Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies.

Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages and increases intestinal permeability in female mice independent of tumor necrosis factor.

Macrophages are essential for homeostatic maintenance of the anti-inflammatory and tolerogenic intestinal environment, yet monocyte-derived macrophages can promote local inflammation. Proinflammatory macrophage accumulation within the intestines may contribute to the development of systemic chronic inflammation and immunometabolic dysfunction in obesity. Using a model of high-fat diet-induced obesity in C57BL/6J female mice, we assessed intestinal paracellular permeability by in vivo and ex vivo assays and quantitated intestinal macrophages in ileum and colon tissues by multicolor flow cytometry after short (6 wk), intermediate (12 wk), and prolonged (18 wk) diet allocation. We characterized monocyte-derived CD4-TIM4- and CD4+TIM4- macrophages, as well as tissue-resident CD4+TIM4+ macrophages. Diet-induced obesity had tissue- and time-dependent effects on intestinal permeability, as well as monocyte and macrophage numbers, surface marker phenotype, and intracellular production of the cytokines IL-10 and tumor necrosis factor (TNF). We found that obese mice had increased paracellular permeability, in particular within the ileum, but this did not elicit recruitment of monocytes nor a local proinflammatory response by monocyte-derived or tissue-resident macrophages in either the ileum or colon. Proliferation of monocyte-derived and tissue-resident macrophages was also unchanged. Wild-type and TNF-/- littermate mice had similar intestinal permeability and macrophage population characteristics in response to diet-induced obesity. These data are unique from reported effects of diet-induced obesity on macrophages in metabolic tissues, as well as outcomes of acute inflammation within the intestines. These experiments also collectively indicate that TNF does not mediate effects of diet-induced obesity on paracellular permeability or intestinal monocyte-derived and tissue-resident intestinal macrophages in young female mice.NEW & NOTEWORTHY We found that diet-induced obesity in female mice has tissue- and time-dependent effects on intestinal paracellular permeability as well as monocyte-derived and tissue-resident macrophage numbers, surface marker phenotype, and intracellular production of the cytokines IL-10 and TNF. These changes were not mediated by TNF.

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism†.

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8-10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

Associations of Adverse Childhood Experiences with Frailty in Older Adults: A Cross-Sectional Analysis of Data from the Canadian Longitudinal Study on Aging.

INTRODUCTION: Frailty in older adults, characterized by a decline in multiple physiological systems and increasing vulnerability to loss of independence, disability, and death, is a public health priority in developed countries. Etiology of frailty extends across the lifespan and may begin in early life, but empirical evidence for this association is scarce. In this study, we examined whether adverse childhood experiences (ACEs) are associated with frailty in later life. METHODS: We conducted a cross-sectional analysis of data for a population-based sample of 27,748 adults aged 45-85 years from the Canadian Longitudinal Study on Aging. The frailty index (FI) was computed with 76 health-related characteristics of physical and cognitive performance, self-rated health, chronic conditions, visual and hearing ability, activities of daily living, and well-being. Self-reported exposure to ACEs included physical, emotional, and sexual abuse, neglect, and witnessing intimate partner violence prior age of 16 and parental death, divorce, and living with a family member with mental illness prior age of 18. Generalized linear regression models with gamma error distribution and identity link function, adjusted for age and sex, were used to examine associations of each ACE type and the number of ACE types (0, 1, 2, or 3+) reported by an individual with FI. All models were adjusted for income, education, smoking, and alcohol consumption in sensitivity analysis. RESULTS: Individuals exposed to ACEs had elevated levels of FI (mean = 0.13, SD = 0.09) than those unexposed, with the largest difference observed for neglect (B [95% CI]: 0.05 [0.04, 0.06]) and the smallest for parental death and divorce (0.015 [0.01,0.02]). The ACE count was associated with frailty in a graded manner, with the FI difference reaching 0.04 [0.037, 0.044] for participants exposed to 3+ ACE types. The association between ACEs and frailty tended to be stronger for women than men and for men aged 45-64 years than older men. CONCLUSIONS: Our study supports previous studies showing that exposure to ACEs is associated with frailty in adults. Our findings suggest that screening for ACEs involving childhood maltreatment may be useful for identifying individuals at risk of frailty and prevention of ACEs may have long-term benefits for healthy aging.

Biological sex, not reproductive cycle, influences peripheral blood immune cell prevalence in mice.

KEY POINTS: Traditionally the female sex, compared with the male sex, has been perceived as having greater variability in many physiological traits, including within the immune system. We investigated effects of biological sex and the female reproductive cycle on numbers of circulating leukocytes in C57BL/6J mice. We show that biological sex, but not female reproductive cyclicity, has a significant effect on peripheral blood immune cell prevalence and variability, and that sex differences were not consistent amongst common inbred laboratory mouse strains. We found that male C57BL/6J mice, compared with female mice, have greater variability in peripheral blood immunophenotype, and that this was influenced by body weight. We created summary tables for researchers to facilitate experiment planning and sample size calculations for peripheral immune cells that consider the effects of biological sex. ABSTRACT: Immunophenotyping (i.e. quantifying the number and types of circulating leukocytes) is used to characterize immune changes during health and disease, and in response to pharmacological and other interventions. Despite the importance of biological sex in immune function, there is considerable uncertainty amongst researchers as to the extent to which biological sex or the female reproductive cycle influence blood immunophenotype. We quantified circulating leukocytes by multicolour flow cytometry in young C57BL/6J mice and assessed the effects of the reproductive cycle, biological sex, and other experimental and biological factors on data variability. We found that there are no significant effects of the female reproductive cycle on the prevalence of peripheral blood B cells, NK cells, CD4+ T cells, CD8+ T cells, monocytes, or neutrophils. Immunophenotype composition and variability do not significantly change between stages of the female reproductive cycle. There are, however, sex-specific differences in immune cell prevalence, with fewer monocytes, neutrophils, and NK cells in female mice. Surprisingly, immunophenotype is more variable in male mice, and weight is a significant contributing factor. We provide tools for researchers to perform a priori sample size calculations for two-group and factorial analyses. We show that immunophenotype varies between inbred mouse strains, and that using equal sample sizes of male and female mice is not always appropriate for within-sex evaluations of immune cell populations in peripheral blood.

Exposure to high fructose corn syrup during adolescence in the mouse alters hepatic metabolism and the microbiome in a sex-specific manner.

KEY POINTS: The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific. ABSTRACT: The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.

Maternal undernutrition during pregnancy and lactation increases transcription factors, ETV5 and GDNF, and alters regulation of apoptosis and heat shock proteins in the testis of adult offspring in the rat.

We tested whether changes in Sertoli cell transcription factors and germ cell heat shock proteins (HSPs) are linked to the effects of maternal undernutrition on male offspring fertility. Rats were fed ad libitum with a standard diet (CONTROL) throughout pregnancy and lactation or with 50% of CONTROL intake throughout pregnancy (UNP) or lactation (UNL) or both periods (UNPL). After postnatal Day 21, 10 male pups per group were fed a standard diet ad libitum until postnatal Day 160 when testes were processed for histological, mRNA and immunohistochemical analyses. Compared with CONTROL: caspase-3 was increased in UNP and UNPL (P=0.001); Bax was increased in UNL (P=0.002); Bcl-2 (P<0.0001) was increased in all underfed groups; glial cell line-derived neurotrophic factor (P=0.002) was increased in UNP and UNL; E twenty-six transformation variant gene 5 and HSP70 were increased, and HSP90 was diminished in all underfed groups (P<0.0001). It appears that maternal undernutrition during pregnancy and lactation disrupts the balance between proliferation and apoptosis in germ cells, increasing germ cell production and perhaps exceeding the support capacity of the Sertoli cells. Moreover, fertility could be further compromised by changes in meiosis and spermiogenesis mediated by germ cell HSP90 and HSP70.

Investigating the normalization and normative views of gestational weight gain: Balancing recommendations with the promotion and support of healthy pregnancy diets.

OBJECTIVES: Gestational weight gain (GWG) is increasingly monitored in the United States and Canada. While promoting healthy GWG offers benefits, there may be costs with over-surveillance. We aimed to explore these costs/benefits. METHODS: Quantitative data from 350 pregnant survey respondents and qualitative focus group data from 43 pregnant/post-partum and care-provider participants were collected in the Mothers to Babies (M2B) study in Hamilton, Canada. We report descriptive statistics and discussion themes on GWG trajectories, advice, knowledge, perceptions, and pregnancy diet. Relationships between GWG monitoring/normalization and worry, knowledge, diet quality, and sociodemographics-namely low-income and racialization-were assessed using χ2 tests and a linear regression model and contextualized with focus group data. RESULTS: Most survey respondents reported GWG outside recommended ranges but rejected the mid-20th century cultural norm of "eating for two"; many worried about gaining excessively. Conversely, respondents living in very low-income households were more likely to be gaining less than recommended GWG and to worry about gaining too little. A majority had received advice about GWG, yet half were unable to identify the range recommended for their prepregnancy BMI. This proportion was even lower for racialized respondents. Pregnancy diet quality was associated with household income, but not with receipt or understanding of GWG guidance. Care-providers encouraged normalized GWG, while worrying about the consequences of pathologizing "abnormal" GWG. CONCLUSIONS: Translation of GWG recommendations should be done with a critical understanding of GWG biological normalcy. Supportive GWG monitoring and counseling should consider clinical, socioeconomic, and community contexts.

Synergies between the Developmental Origins of Health and Disease framework and multiple branches of evolutionary anthropology.

The Developmental Origins of Health and Disease (DOHaD) hypothesis derives from the epidemiological and basic/mechanistic health sciences. This well-supported hypothesis holds that environment during the earliest stages of life-pre-conception, pregnancy, infancy-shapes developmental trajectories and ultimately health outcomes across the lifespan. Evolutionary anthropologists from multiple subdisciplines are embracing synergies between the DOHaD framework and developmentalist approaches from evolutionary biology. Even wider dissemination and employment of DOHaD concepts will benefit evolutionary anthropological research. Insights from experimental DOHaD work will focus anthropologists' attention on biochemical/physiological mechanisms underpinning observed links between growth/health/behavioral outcomes and environmental contexts. Furthermore, the communication tools and wide public appeal of developmentalist health scientific research may facilitate the translation/application of evolutionary anthropological findings. Evolutionary Anthropology, in turn, can increase mainstream DOHaD research's use of evolutionary theory; holistic, longitudinal, and community-based perspectives; and engagement with populations whose environmental exposures differ from those most commonly studied in the health sciences.

Knowledge about the Developmental Origins of Health and Disease is independently associated with variation in diet quality during pregnancy.

Environmental factors affecting development through embryogenesis, pregnancy, and infancy impact health through all subsequent stages of life. Known as the Developmental Origins of Health and Disease (DOHaD) hypothesis, this concept is widely accepted among health and social scientists. However, it is unclear whether DOHaD-based ideas are reaching the general public and/or influencing behaviour. This study thus investigated whether and under what circumstances pregnant people in Canada are familiar with DOHaD, and if DOHaD familiarity relates to eating behaviour. Survey responses from pregnant people from Hamilton, Canada, were used to assess respondents' knowledge of DOHaD (hereafter, DOHaDKNOWLEDGE ) compared with their knowledge of more general pregnancy health recommendations (Pregnancy GuidelineKNOWLEDGE ). The survey also characterized respondents' pregnancy diet quality and sociodemographic profiles. We fit two multiple, linear, mixed regression models to the data, one with DOHaDKNOWLEDGE score as the dependent variable and the other with diet quality score as the dependent. In both models, responses were clustered by respondents' neighbourhoods. Complete, internally consistent responses were available for 330 study-eligible respondents. Relative to Pregnancy GuidelineKNOWLEDGE , respondents had lower, more variable DOHaDKNOWLEDGE scores. Additionally, higher DOHaDKNOWLEDGE was associated with higher socio-economic position, older age, and lower parity, independent of Pregnancy GuidelineKNOWLEDGE . Diet quality during pregnancy was positively associated with DOHaDKNOWLEDGE , adjusting for sociodemographic factors. A subset of relatively high socio-economic position respondents was familiar with DOHaD. Greater familiarity with DOHaD was associated with better pregnancy diet quality, hinting that translating DOHaD knowledge to pregnant people may motivate improved pregnancy nutrition and thus later-life health for developing babies.

High-fat diet intake modulates maternal intestinal adaptations to pregnancy and results in placental hypoxia, as well as altered fetal gut barrier proteins and immune markers.

KEY POINTS: Maternal obesity has been associated with shifts in intestinal microbiota, which may contribute to impaired barrier function Impaired barrier function may expose the placenta and fetus to pro-inflammatory mediators We investigated the impacts of diet-induced obesity in mice on maternal and fetal intestinal structure and placental vascularization Diet-induced obesity decreased maternal intestinal short chain fatty acids and their receptors, impaired gut barrier integrity and was associated with fetal intestinal inflammation. Placenta from obese mothers showed blood vessel immaturity, hypoxia, increased transcript levels of inflammation, autophagy and altered levels of endoplasmic reticulum stress markers. These data suggest that maternal intestinal changes probably contribute to adverse placental adaptations and also impart an increased risk of obesity in the offspring via alterations in fetal gut development. ABSTRACT: Shifts in maternal intestinal microbiota have been implicated in metabolic adaptations to pregnancy. In the present study, we generated cohorts of female C57BL/6J mice fed a control (17% kcal fat, n = 10-14) or a high-fat diet (HFD 60% kcal from fat, n = 10-14; ad libitum) aiming to investigate the impact on the maternal gut microbiota, intestinal inflammation and gut barrier integrity, placental inflammation and fetal intestinal development at embryonic day 18.5. HFD was associated with decreased relative abundances of short-chain fatty acid (SCFA) producing genera during pregnancy. These diet-induced shifts paralleled decreased maternal intestinal mRNA levels of SCFA receptor Gpr41, modestly decreased cecal butyrate, and altered mRNA levels of inflammatory cytokines and immune cell markers in the maternal intestine. Maternal HFD resulted in impaired gut barrier integrity, with corresponding increases in circulating maternal levels of lipopolysaccharide (LPS) and tumour necrosis factor. Placentas from HFD dams demonstrated blood vessel immaturity and hypoxia; decreased free carnitine, acylcarnitine derivatives and trimethylamine-N-oxide; and altered mRNA levels of inflammation, autophagy, and ER stress markers. HFD exposed fetuses had increased activation of nuclear factor-kappa B and inhibition of the unfolded protein response in the developing intestine. Taken together, these data suggest that HFD intake prior to and during pregnancy shifts the composition of the maternal gut microbiota and impairs gut barrier integrity, resulting in increased maternal circulating LPS, which may ultimate contribute to changes in placental vascularization and fetal gut development.

Maternal nutrient restriction impairs young adult offspring ovarian signaling resulting in reproductive dysfunction and follicle loss.

Reproductive abnormalities are included as health complications in offspring exposed to poor prenatal nutrition. We have previously shown in a rodent model that offspring born to nutrient restriction during pregnancy are born small, enter puberty early, and display characteristics of early ovarian aging as adults. The present study investigated whether key proteins involved in follicle recruitment and growth mediate ovarian follicle loss. Pregnant rats were randomized to a standard diet throughout pregnancy and lactation (CON), or a calorie-restricted (50% of control) diet (UN) during pregnancy. Offspring reproductive phenotype was investigated at postnatal days 4, 27, and 65. Maternal UN resulted in young adult (P65) irregular estrous cyclicity due to persistent estrus, a significant loss of antral follicles, corpora lutea, and an increase in atretic follicles. This decrease in growing follicles in UN offspring appears to be due to increased apoptosis as seen by immunopositive staining of pro-apoptotic factor CASP3 (caspase 3) in ovaries of young adult offspring. UN prepubertal offspring had reduced expression levels of Fshr in antral follicles, which may contribute to a decrease in PI3K/AKT activation evident as a decrease in pAKT immunolocalization in prepubertal antral follicles. Moreover, neonatal ovaries of UN offspring show decreased levels of immunopositive staining for AMHR2 (anti-mullerian hormone receptor 2). Collectively, these data demonstrate that maternal UN during pregnancy impacts ovarian function in offspring as early as P65 and provides a model for understanding the mechanisms driving early life UN-induced follicle loss and reproductive dysfunction.

Histomorphologic Analysis of the Late-term Rat Fetus and Placenta.

Histological examination of the rat placenta and fetus is uncommon. Toxicological studies mainly rely on gross examination of the fetus and on fetal and placental weights. These are often insufficient to assess the fetal and placental toxicity of xenobiotics. The small size of the fetus makes its dissection labor-intensive. Thus, our objective was to develop a simple and accurate technique to evaluate the rat fetus and placenta. Sprague-Dawley rat fetuses at gestational day 19.5 ( n = 18) and their placentas ( n = 32) were fixed in formalin. Placentas were cut transversally in the center. Fetuses were cut following a freehand whole-body serial sectioning diagram adapted from Wilson's method. Sections were stained with hematoxylin-eosin-phloxine-saffron, and histomorphometry was used to measure the area of the fetal placental region (27.2 ± 1.7 mm2), including the labyrinth (22.2 ± 1.0 mm2) and the basal zone (4.8 ± 0.8 mm2). Our whole-fetus serial sectioning technique resulted in 12 precise cutting planes that fit on 3 histological slides, enabling the examination of most organs without labor-intensive dissection. Quantitative analysis of placental areas improves the understanding of the pathogenesis of treatment-related changes. This technique provides a standardized method for future research in pertinent fields such as developmental biology and toxicology.

Maternal High-Fat Diet-Induced Loss of Fetal Oocytes Is Associated with Compromised Follicle Growth in Adult Rat Offspring.

Maternal obesity predisposes offspring to metabolic and reproductive dysfunction. We have shown previously that female rat offspring born to mothers fed a high-fat (HF) diet throughout pregnancy and lactation enter puberty early and display aberrant reproductive cyclicity. The mechanisms driving this reproductive phenotype are currently unknown thus we investigated whether changes in ovarian function were involved. Wistar rats were mated and randomized to: dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Ovaries were collected from fetuses at Embryonic Day (E) 20, and neonatal ovaries at Day 4 (P4), prepubertal ovaries at P27 and adult ovaries at P120. In a subset of offspring, the effects of a HF diet fed postweaning were evaluated. The present study shows that fetuses of mothers fed a HF diet had significantly fewer oocytes at E20, and in neonates, have reduced AMH signaling that may facilitate an increased number of assembled primordial follicles. Both prepubertally and in adulthood, ovaries show increased follicular atresia. As adults, offspring have reduced FSH responsiveness, low expression levels of estrogen receptor alpha (Eralpha), the oocyte-secreted factor, Gdf9, oocyte-specific RNA binding protein, Dazl, and high expression levels of the granulosa-cell derived factor, AMH, in antral follicles. Together, these data suggest that ovarian compromise in offspring born to HF-fed mothers may arise from changes already observable in the fetus and neonate and in the long term, associated with increased follicular atresia through adulthood.

Adverse metabolic phenotype of adolescent girls with non-alcoholic fatty liver disease plus polycystic ovary syndrome compared with other girls and boys.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) share risk associations of adiposity and insulin resistance. We examined the impact of a PCOS diagnosis on the metabolic phenotype of adolescent girls with NAFLD and compared this to girls without PCOS or NAFLD and to age-matched boys. METHODS: Community-based adolescents from the Raine Cohort participated in assessments for NAFLD (572 girls and 592 boys) and PCOS (244 girls). One hundred and ninety-nine girls attended both assessments. RESULTS: Amongst the 199 girls, PCOS was diagnosed in 16.1% and NAFLD in 18.6%. NAFLD was diagnosed in 10.1% of the boys. NAFLD was more prevalent in girls with PCOS than girls without PCOS (37.5% vs 15.1%, P = 0.003). Girls with NAFLD plus PCOS had greater adiposity (waist circumference, body mass index, suprailiac skinfold thickness [SST], serum androgens, high-sensitivity C-reactive protein, ferritin, homeostasis model assessment for insulin resistance (HOMA-IR), and lower serum sex hormone binding globulin levels than girls with NAFLD without a PCOS diagnosis (all P < 0.05). Girls with NAFLD plus PCOS had similar adiposity, HOMA-IR, and adiponectin levels to boys with NAFLD, but more adiposity, serum leptin and HOMA-IR than both girls and boys without NAFLD. PCOS (odds ratios 2.99, 95% confidence intervals 1.01-8.82, P = 0.048) and SST (odds ratios 1.14, 95% confidence intervals 1.08-1.20, P < 0.001) independently predicted NAFLD in adolescent girls, however, serum androgens and HOMA-IR levels did not. CONCLUSIONS: Adolescent girls with NAFLD plus PCOS have a similar metabolic phenotype to boys with NAFLD. Increasing SST and pre-existing PCOS independently predict NAFLD in adolescent girls.

Early life exposure to undernutrition induces ER stress, apoptosis, and reduced vascularization in ovaries of adult rat offspring.

Maternal nutritional restriction has been shown to induce impairments in a number of organ systems including the ovary. We have previously shown that maternal undernutrition induces fetal growth restriction and low birth weight, and results in an offspring ovarian phenotype characteristic of premature ovarian aging with reduced ovarian reserve. In the present study, we set out to investigate the underlying mechanisms that lead offspring of undernourished mothers to premature ovarian aging. Pregnant dams were randomized to 1) a standard diet throughout pregnancy and lactation (control), 2) a calorie-restricted (50% of control) diet during pregnancy, 3) a calorie-restricted (50% of control) diet during pregnancy and lactation, or 4) a calorie-restricted (50% of control) diet during lactation alone. The present study shows that early life undernutrition-induced reduction of adult ovarian follicles may be mediated by increased ovarian endoplasmic reticulum stress in a manner that increased follicular apoptosis but not autophagy. These changes were associated with a loss of ovarian vessel density and are consistent with an accelerated ovarian aging phenotype. Whether these changes are mediated specifically by a reduction in the local antioxidant environment is unclear, although our data suggest the possibility that ovarian melatonin may play a part in early life nutritional undernutrition and impaired offspring folliculogenesis.

Of the bugs that shape us: maternal obesity, the gut microbiome, and long-term disease risk.

Chronic disease risk is inextricably linked to our early-life environment, where maternal, fetal, and childhood factors predict disease risk later in life. Currently, maternal obesity is a key predictor of childhood obesity and metabolic complications in adulthood. Although the mechanisms are unclear, new and emerging evidence points to our microbiome, where the bacterial composition of the gut modulates the weight gain and altered metabolism that drives obesity. Over the course of pregnancy, maternal bacterial load increases, and gut bacterial diversity changes and is influenced by pre-pregnancy- and pregnancy-related obesity. Alterations in the bacterial composition of the mother have been shown to affect the development and function of the gastrointestinal tract of her offspring. How these microbial shifts influence the maternal-fetal-infant relationship is a topic of hot debate. This paper will review the evidence linking nutrition, maternal obesity, the maternal gut microbiome, and fetal gut development, bringing together clinical observations in humans and experimental data from targeted animal models.

A Scoping Review of the Relationship Between Maternal BMI and Offspring Incidence of Respiratory Infection: Where Do We Go From Here?

Introduction: Pregnancy complications, including high maternal BMI, are associated with altered early development and child health outcomes. A growing body of work links the prenatal environment, specifically maternal BMI, with respiratory infections in offspring. In this rapid review, the authors review the literature supporting the hypothesis that high maternal BMI during pregnancy is associated with childhood respiratory infection incidence. Methods: The authors employed systematic search criteria in known databases-EMBASE, EMCARE, MEDLINE, CINAHL, and PsychINFO-searching from inception to January 2023. Included were primary research studies that involved (1) human pregnancy, (2) pregravid or gestational overweight or obesity, and (3) childhood respiratory infection with or without hospitalization. Results: Only 7 population-based cohort studies met the criteria, investigating maternal BMI as an exposure and childhood respiratory infection as an outcome (age 6 months to 18 years). Therefore, the authors conducted a qualitative analysis, and outcomes were reported. The authors found that >85% of the albeit few published studies support the hypothesis that maternal BMI may have independent and profound consequences on respiratory infection risk across childhood. Discussion: This area of research needs large-scale, well-controlled studies to better understand the relationship between maternal BMI and childhood respiratory infection. Possible resources such as cohort catalogs and combined databases are discussed. These findings add to the growing evidence that early environmental factors influence lifelong respiratory health. By incorporating a life course approach to infectious disease risk, policy makers can put this research to work and target health vulnerabilities before they arise.

Maternal high-fat diet during pregnancy and lactation affects factors that regulate cell proliferation and apoptosis in the testis of adult progeny.

Context A maternal high-fat diet is thought to pose a risk to spermatogenesis in the progeny. Aims We tested whether a maternal high-fat diet would affect Sertoli cell expression of transcription factors (insulin-like growth factor I (IGF-I); glial-cell line-derived neurotrophic factor (GDNF); Ets variant 5 (ETV5)) and cell proliferation and apoptotic proteins, in the testis of adult offspring. Methods Pregnant rats were fed ad libitum with a standard diet (Control) or a high-fat diet (HFat) throughout pregnancy and lactation. After weaning, male pups were fed the standard diet until postnatal day 160. Males were monitored daily from postnatal day 34 to determine onset of puberty. On postnatal day 160, their testes were processed for morphometry and immunohistochemistry. Key results The HFat diet increased seminiferous-tubule diameter (P P P P P P P P Conclusions A maternal high-fat diet alters the balance between spermatogonia proliferation and spermatid apoptosis. Implications A maternal high-fat diet seems to 'program' adult male fertility.