Promoting a more diverse and inclusive research workforce through the research scholars program.

BACKGROUND: Novel and comprehensive approaches are needed to address shortcomings in the diversity and inclusiveness of the scientific workforce. In response to this need and informed by multiple programs and data sources, we created the Research Scholars Program (RSP). The RSP is a yearlong program for early-career faculty with an overall objective to overcome barriers to the academic success, retention, progression, and promotion of groups underrepresented in biomedical and behavioral research. The goal of the RSP is to increase research confidence and productivity, build a supportive research community, and reduce isolation by providing personal and group research enrichment to junior faculty through professional development, mentorship, and networking. METHODS: We adapted evidence-based approaches for our institutional context and vetted the RSP across our campus. The resulting RSP consists of three main elements: (1) five levels of Mosaic Mentorship; (2) group and tailored professional development programming; and (3) scientific and social networking. To determine the potential of the RSP to improve research confidence critical to success, we used a modified shortened version of the Clinical Research Appraisal Inventory (CRAI-12) to assess participants' confidence in performing a variety of research tasks before and after program participation. We collected information about retention, promotion, and grants submitted and awarded. Additionally, we conducted semi-structured exit interviews with each scholar after program participation to identify programmatic strengths and areas for improvement. Data for Cohorts 1 and 2 (N = 12) were analyzed. RESULTS: Our assessment finds, with one exception, increasing confidence in participants' research skills across all items, ranging from 0.4 (4.7%) to 2.6 (40.6%). In their exit interviews, the Research Scholars (RS) described their improved productivity and increased sense of belonging and support from others. Research Scholars noted numerous components of the RSP as strengths, including the Mosaic Mentorship model, professional development programming, and opportunities for both informal and formal interactions. Respondents identified time pressure, a lack of feedback, and unclear expectations of the various mentorship roles as areas in which the program can improve. CONCLUSION: Preliminary findings indicate that the RSP is successful in building the research confidence of underrepresented and disadvantaged early-career faculty. While this report focuses on the development and protocol of the RSP, additional cohorts and data will provide the evidence base to support dissemination as a national model of research professional development. Such programming is critical to ensure sustainable support structures, institutional networks, infrastructure, and resources that will improve discovery and equity through inclusive excellence.

Elevated lipid oxidation is associated with exceeding gestational weight gain recommendations and increased neonatal anthropometrics: a cross-sectional analysis.

BACKGROUND: Deviations from gestational weight gain (GWG) recommendations are associated with unfavorable maternal and neonatal outcomes. There is a need to understand how maternal substrate metabolism, independent of weight status, may contribute to GWG and neonatal outcomes. The purpose of this study was to explore the potential link between maternal lipid oxidation rate, GWG, and neonatal anthropometric outcomes. METHODS: Women (N = 32) with a lean pre-pregnancy BMI were recruited during late pregnancy and substrate metabolism was assessed using indirect calorimetry, before and after consumption of a high-fat meal. GWG was categorized as follows: inadequate, adequate, or excess. Shortly after delivery (within 48 h), neonatal anthropometrics were obtained. RESULTS: Using ANOVA, we found that fasting maternal lipid oxidation rate (grams/minute) was higher (p = 0.003) among women with excess GWG (0.1019 ± 0.0416) compared to women without excess GWG (inadequate = 0.0586 ± 0.0273, adequate = 0.0569 ± 0.0238). Findings were similar when lipid oxidation was assessed post-meal and also when expressed relative to kilograms of fat free mass. Absolute GWG was positively correlated to absolute lipid oxidation expressed in grams/minute at baseline (r = 0.507, p = 0.003), 2 h post-meal (r = 0.531, p = 0.002), and 4 h post-meal (r = 0.546, p = 0.001). Fasting and post-meal lipid oxidation (grams/minute) were positively correlated to neonatal birthweight (fasting r = 0.426, p = 0.015; 2-hour r = 0.393, p = 0.026; 4-hour r = 0.540, p = 0.001) and also to neonatal absolute fat mass (fasting r = 0.493, p = 0.004; 2-hour r = 0.450, p = 0.010; 4-hour r = 0.552, p = 0.001). CONCLUSIONS: A better understanding of the metabolic profile of women during pregnancy may be critical in truly understanding a woman's risk of GWG outside the recommendations. GWG counseling during prenatal care may need to be tailored to women based not just on their weight status, but other metabolic characteristics.

Smoking during pregnancy increases chemerin expression in neonatal tissue.

NEW FINDINGS: What is the central question of this study? Is chemerin, an adipokine implicated in obesity, increased in neonates following in utero cigarette smoke exposure. What is the main finding and its importance? Chemerin mRNA expression was increased and chemerin DNA methylation was decreased in babies born to mothers who smoked during pregnancy. These data provide a potential mechanism that may be mediating the increased obesity risk in individuals that are born to mothers who smoked during pregnancy. ABSTRACT: It has been shown that in utero tobacco exposure increases offspring risk for obesity, but the mechanisms responsible for this increased risk are not well understood. Chemerin is an adipokine that regulates adipocyte differentiation. This chemokine is elevated in obese individuals and with smoke exposure, but its levels have not been measured in neonates exposed to cigarette smoke in utero. We examined chemerin gene expression [n = 31 non-smoker (NS) and 15 smoker (S)] and DNA methylation (n = 28 NS and n = 11 S) in skin collected from babies born to mothers who smoked during pregnancy as compared to non-smoking controls. Quality RNA and DNA were isolated from foreskin tissue following circumcision, and chemerin gene expression and DNA methylation were assessed. Further, in a second cohort, we utilized primary dermal foreskin fibroblasts as a functional measure of adipogenesis in living cells (n = 11 NS and n = 8 S). Cells were stimulated with an adipogenic cocktail, mRNA was isolated from cells after 14 days, and chemerin gene expression assessed via real-time PCR. Chemerin mRNA was elevated in both whole tissue (NS: 2409.20 ± 555.28 counts and S: 2966.72 ± 636.84 counts; P < 0.01) and primary fibroblasts (NS: 1.12 ± 0.55 2 Δ Δ C T and S: 2.13 ± 1.34 2 Δ Δ C T ; P = 0.04) collected from infants born to smoking mothers. Chemerin DNA methylation was reduced in whole tissue of offspring born to smokers (NS: 4.18 ± 1.28 and S: 3.07 ± 1.31%; P = 0.02), which may contribute to the increased gene expression. Neonates born to mothers who smoke during pregnancy exhibit distinct changes in chemerin gene expression in response to in utero tobacco smoke exposure which are regulated in part by epigenetic alterations.

Developmental Origins of Health Span and Life Span: A Mini-Review.

BACKGROUND: A vast body of research has demonstrated that disease susceptibility and offspring health can be influenced by perinatal factors, which include both paternal and maternal behavior and environment. Offspring disease risk has the potential to affect the health span and life span of offspring. KEY FINDINGS: Various maternal factors, such as environmental toxicant exposure, diet, stress, exercise, age at conception, and longevity have the potential to influence age-associated diseases such as cardiovascular disease, obesity, diabetes, and cancer risk in offspring. Paternal factors such as diet, age at conception, and longevity can potentially impact offspring health span and life span-reducing traits as well. PRACTICAL IMPLICATIONS: Continued research could go a long way toward defining mechanisms of the developmental origins of life span and health span, and eventually establishing regimens to avoid negative developmental influences and to encourage positive interventions to potentially increase life span and improve health span in offspring.

Gestational exercise protects adult male offspring from high-fat diet-induced hepatic steatosis.

BACKGROUND & AIMS: Mounting evidence indicates that maternal exercise confers protection to adult offspring against various diseases. Here we hypothesized that maternal exercise during gestation would reduce high-fat diet (HFD)-induced hepatic steatosis in adult rat offspring. METHODS: Following conception, pregnant dams were divided into either voluntary wheel running exercise (GE) or wheel-locked sedentary (GS) groups throughout gestation (days 4-21). Post-weaning, offspring received either normal chow diet (CD; 10% fat, 70% carbohydrate, 20% protein) or HFD (45% fat, 35% carbohydrate, and 20% protein) until sacrificed at 4- or 8-months of age. RESULTS: GE did not affect offspring birth weight or litter size. HFD feeding in offspring increased weight gain, body fat percentage, and glucose tolerance test area under the curve (GTT-AUC). Male offspring from GE dams had reduced body fat percentage across all ages (p<0.05). In addition, 8-month male offspring from GE dams were protected against HFD-induced hepatic steatosis, which was associated with increased markers of hepatic mitochondrial biogenesis (PGC-1α and TFAM), autophagic potential (ATG12:ATG5 conjugation) and hepatic triacylglycerol secretion (MTTP). CONCLUSIONS: The current study provides the first evidence that gestational exercise can reduce susceptibility to HFD-induced hepatic steatosis in adult male offspring.

Impact of Maternal Exercise during Pregnancy on Offspring Chronic Disease Susceptibility.

Maternal behaviors during pregnancy have been reported to impact offspring health in adulthood. In this article we explore the novel hypothesis that exercise during pregnancy can protect against chronic disease susceptibility in the offspring. To date, research has demonstrated that improvements in metabolic outcomes, cardiovascular risk, and cancer can occur in response to maternal exercise during pregnancy.

Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt.

OBJECTIVE: Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown. APPROACH AND RESULTS: We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm. CONCLUSIONS: The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.

Placental PFAS concentrations are associated with perturbations of placental DNA methylation at loci with important roles on cardiometabolic health.

The placenta is crucial for fetal development, is affected by PFAS toxicity, and evidence is accumulating that gestational PFAS perturb the epigenetic activity of the placenta. Gestational PFAS exposure is can adversely affect offspring, yet individual and cumulative impacts of PFAS on the placental epigenome remain underexplored. Here, we conducted an epigenome-wide association study (EWAS) to examine the relationships between placental PFAS levels and DNA methylation in a cohort of mother-infant dyads in Arkansas. We measured 17 PFAS in human placental tissues and quantified placental DNA methylation levels via the Illumina EPIC Microarray. We tested for differential DNA methylation with individual PFAS, and with mixtures of multiple PFAS. Our results demonstrated that numerous epigenetic loci were perturbed by PFAS, with PFHxS exhibiting the most abundant effects. Mixture analyses suggested cumulative effects of PFOA and PFOS, while PFHxS may act more independently. We additionally explored whether sex-specific effects may be present and concluded that future large studies should explicitly test for sex-specific effects. The genes that are annotated to our PFAS-associated epigenetic loci are primarily involved in growth processes and cardiometabolic health, while some genes are involved in neurodevelopment. These findings shed light on how prenatal PFAS exposures affect birth outcomes and children's health, emphasizing the importance of understanding PFAS mechanisms in the in-utero environment.

Satellite-based time-series of sea-surface temperature since 1980 for climate applications.

A 42-year climate data record of global sea surface temperature (SST) covering 1980 to 2021 has been produced from satellite observations, with a high degree of independence from in situ measurements. Observations from twenty infrared and two microwave radiometers are used, and are adjusted for their differing times of day of measurement to avoid aliasing and ensure observational stability. A total of 1.5 × 1013 locations are processed, yielding 1.4 × 1012 SST observations deemed to be suitable for climate applications. The corresponding observation density varies from less than 1 km-2 yr-1 in 1980 to over 100 km-2 yr-1 after 2007. Data are provided at their native resolution, averaged on a global 0.05° latitude-longitude grid (single-sensor with gaps), and as a daily, merged, gap-free, SST analysis at 0.05°. The data include the satellite-based SSTs, the corresponding time-and-depth standardised estimates, their standard uncertainty and quality flags. Accuracy, spatial coverage and length of record are all improved relative to a previous version, and the timeseries is routinely extended in time using consistent methods.

Sex differences in type 2 diabetes: an opportunity for personalized medicine.

Over the past several decades, substantial ground has been gained in understanding the biology of sex differences. With new mandates to include sex as a biological variable in NIH-funded research, greater knowledge is forthcoming on how sex chromosomes, sex hormones, and social and societal differences between sexes can affect the pathophysiology of health and disease. A detailed picture of how biological sex impacts disease pathophysiology will directly inform clinicians in their treatment approaches and challenge canonical therapeutic strategies. Thus, a profound opportunity to explore sex as a variable in personalized medicine now presents itself. While many sex differences are apparent in humans and have been described at length, we are only beginning to see how such differences impact disease progression, treatment efficacy, and outcomes in obesity, type 2 diabetes, and cardiovascular disease. Here, we briefly present the most salient and convincing evidence of sex differences in type 2 diabetes detection, diagnostics, disease course, and therapeutics. We then offer commentary on how this evidence can inform clinicians on how to approach the clinical workup and management of different patients with diabetes. Finally, we discuss some gaps that remain in the literature and propose several research questions to guide basic and translational researchers as they continue in this growing area of scientific exploration.

For decades, most research in the laboratory and clinical settings focused primarily on males. However, more recently, grant-funding agencies, including the National Institutes of Health, have prioritized research that studies both males and females. This has dramatically improved our understanding of how biological sex impacts whether a person is at higher risk for developing a particular disease and what treatment options may be best to achieve the healthiest outcomes. This article offers the perspectives of practicing physicians and scientists on how our knowledge about biological sex may impact disease incidence, progression, treatment options, and outcomes in obesity, diabetes, and heart disease. The piece will offer a broad overview of the current science and personalized medicine approaches in these areas. It then discusses gaps in our knowledge and proposes several questions to guide future research.

PCB126 exposure during pregnancy alters maternal and fetal gene expression.

Polychlorinated biphenyls (PCBs) are organic pollutants that can have lasting impacts on offspring health. Here, we sought to examine maternal and fetal gene expression differences of aryl hydrocarbon receptor (AHR)-regulated genes in a mouse model of prenatal PCB126 exposure. Female mice were bred and gavaged with 1 µmole/kg bodyweight PCB126 or vehicle control on embryonic days 0 and 14, and maternal and fetal tissues were collected on embryonic day 18.5. Total RNAs were isolated, and gene expression levels were analyzed in both maternal and fetal tissues using the NanoString nCounter system. Interestingly, we found that the expression levels of cytochrome P450 (Cyp)1a1 and Cyp1b1 were significantly increased in response to PCB exposure in the tested maternal and fetal tissues. Furthermore, PCB exposure altered the expression of several other genes related to energy balance, oxidative stress, and epigenetic regulation in a manner that was less consistent across tissue types. These results indicate that maternal PCB126 exposure significantly alters gene expression in both developing fetuses and pregnant dams, and such changes vary in intensity and expressivity depending on tissue type. The altered gene expression may provide insights into pathophysiological mechanisms by which in utero PCB exposures contribute to PCB-induced postnatal metabolic diseases.

Maternal polychlorinated biphenyl 126 (PCB 126) exposure modulates offspring gut microbiota irrespective of diet and exercise.

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations. To test this, dams were exposed to PCB 126 (0.5 µmole/kg body weight) or vehicle oil by oral gavage during preconception, gestation, and during lactation. Half of each group was allowed access to running wheels for ≥ 7 days before and during pregnancy and up through day 14 of lactation. Female offspring born from the 4 maternal groups (PCB exposure or not, with/without exercise) were subsequently placed either on regular diet or switched to a high-fat diet during adulthood. Microbiota composition was quantified in female offspring at 49 weeks of age by 16 S rRNA sequencing. Maternal exposure to PCB 126 resulted in significantly reduced richness and diversity in offspring microbiota regardless of diet or exercise. Overall compositional differences were largely driven by offspring diet, but alterations in specific taxa due to maternal PCB 126 exposure, included the depletion of Verrucomicrobiaceae and Akkermansia muciniphila, and an increase in Anaeroplasma. Perturbation of microbiota due to PCB 126 may predispose offspring to a variety of chronic diseases later in adulthood.

Exposure to PCB126 during the nursing period reversibly impacts early-life glucose tolerance.

Polychlorinated biphenyls (PCBs) are persistent environmental organic pollutants known to have detrimental health effects. Using a mouse model, we previously demonstrated that PCB126 exposure before and during pregnancy and throughout the perinatal period adversely affected offspring glucose tolerance and/or body composition profiles. The purpose of this study was to investigate the glucose tolerance and body composition of offspring born to dams exposed to PCB126 during the nursing period only. Female ICR mice were bred, and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal days (PND) 3, 10, and 17 (n = 9 per group). Offspring body weight, lean and fat mass, and glucose tolerance were recorded every three weeks. PCB126 treatment did not alter dam nor offspring body weight (p > 0.05). PCB126-exposed male and female offspring displayed normal body composition (p > 0.05) relative to vehicle-exposed offspring. However, both male and female offspring that were exposed to PCB126 during the nursing period had significantly impaired glucose tolerance at 3 and 9 weeks of age (p < 0.05). At 6 and 12 weeks of age, no impairments in glucose tolerance existed in offspring (p > 0.05). Our current study demonstrates that exposure to PCB126 through the mother's milk does not affect short- or long-term body composition but impairs glucose tolerance in the short-term.

Perinatal exercise improves glucose homeostasis in adult offspring.

Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Effects of maternal controlled exercise on offspring adiposity and glucose tolerance.

While metabolic disorders such as obesity and diabetes are costly and deadly to the current population, they are also extremely detrimental to the next generation. Much of the current literature focuses on the negative impact of poor maternal choices on offspring disease, while there is little work examining maternal behaviors that may improve offspring health. Research has shown that voluntary maternal exercise in mouse models improves metabolic function in offspring. In this study, we hypothesized that controlled maternal exercise in a mouse model will effect positive change on offspring obesity and glucose homeostasis. Female mice were separated into three groups: home cage, sedentary, and exercise. The sedentary home cage group was not removed from the home cage, while the sedentary wheel group was removed from the cage and placed in an immobile wheel apparatus. The exercise group was removed from the home cage and run on the same wheel apparatus but with the motor activated at 5-10 m/min for 1 h/d prior to and during pregnancy. Offspring were subjected to oral glucose tolerance testing and body composition analysis. There was no significant difference in offspring glucose tolerance or body composition as a consequence of the maternal exercise intervention compared to the sedentary wheel group. There were no marked negative consequences of the maternal controlled exercise intervention. Further research should clarify the potential advantages of the controlled exercise model and improve experimental techniques to facilitate translation of this research to human applications.

Dietary whey protein lowers the risk for metabolic disease in mice fed a high-fat diet.

Consuming a high-fat (HF) diet produces excessive weight gain, adiposity, and metabolic complications associated with risk for developing type 2 diabetes and fatty liver disease. This study evaluated the influence of whey protein isolate (WPI) on systemic energy balance and metabolic changes in mice fed a HF diet. Female C57BL/6J mice received for 11 wk a HF diet, with or without 100 g WPI/L drinking water. Energy consumption and glucose and lipid metabolism were examined. WPI mice had lower rates of body weight gain and percent body fat and greater lean body mass, although energy consumption was unchanged. These results were consistent with WPI mice having higher basal metabolic rates, respiratory quotients, and hepatic mitochondrial respiration. Health implications for WPI were reflected in early biomarkers for fatty liver disease and type 2 diabetes. Livers from WPI mice had significantly fewer hepatic lipid droplet numbers and less deposition of nonpolar lipids. Furthermore, WPI improved glucose tolerance and insulin sensitivity. We conclude that in mice receiving a HF diet, consumption of WPI results in higher basal metabolic rates and altered metabolism of dietary lipids. Because WPI mice had less hepatosteatosis and insulin resistance, WPI dietary supplements may be effective in slowing the development of fatty liver disease and type 2 diabetes.

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction.

Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogen-detoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR.

Metabolic flexibility during late pregnancy is associated with neonatal adiposity.

The aim of this study was to determine the relationships between maternal metabolic flexibility during pregnancy and neonatal health outcomes. Percent change in lipid oxidation (before and after a high-fat meal) was calculated as the measure of "metabolic flexibility". Neonatal adiposity was assessed within 48 h of delivery by skinfold anthropometry. Metabolic flexibility (r = -0.271, p = 0.034), maternal HOMA-IR (r = 0.280, p = 0.030), and maternal body mass index (r = 0.299, p = 0.018) were correlated with neonatal subscapular skinfold (i.e., measure of neonatal adiposity). Clinical Trail Registration Number: NCT03504319. Novelty: This is the first study to link maternal metabolic flexibility, body mass index, and insulin resistance during pregnancy to neonatal adiposity at parturition.

Chronic Exposure to Cadmium Induces Differential Methylation in Mice Spermatozoa.

Cadmium exposure is ubiquitous and has been linked to diseases including cancers and reproductive defects. Since cadmium is nonmutagenic, it is thought to exert its gene dysregulatory effects through epigenetic reprogramming. Several studies have implicated germline exposure to cadmium in developmental reprogramming. However, most of these studies have focused on maternal exposure, while the impact on sperm fertility and disease susceptibility has received less attention. In this study, we used reduced representation bisulfite sequencing to comprehensively investigate the impact of chronic cadmium exposure on mouse spermatozoa DNA methylation. Adult male C57BL/J6 mice were provided water with or without cadmium chloride for 9 weeks. Sperm, testes, liver, and kidney tissues were collected at the end of the treatment period. Cadmium exposure was confirmed through gene expression analysis of metallothionein-1 and 2, 2 well-known cadmium-induced genes. Analysis of sperm DNA methylation changes revealed 1788 differentially methylated sites present at regulatory regions in sperm of mice exposed to cadmium compared with vehicle (control) mice. Furthermore, most of these differential methylation changes positively correlated with changes in gene expression at both the transcription initiation stage as well as the splicing levels. Interestingly, the genes targeted by cadmium exposure are involved in several critical developmental processes. Our results present a comprehensive analysis of the sperm methylome in response to chronic cadmium exposure. These data, therefore, highlight a foundational framework to study gene expression patterns that may affect fertility in the exposed individual as well as their offspring, through paternal inheritance.