes or individual EDCs, multiple linear regression was used. Correlations between the steroids and potential confounding variables were analyzed using Spearman correlation. The cumulative effect of EDC mixtures generated by Principal Component Analysis on steroid measures was determined using Principal Component regression. The Benjamini-Hochberg False Discovery Rate procedure was employed to account for the multiple outcomes in each analysis. The findings showed 1) steroid-specific positive or negative associations with pregnancy measures; (2) many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; (3) EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex and (4) EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids. These findings indicate that maternal and neonatal steroids influence pregnancy outcomes depending on maternal age, pre-pregnancy BMI, and fetal sex and that the effects of EDCs on steroids differs when considered individually or as mixtures. Our results suggest that steroid measures might serve as biomarkers for the impact of EDC exposures on fetal outcomes during pregnancy, but these measures must be corrected for maternal factors. (Supported by P01 ES022844/RD 83543601, 1U2C ES026553, P30 ES017885)

Systemic inflammation (e.g., higher levels of pro-inflammatory cytokine interleukin [IL]-6 and C-reactive protein [CRP]) during pregnancy increases risk for both the mother and the infant. For the mother, systemic inflammation is associated with an increased risk of pregnancy complications (e.g., preeclampsia). For the infant, cytokine dysregulation may lead to long term immune dysregulation and susceptibility to metabolic diseases. Pregnant African American women are more likely to have greater systemic inflammation compared with pregnant non-Hispanic White women. They also experience a higher prevalence of chronic conditions (e.g., asthma), have higher levels of depressive symptoms, and report more incidents of intimate partner violence (IPV). We hypothesize that maternal systemic inflammation is related to chronic disease, depressive symptoms, and IPV among pregnant African American women. Pregnant African American women (n=180) were recruited at prenatal clinics in the Midwest. Women completed a questionnaire and had blood drawn at a prenatal visit. Plasma cytokine levels (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, IL-6, IL8 and IL10) were measured by multiplex array and CRP was measured by ELISA. Data were log (x+1) transformed and analyzed using descriptive statistics and correlational analysis (Pearson and point-biserial correlations). Women had a mean age of 27±5.5 years (range 18-41) and a mean gestational age at data collection of 16±5.8 weeks (range 8-29). Fifty-five percent of women were employed, 42% had annual household income < $10,000, and 16% smoked cigarettes during pregnancy. Twenty-five percent of women reported asthma, 8% hypertension, 6% diabetes, and 4% thyroid disease. Twenty-seven percent of women had Center for Epidemiological Studies-Depression (CES-D) scores ≥ 23, which have been correlated with depression diagnosis. IPV during the year before pregnancy was more frequent (8%) than IPV during pregnancy (5.1%). Women who reported hypertension had higher levels of TNF-α (r= 0.151, p< 0.05); and women with asthma had higher levels of CRP (r= 0.20, p< 0.01). Women who reported higher CES-D scores (r= 0.19, p< 0.05) had higher CRP levels. Women who reported IPV during pregnancy had higher IL-8 levels (r= 0.17, p< 0.05). Women who were employed had lower levels of IL-6 compared to women who were not employed (r= -0.180, p< 0.05). These results indicate that systemic inflammation is related to chronic health conditions (hypertension, asthma), depressive symptoms, IPV and employment status in pregnant African American women. The relationships between systemic inflammation, depressive symptoms and IPV, with a focus on metabolic and molecular pathways should be investigated to better understand the mechanisms by which maternal and fetal health are affected.