Long-term Health Of Offspring Research Articles

Maternal obesity and offspring neurodevelopment are associated with hypoxic gene expression in term human placenta.

One third of women in the United States are affected by obesity during pregnancy. Maternal obesity (MO) is associated with an increased risk of neurodevelopmental and metabolic disorders in the offspring. The placenta, located at the maternal-fetal interface, is a key organ determining fetal development and likely contributes to programming of long-term offspring health. We profiled the term placental transcriptome in humans (pre-pregnancy BMI 35+ [MO condition] or 18.5-25 [lean condition]) using single-nucleus RNA-seq to compare expression profiles in MO versus lean conditions, and to reveal potential mechanisms underlying offspring disease risk. We recovered 62,864 nuclei of high quality from 10 samples each from the maternal-facing and fetal-facing sides of the placenta. On both sides in several cell types, MO was associated with upregulation of hypoxia response genes. On the maternal-facing side only, hypoxia gene expression was associated with offspring neurodevelopmental measures, in Gen3G, an independent pregnancy cohort with bulk placental tissue RNA-seq. We leveraged Gen3G to determine genes that correlated with impaired neurodevelopment and found these genes to be most highly expressed in extravillous trophoblasts (EVTs). EVTs further showed the strongest correlation between neurodevelopment impairment gene scores (NDIGSs) and the hypoxia gene score. We reanalyzed gene expression of cultured EVTs, and found increased NDIGSs associated with exposure to hypoxia. Among EVTs, accounting for the hypoxia gene score attenuated 44% of the association between BMI and NDIGSs. These data suggest that hypoxia in EVTs may be a key process in the neurodevelopmental programming of fetal exposure to MO.

P-636 Effects of maternal circadian rhythm changes: intergenerational influences on testicular steroidogenesis in offspring

Abstract Study question Do alterations in the maternal circadian rhythm during pregnancy and lactation result in changes to the male offspring’s testicular steroidogenesis intergenerationally? Summary answer The expression of proteins associated with steroidogenesis is altered due to maternal circadian rhythm changes during pregnancy and lactation periods. What is known already Circadian rhythms impact diverse physiological processes, including reproduction. Several clock genes have been linked to reproductive function. However, there is a complex interaction between hormones, fertility, and the circadian clock. It has been shown that disruption of the circadian clock machinery has negative effects on reproductive biology. Current literature indicates a potential relationship between the circadian clock, testicular steroidogenic-related gene expression profiles, and testosterone synthesis. Steroidogenesis involves a complex cascade of enzymatic reactions. An increasing body of evidence from animal studies suggests a relationship between maternal chronodisruption and long-term offspring health and fertility. Study design, size, duration Male offspring from pregnant Wistar rats (n = 60) were exposed to control (12 hours light/12 hours dark), short day (SD) (8 hours light/16 hours dark), or long day (LD) periods (16 hours light/8 hours dark) during only pregnancy, only lactation, or both periods (n = 6/group) categorized as control, SD pregnancy (SD-P), SD lactation (SD-L), SD pregnancy and lactation (SD-P+L), LD pregnancy (LD-P), LD lactation (LD-L), LD pregnancy and lactation (LD-P+L) groups. Participants/materials, setting, methods The expression of critical components of testicular steroidogenesis, including steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (cytochrome p450scc), 17-beta hydroxysteroid dehydrogenase 3 (HSD17B3), androgen receptor (AR), and luteinizing hormone receptor (LHR), was analyzed in the testis by counting the percentage of positively-stained Leydig cells and ImageJ analysis of immunohistochemistry and western blot. Serum FSH, LH, and testosterone hormones were measured at four zeitgeber time (ZT) points (ZT0, ZT6, ZT12, and ZT18) using ELISA. Main results and the role of chance All of these testicular steroidogenic enzymes were localized in the Leydig cell, and AR was predominantly observed in the Sertoli cell. Although there are no significant differences between the groups in terms of immunolocalization patterns, the expressions of p450scc and AR proteins were significantly decreased in the SD-P and SD-L groups compared to the control group (p < 0.001). In addition, western blot data indicated a decreased expression of p450scc in the SD-P+L group. However, an increased expression of HSD17B3 was detected in both SD-P+L and LD-P+L groups compared to the control group (p = 0.003, p < 0.001, respectively). Among the steroidogenesis-related proteins evaluated, the protein expression levels of StAR and LHR proteins were not altered. FSH showed a statistically significant increase in the LD-L (ZT0), SD-P+L (ZT12), LD-L (ZT12), and LD-P+L (ZT18) groups when compared to the corresponding control groups at the respective time points (p < 0.05). In contrast, LH levels decreased significantly in the LD-P+L (ZT0) group (p < 0.05). Nevertheless, no statistical difference was determined for testosterone levels between groups. Limitations, reasons for caution Most studies on circadian rhythm have used rodent models. Results from animal models are often informative. However, there is a limitation in the appropriate translation of findings in rodents to human studies. Wider implications of the findings The effects triggered by maternal chronodisruption can be intergenerationally transmitted, potentially affecting offspring health. Our results indicate alterations in the expression of proteins involved in testicular steroidogenesis and time-point-dependent changes in the FSH and LH hormone levels due to maternal circadian rhythm changes, further supporting the potential implications for offspring. Trial registration number This work was supported by research grants from the Scientific and Technological Research Council of Turkey (TUBITAK) (SBAG 219S636) and Akdeniz University, The Scientific Research Projects Coordination Unit (TYL-2018-3580).

Maternal smoking during pregnancy could accelerate aging in the adulthood: evidence from a perspective study in UK Biobank

BackgroundMaternal smoking during pregnancy (MSDP) is significantly linked to the short- or long-term health of offspring. However, little research has examined whether MSDP affect the aging rate of offspring. MethodsThis study used questionnaires to determine out whether the participants' mothers smoked when they were pregnant. For evaluating aging rate, we used the following several outcome measures: telomere length, frailty index, cognitive function, homeostatic dysregulation score, KDM-age, age-related hospitalization rate, premature death, and life expectancy. ResultAfter adjusting for covariates, we found that the offspring of the MSDP group had significantly shorter telomere length in adulthood by 0.8 % (β = −0.008,95%CI:−0.009 to −0.006) compared with non-MSDP group. Compared to the non-MSDP group, participants in MSDP group showed higher levels of homeostatic dysregulation (β = 0.015,95%CI: 0.007–0.024) and were frailer (β = 0.008,95%CI:0.007–0.009). The KDM age increased by 0.100 due to MSDP (β = 0.100,95 % CI:0.018–0.181), and the age acceleration of KDM algorithm also increases significantly (β = 0.101, 95%CI:0.020–0.183). Additionally, we found that the risk of aging-related hospitalizations was significantly higher than the non-MSDP group by 10.4 %(HR = 1.104,95%CI:1.066–1.144). Moreover, MSDP group had a 12.2 % increased risk of all-cause premature mortality (HR = 1.122,95%CI:1.064–1.182) and a significant risk of lung cancer-specific premature mortality increased by 55.4 %(HR = 1.554,95%CI:1.346–1.793). In addition, participants in the MSDP group had significantly decreased cognitive function and shorter life expectancies than those in non-MSDP group. ConclusionOur findings indicated a significant association between MSPD and accelerated aging, elevated hospitalization rates, increased premature mortality rates, and reduced life expectancies in offspring.

Respiratory morbidity among offspring misclassified as growth restricted.

An ultrasound-based diagnosis implies that some fetuses suspected to be growth-restricted (FGR) are discovered at birth to be appropriately grown (appropriate for gestational age [AGA] birth weight, between the 10th and 90th percentile). These fetuses may thus be exposed to unnecessary medical interventions, including early labor induction. In this study, we have evaluated the long-term respiratory health of offspring misclassified as FGR. A population-based cohort analysis was conducted, including deliveries of AGA singletons between 1991 and 2021 at a tertiary referral hospital. Incidence of morbidity due to various respiratory conditions was compared between AGA offspring with prenatal diagnosis of FGR, and those without a false diagnosis of FGR. The Kaplan-Meier approach was used to estimate cumulative morbidity incidence. The stratified Cox proportional-hazards model was used to control for confounders. A total of 324,620 deliveries of AGA newborns were included in the analyses; 3249 of them (1.0%) were misclassified prenatally as FGR. The FGR subgroup delivered at an earlier gestational age (36.7 vs. 39.1 weeks, p < .001) and had more than 25% higher incidence of respiratory-related morbidity during childhood (33.2% vs. 26.5%), specifically related to asthma and obstructive sleep apnea (p < .001 for all). A higher cumulative morbidity rate due to respiratory conditions was observed in the Kaplan-Meier survival curve (log-rank p value < .001). This association between FGR and respiratory morbidity was independent of preterm delivery, maternal age, cesarean delivery, and child's birth year (adjusted hazard ratio = 1.14, 95% confidence interval: 1.07-1.21, p < .001), using a Cox proportional hazards model. AGA newborns misclassified as FGR, are at an increased risk for long-term respiratory morbidity during childhood and adolescence.

Early-life exposures and long-term health: adverse gestational environments and the programming of offspring renal and vascular disease.

According to the Developmental Origins of Health and Disease hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight-indicators of a suboptimal intrauterine environment. In different animal models, the main suboptimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signaling pathways controlling endocrine, excretion, and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.NEW & NOTEWORTHY Human data and experimental animal data show that suboptimal environments during fetal development increase the risk of renal and vascular diseases in adult-life. This is related to permanent changes in kidney structure, function, and expression of genes and signaling pathways controlling filtration, excretion, and endocrine function. Uncovering the mechanisms by which offspring renal development and function is impacted is important for identifying ways to mitigate the development of diseases that strain health care services worldwide.

Contribution of the seminal microbiome to paternal programming.

The field of Developmental Origins of Health and Disease (DOHaD) has primarily focused on maternal programming of offspring health. However, emerging evidence suggests that paternal factors, including the seminal microbiome, could potentially play important roles in shaping the developmental trajectory and long-term offspring health outcomes. Historically, the microbes present in the semen were regarded as inherently pathogenic agents. However, this dogma has recently been challenged by the discovery of a diverse commensal microbial community within the semen of healthy males. In addition, recent studies suggest that the transmission of semen-associated microbes into the female reproductive tract during mating has potentials to not only influence female fertility and embryo development but could also contribute to paternal programming in the offspring. In this review, we summarize the current knowledge on the seminal microbiota in both humans and animals followed by discussing their potential involvement in paternal programming of offspring health. We also propose and discuss potential mechanisms through which paternal influences are transmitted to offspring via the seminal microbiome. Overall, this review provides insights into the seminal microbiome-based paternal programing, which will expand our understanding of the potential paternal programming mechanisms that currently are focused on the epigenetic modifications, oxidative stresses, and cytokines.

The influence of maternal prepregnancy weight and gestational weight gain on the umbilical cord blood metabolome: a case–control study

BackgroundMaternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles.MethodsA case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS.ResultsForty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P < 0.01).ConclusionsPrepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.

A maternal ketogenic diet alters oviduct fluid nutrients and embryo histone acetylation in mice.

A ketogenic diet (KD) elevates blood β-hydroxybutyrate to concentrations that are known to perturb the development, metabolism, histone acetylation and viability of preimplantation mouse embryos in culture. This study shows that a maternal KD changes available nutrient levels in the oviduct, leading to altered embryo development and epigenetic state in vivo. A ketogenic diet elevates blood β-hydroxybutyrate to concentrations that perturb the development, metabolism, histone acetylation (H3K27ac) and viability of preimplantation mouse embryos in vitro. However, whether a ketogenic diet alters β-hydroxybutyrate concentrations within female reproductive fluid is unknown. This study aimed to quantify glucose and β-hydroxybutyrate within mouse blood and oviduct fluid following standard diet and ketogenic diet consumption and to assess whether a maternal periconceptional ketogenic diet impacts in vivo embryo development and blastocyst H3K27ac. Female C57BL/6 × CBA mice were fed a standard or ketogenic diet (n = 24 each) for 24-27 days. Glucose and β-hydroxybutyrate were quantified in blood via an electronic monitoring system and in oviduct fluid via ultramicrofluorescence. The developmental grade of flushed blastocysts was recorded, and blastocyst cell number and H3K27ac were assessed via immunofluorescence. A maternal ketogenic diet elevated β-hydroxybutyrate in day 24 blood (P < 0.001) and oviduct fluid (P < 0.05) compared with a standard diet, whereas glucose was unchanged. A periconceptional ketogenic diet did not impact blastocyst cell number; however, it significantly delayed blastocyst development (P < 0.05) and reduced trophectoderm-specific H3K27ac (P < 0.05) compared with standard diet-derived embryos. Maternal ketogenic diet consumption is, therefore, associated with reproductive tract nutrient changes and altered embryonic development and epigenetics in vivo. Future studies to assess whether periconceptional/gestational ketogenic diet consumption impacts human preimplantation, fetal, and long-term offspring development and health are warranted.

Improving Women's Health and Immunity: A Thorough Mapping Micronutrients and Dietary Recommendations

Abstract: In particular, throughout life, women's health depends on having an ideal micronutrient level. Thus, pregnancy outcomes and the long-term health of a woman's offspring are significantly influenced by her physical and nutritional well-being during the preconception stage. Various nutrients are required in sufficient amounts to fulfill the requirements at the various phases in the life of females. Our analysis of the state of nutrition shows illnesses connected to micronutrient deficiencies, particularly anemia and its related deficiencies. Peer-reviewed publication databases and publicly available data from international and national sources were targeted in a structured literature search to sort out the direct or indirect association between the different micronutrients, their levels, sources and significance in the various stages of life of females. The goal of the current review is to identify any direct or indirect relationships between the numerous micronutrients, their sources, concentrations, and importance at different phases of female development.

Long-term health risk of offspring born from assisted reproductive technologies.

Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

High-Dose Vitamin D Supplementation Significantly Affects the Placental Transcriptome.

Vitamin D deficiency is a highly prevalent obstetrical concern associated with an increased risk of complications like pre-eclampsia, gestational diabetes, and growth retardation. Vitamin D status in pregnancy is also linked to long-term offspring health, e.g., the risk of obesity, metabolic disease, and neurodevelopmental problems. Despite the suspected role of vitamin D in placental diseases and fetal development, there is limited knowledge on the effect of vitamin D on placental function. Thus, we performed next-generation RNA sequencing, comparing the placental transcriptome from uncomplicated term pregnancies receiving the often-recommended dose of 10 µg vitamin D/day (n = 36) with pregnancies receiving 90 µg/day (n = 34) from late first trimester to delivery. Maternal vitamin D status in the first trimester was also considered. We found that signaling pathways related to cell adhesion, immune function, and neurodevelopment were affected, supporting that increased vitamin D supplementation benefits placental function in established pregnancies without severe vitamin D deficiency, also underlining the importance of vitamin D in brain development. Specific effects of the first trimester vitamin D status and offspring sex were also identified. Further studies are warranted, addressing the optimal vitamin status during pregnancy with a focus on organ-specific vitamin D needs in individual pregnancies.

Early life gut microbiome in children following spontaneous preterm birth and maternal preeclampsia

The early life microbiome plays an important role in developmental and long-term health outcomes. However, it is unknown whether adverse pregnancy complications affect the offspring's gut microbiome postnatally and in early years. In a longitudinal cohort with a five-year follow-up of mother-child pairs affected by preeclampsia (PE) or spontaneous preterm birth (sPTB), we evaluated offspring gut alpha and beta diversity as well as taxa abundances considering factors like breastfeeding and mode of delivery. Our study highlights a trend where microbiome diversity exhibits comparable development across adverse and normal pregnancies. However, specific taxa at genus level emerge with distinctive abundances, showing enrichment and/or depletion over time in relation to PE or sPTB. These findings underscore the potential for certain adverse pregnancy complications to induce alterations in the offspring's microbiome over the course of early life. The implications of these findings on the immediate and long-term health of offspring should be investigated in future studies.

Research Progress of Maternal Metabolism on Cardiac Development and Function in Offspring.

The developmental origin of health and disease (DOHaD) hypothesis refers to the adverse effects of suboptimal developmental environments during embryonic and early fetal stages on the long-term health of offspring. Intrauterine metabolic perturbations can profoundly impact organogenesis in offspring, particularly affecting cardiac development and giving rise to potential structural and functional abnormalities. In this discussion, we contemplate the existing understanding regarding the impact of maternal metabolic disorders, such as obesity, diabetes, or undernutrition, on the developmental and functional aspects of the offspring's heart. This influence has the potential to contribute to the susceptibility of offspring to cardiovascular health issues. Alteration in the nutritional milieu can influence mitochondrial function in the developing hearts of offspring, while also serving as signaling molecules that directly modulate gene expression. Moreover, metabolic disorders can exert influence on cardiac development-related genes epigenetically through DNA methylation, levels of histone modifications, microRNA expression, and other factors. However, the comprehensive understanding of the mechanistic underpinnings of these phenomena remains incomplete. Further investigations in this domain hold profound clinical significance, as they can contribute to the enhancement of public health and the prevention of cardiovascular diseases.

Early life impacts of maternal obesity: a window of opportunity to improve the health of two generations.

The number of pregnancies complicated by obesity is increasing in line with the worldwide obesity crisis; recent estimates suggest that in developed countries more than 50% of pregnancies are in women who are overweight or have obesity. Maternal obesity is associated with an increased risk of many adverse outcomes for both the mother and baby during pregnancy and birth. In addition to these immediate outcomes, maternal obesity before and during pregnancy is associated with an increased risk of offspring cardio-metabolic disease later in life. Studies comparing siblings discordant for in utero exposure to maternal obesity suggest this is not simply due to transmission of 'obesogenic genes' between mother and child or current lifestyle factors, but reflects a direct impact of the obese intrauterine environment on fetal development. This review will describe the long-term consequences of exposure to maternal obesity during development for the cardio-metabolic health of the offspring. It will also discuss the potential molecular mechanisms that underlie the increased risk of metabolic disease in offspring of mothers with obesity, and explore interventions that may be implemented during pregnancy to limit the impact of obesity on offspring long-term health. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Burden of excessive gestational weight gain and postpartum weight retention among Indian women - A systematic review and meta-analysis

BackgroundExcessive weight gain during pregnancy and weight retention in the postpartum period may lead to obesity, diabetes mellitus, and cardiovascular events among women in later life, as well as adverse perinatal outcomes, and long-term offspring health outcomes during the current and subsequent pregnancies. However, most studies of gestational weight gain (GWG) and postpartum weight retention (PPWR) are in western and developed countries. Therefore, this paper aimed to determine the burden of gestational weight gain and postpartum weight retention among Indian women. Materials & methodsThree electronic database- Medline, Google Scholar, and Cochrane library were searched for studies up until March 31, 2022. Studies on GWG and PPWR from India were included in the review. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist was used for reporting the current review. Online platform Rayyan was used to screen and select the studies. Data were extracted from the 13 selected articles and pooled estimates, proportion and mean of GWG & PPWR along with 95% CI were estimated. ResultsOverall 271 articles were identified after the initial search and 13 articles were included (n = 6656) in the review. Nine studies reported proportion of women with excessive GWG, seven studies reported mean GWG and three studies described weight retention among postpartum mothers. The pooled proportion of Indian pregnant women with excessive GWG was found to be 16.48% (95% CI: 11.52, 21.43) and the pooled mean of GWG was 10.08 kg (95% CI: 7.81–12.34). The highest pooled proportion of women with excessive GWG was reported in the North region with 22.57% and the lowest in the East region with 9.15%. The highest pooled mean of GWG was reported in the East region with 12.90 kg and the lowest in the North region with 6.40 kg. Findings from three studies were systematically reviewed and summarized for postpartum weight retention among Indian women. ConclusionAlthough majority of Indian women achieved GWG less than the recommendations, there is a need for larger population based surveys among Indian women to obtain adequate, appropriate and complete health related information about weight changes during and after pregnancy.

Prenatal exposure to CB2 receptors agonist differentially impacts male and female germ cells via histone modification

Cannabis use during pregnancy is increasing in the last few years potentially because of decreased perception of the risk of harm. Regardless, recent evidence demonstrated that prenatal cannabis exposure is associated with adverse outcomes. To date there is limited evidence of the impact of cannabis exposure during pregnancy on the reproductive health of the offspring. The biological effects of cannabis are mediated by two cannabinoid receptors, CB1 and CB2. We previously demonstrated that CB2 is highly expressed in mouse male and female fetal germ cells. In this study, we investigated the effects of prenatal exposure to a selective CB2 agonist, JWH-133, on the long-term reproductive health of male and female offspring and on the involved molecular epigenetic mechanisms. Notably, we focused on epigenetic histone modifications that can silence or activate gene expression, playing a pivotal role in cell differentiation. We reported that prenatal activation of CB2 has a sex-specific impact on germ cell development of the offspring. In male it determines a delay of germ cell differentiation coinciding with an enrichment of H3K27me3, while in female it causes a reduction of the follicles number through an increased apoptotic process not linked to modified H3K27me3 level.

O-159 Impact of open and closed methods of vitrification on oocyte mitochondria function and RNAseq transcriptome profile: a preclinical screening study

Abstract Study question Do current methods of open vitrification (OV) and closed vitrification (CV) impact on oocyte mitochondria function and transcriptome? Summary answer Oocyte vitrification confers unique mitochondria distribution patterns and alters the expression of stress response genes and mitochondria function relative to control (fresh) oocytes. What is known already Mitochondria are essential for maintenance of metabolic function and developmental competence at physiological conditions. Conversely, open and closed methods of oocyte vitrification are associated with physical, chemical and non-physiological changes, and exposures to cryoprotecting agents which could be harmful at extremely high and low temperatures. Study design, size, duration Ninety-four unfertilised Metaphase II (MII) oocytes were donated to research between May 2018 and August 2021. Fifty-seven oocytes were randomly allocated to the different study groups. Similarly, thirty-seven oocytes were allocated to the different study control groups. Participants/materials, setting, methods Fourteen women underdoing IVF/ICSI treatment cycles were involved in the study. cDNA was obtained for qPCR and the Smart-Seq2 protocol and single-cell RNA-Seq was performed (illumina NextSeq2000). Mitochondrial staining on live-oocytes was performed using Mito-tracker Deep Red stain, and images evaluated using fluorescence microscopy. Differentially expressed genes were identified using the R package edgeR and functional gene ontology was performed using an over-representation analysis via WebGestalt. Correction for multiple testing was calculated using Benjamini-Hochberg method Main results and the role of chance Mean mitochondrial intensity/density showed similarities between open (OV) and closed vitrification (CV) and control (fresh oocytes FO): 25.8 (12.7-44.9, standard deviation [SD] 10.2) for FO oocytes (n = 15), 30.3 (16.2-44.8, SD 10.1) for OV oocytes (n = 11), 26.6 (13.3-64.6, SD 15.3) for CV oocytes (n = 12) (p = 0.617). Distinct mitochondria distribution patterns (cytoplasmic and peripheral) were associated with OV and CV oocytes. Twice as many peripheral to cytoplasmic patterns were observed in FO and OV oocytes in contrast to CV oocytes (p = 037). Mean expression of the gene SDHB, which is associated with the TCA cycle and the mitochondrial electron transport chain was reduced in vitrified oocytes (n = 13) (0.0879 ± 0.0216 vs 0.0593 ± 0.0479), as was the anti-apoptotic gene BCL2 (p = 0.0061), relative to control oocytes (n = 13), (p = 0.01). Conversely, genes associated with apoptosis and stress response (BAX (p = 0.002) and BCL2L1 (p = 0.016)) were significantly enriched relative to control oocytes. RNAseq transcriptome analysis revealed a total of 71 differentially expressed genes following vitrification relative to control oocytes. Genes associated with critical metabolic processes (death domain binding, BCL-2 homology 3 (BH3) domains, and exopolyphosphatatse activities) were enriched in vitrified oocytes relative to the control group (FDR&amp;gt;0.05). Limitations, reasons for caution The use of unfertilised metaphase II (MII) oocytes on day 1 as a preclinical application screening model for vitrification may not reflect the molecular status and integrity of clinical grade MII oocytes on day 0. Wider implications of the findings This study emphasizes the inherent impact of vitrification on oocyte mitochondria function and transcriptome relative to control oocytes. Importantly, unintended perturbations may be detrimental to oocyte health and developmental competence, suggesting the need for a continuous safety screening and monitoring of ART methods of cryopreservation and offspring long-term health. Trial registration number National Institute for Health Research (NIHR). Grant Reference: ICA-CDRF-2015-01-068

The impact of maternal bariatric surgery on long-term health of offspring: a scoping review.

While pregnancy post-bariatric surgery has become increasingly common, little is known about whether and how maternal bariatric surgery affects the next generation. This scoping review aimed to collate available evidence about the long-term health of offspring following maternal bariatric surgery. A literature search was conducted using three databases (PubMed, PsycINFO, EMBASE) to obtain relevant human and animal studies. A total of 26 studies were included: 17 were ancillary reports from five "primary" studies (three human, two animal studies) and the remaining nine were "independent" studies (eight human, one animal studies). The human studies adopted sibling-comparison, case-control, and single-group descriptive designs. Despite limited data and inconsistent results across studies, findings suggested that maternal bariatric surgery appeared to (1) modify epigenetics (especially genes involved in immune, glucose, and obesity regulation); (2) alter weight status (unclear direction of alteration); (3) impair cardiometabolic, immune, inflammatory, and appetite regulation markers (primarily based on animal studies); and (4) not affect the neurodevelopment in offspring. In conclusion, this review supports that maternal bariatric surgery has an effect on the health of offspring. However, the scarcity of studies and heterogenous findings highlight that more research is required to determine the scope and degree of such effects. IMPACT: There is evidence that bariatric surgery modifies epigenetics in offspring, especially genes involved in immune, glucose, and obesity regulation. Bariatric surgery appears to alter weight status in offspring, although the direction of alteration is unclear. There is preliminary evidence that bariatric surgery impairs offspring's cardiometabolic, immune, inflammatory, and appetite regulation markers. Therefore, extra care may be needed to ensure optimal growth in children born to mothers with previous bariatric surgery.

Maternal particulate matter exposure and gestational diabetes mellitus: a population–based cohort study

Gestational diabetes mellitus (GDM) prevalence is steadily increasing worldwide, posing a significant threat to the short- and long-term health of both mother and offspring. As particulate matter (PM) air pollution has been reported to affect glucose metabolism, it was suggested that maternal PM exposure may be associated with the development of GDM; however, evidence is limited and inconsistent. To study the association between maternal exposure to PM2.5 and PM10 and the risk of GDM, to identify critical windows of susceptibility and to evaluate effect modification by ethnicity. A retrospective cohort study was conducted including pregnancies of women who delivered at a large tertiary medical center in Israel between the years 2003 and 2015. Residential PM levels were estimated by a hybrid spatiotemporally resolved satellite-based model at 1-km spatial resolution. Multivariable logistic analyses were applied to study the association between maternal PM exposure in different pregnancy periods and GDM risk, while adjusting for background, obstetrical and pregnancy characteristics. Analyses were also stratified by ethnicity (Jewish / Bedouin). The study included 89,150 pregnancies, 3,245 (3.6%) were diagnosed with GDM. First trimester exposure to both PM2.5 (adj. OR per 5 μg/m3 = 1.09; 95%CI: 1.02, 1.17) and PM10 (adj. OR per 10 μg/m3 = 1.11; 95%CI: 1.06, 1.17) was significantly associated with increased risk for GDM. In the stratified analyses, the association with first trimester PM10 exposure was consistent among pregnancies of both Jewish and Bedouin women, while the association with first trimester PM2.5 exposure was significant among pregnancies of Jewish women only (adj. OR per 5 μg/m3 = 1.09; 95%CI: 1.00, 1.19), as well as association with preconception PM10 exposure (adj. OR per 10 μg/m3 = 1.07; 95%CI: 1.01, 1.14). No association was found between second trimester PM exposure and GDM risk. Maternal exposure to both PM2.5 and PM10 during the first trimester of pregnancy is associated with GDM, suggesting the first trimester as a particular window of susceptibility to the effect of PM exposure on GDM risk. The effects found in this study differed by ethnic group, emphasizing the importance of addressing ethnic disparities when assessing environmental impacts on health.

Maternal Obesity Increases the Risk for Hepatocellular Carcinoma in a Toxic Liver Cancer Model Through the Gut Microbiome

Abstract Background The obesity pandemic leads to rising obesity rate in women of reproductive age with emerging evidence that maternal obesity has a negative impact on the long-term health of offspring. Additionally, obesity is an independent risk factor for malignancies and particularly hepatocellular carcinoma (HCC). Aims The aim of our study is to investigate the impact of maternal obesity on the risk for HCC in the offspring and identify potential mechanisms of transmission. Methods Female mice were fed either a high fat (HFD) or a normal diet (ND) before mating. Offspring received ND throughout life. We studied the liver histology and tumor load in a short-term transgenic (12 weeks) or a toxin induced long-term (36 weeks) HCC mouse model. To normalize the gut microbiome, we co-housed offspring of HFD and ND mothers after weaning. The composition of the gut microbiota was assessed through 16S rRNA sequencing. Results Maternal obesity induced a distinguishable shift in the microbial composition towards decreased microbial diversity (2.56 vs. 2.92, p=0.0089), increased proportions of Firmicutes and decreased abundance of Bacteroidota. At 40 weeks female HFD offspring developed steatosis (9.43 vs 3.09%, p=0.0023) and a higher number of inflammatory infiltrates (4.8 vs 1.0, p=0.018) compared to ND offspring. A higher proportion of female HFD offspring developed liver tumors after DEN induction (79.8 vs 37.5%, p=0.0084) with a higher total tumor volume at 36 weeks (234 vs 3 µm3, p=0.0041). An effect that we did not observe in the short-term transgenic model. Gut microbiome composition was corrected through co-housing offspring and co-housing normalized the tumor number and volume to the level of ND offspring. Conclusions Maternal obesity increases the susceptibility to develop HCC in offspring. The transmission of an altered gut microbiome appears to play an important role in this increased long-term risk profile.