Multigenerational Programming Research Articles

Abstract Tu111: Effect Of Grandmaternal Diabetes and High Fat Diet on Cardiometabolic Dysfunction in the Second Generation (F2) Newborns

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. We have previously used a rat model to demonstrate that a combination of high fat diet (HFD) and late gestational diabetes causes impaired cardiac function in first generation (F1) newborn and adult offspring via mitochondrial dysfunction and metabolic stress. The objective of this study was to determine whether grandmaternal HFD and diabetes can cause inheritable CVD in second generation offspring (F2), even if the first generation is cross fostered during lactation and fed a standard control diet throughout life. Myocardial function in the F2 newborns was assessed using echocardiography and mitochondrial function in the isolated neonatal cardiomyocytes (NRCM) was assessed using extracellular flux analyses. Exposed F2 newborns had a higher birthweight (p=0.03) and blood glucose (p<0.0001) compared to control newborns and F1 generation parents (p=0.0002 and p<0.0001). Of significant interest, exposed F2 newborns had higher heart rates (p<0.0001), heart:body weight ratios (p<0.0001) and systolic dysfunction which was evident from lower ejection fraction (p<0.0001) and fractional shortening (p<0.0001) compared to control F2 newborns. While control and combination exposed NRCM had similar basal respiration, exposed F2 NRCM had a higher proton leak (p=0.0004) which indicates damage to the inner mitochondrial membrane and/or electron transport chain complex. There was also shift to higher glycolysis at baseline (p=0.005), but blunted glucose-induced glycolytic rate (p=0.04) in F2 newborns compared to controls. Overall results suggest that maternal HFD and diabetes causes multigenerational programming of cardiometabolic dysfunction in F2 offspring despite the F1 parent having normal diet, weight, and euglycemia during the pregnancy.

A SCOPING REVIEW OF LGBTQ+ MULTIGENERATIONAL PROGRAMMING: GAPS AND OPPORTUNITIES

Abstract Extensive research has revealed disparities in health, housing, employment, and economics among LGBTQ+ older adults (Emlet, 2016). However, the LGBTQ+ community has a long-standing tradition of multigenerational support that can potentially alleviate some of these challenges. Innovative caregiving models and non-traditional support systems involving multigenerational networks have emerged during crises such as the AIDS epidemic of the 1980s and 1990s and the recent COVID-19 pandemic (Cahill & Valadéz, 2013; Hafford-Letchfield et al., 2022). Nevertheless, despite the growing attention to LGBTQ+ multigenerational programs, the current state of scholarly research in this area remains uncertain. To address this gap, this scoping review aims to map the literature on intergenerational interventions for the LGBTQ+ community. This study includes peer-reviewed research in English with various study designs related to different categories of intervention, program, or activity that involve LGBTQ+ participants from more than one generation. To ensure accurate and reliable results, we conducted a comprehensive search on seven databases: PsycINFO, PubMed, Web of Science, Scopus, Sociological Abstract, Embase, and CINAHL. After deleting duplicates, 130 peer-reviewed articles were identified. Preliminary findings from the scoping review reveal historical moments when research on multigenerational programming surged, which aligns with pivotal crisis moments in the LGBTQ+ community. It also underscores emerging trends in multigenerational programming, including critical inquiry about what constitutes “multigenerational” and deeper commitment to inclusion of communities of color and transgender communities. These findings provide important insights for practitioners, policymakers, and researchers to strengthen services and support for LGBTQ+ older adults.

Maternal High-Fat Diet Multigenerationally Programs HPA Function and Behaviors in Male Rat Offspring.

Maternal environmental factors have been demonstrated to exert significant influences on the health of offspring. The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine stress system that can be influenced by early life challenges. Our previous research has revealed that the consumption of a high-fat diet (HFD) by pregnant and lactating rats leads to the programming of HPA axis activity in male offspring of the first generation (referred to as F1HFD/C). The present study aimed to investigate whether the observed remodeling of the HPA axis could be inherited by second-generation male offspring (referred to as F2HFD/C), following maternal HFD exposure. The results showed that F2HFD/C rats exhibited enhanced basal HPA axis activity, similar to their F1HFD/C ancestors. Moreover, F2HFD/C rats displayed exacerbated corticosterone responses to restraint and lipopolysaccharide-induced stress, but not to insulin-induced hypoglycemia stress. Furthermore, maternal HFD exposure significantly aggravated depression-like behavior in the F2 generation subjected to chronic unpredictable mild stress. To investigate the role of central calcitonin gene-related peptide (CGRP) signaling in maternal diet-induced programming of the HPA axis across generations, we conducted central infusion of αCGRP8-37, a CGRP receptor antagonist, in F2HFD/C rats. The results demonstrated that αCGRP8-37 attenuated depression-like behaviors and reduced the hyperresponsiveness of the HPA axis to restraint stress in these rats. Therefore, central CGRP signaling may contribute to maternal diet-induced programming of HPA axis across generations. In conclusion, our study provides evidence that maternal HFD consumption can lead to multigenerational programming of the HPA axis and behaviors in adult male descendants.

Effects of maternal obesity in an ovine model on metabolic outcomes in F2 adults and F3 neonates

Accumulating evidence suggests that indications of metabolic syndrome can be inherited through the germline as a result of maternal obesity. We hypothesized that diet-induced maternal obesity during gestation would program metabolic consequences for multiple generations of offspring, even when first, second, and third generation offspring (F1, F2, F3, respectively) were fed only to requirements. Control (CON) and obese (OB) ewes (generation 0; F0) were bred to a single ram to produce the first generation of offspring (F1). From 60 d prior to conception through term, CONF0 ate 100% National Research Council recommendations (NRC), while OBF0 ewes ate 150% NRC. All F1, F2, and F3 ate 100% NRC after weaning. All mature F1 ewes were bred to a single ram to generate CONF2 (n = 6) and OBF2 (n = 10). All mature F2 ewes were bred to a single ram to produce CONF3 (n = 6) and OBF3 (n = 10). OBF2 ewes exhibited greater (P < 0.0001) plasma cortisol than CONF2 throughout gestation. A glucose tolerance test at 90% gestation revealed OBF2 ewes had higher (P < 0.05) insulin response with similar glucose, resulting in greater (P < 0.05) insulin resistance. OBF3 neonates had similar weight, lean mass, and body fat mass to CONF3 neonates. These data suggest that multigenerational programming of adverse metabolic phenotypes occur in association with F0 maternal obesity, yet adiposity may return to CON levels in F3 neonates.

Developmental Programming of NAFLD by Parental Obesity.

The surge of obesity across generations has become an increasingly relevant issue, with consequences for associated comorbidities in offspring. Data from longitudinal birth cohort studies support an association between maternal obesity and offspring nonalcoholic fatty liver disease (NAFLD), suggesting that perinatal obesity or obesogenic diet exposure reprograms offspring liver and increases NAFLD susceptibility. In preclinical models, offspring exposed to maternal obesogenic diet have increased hepatic steatosis after diet-induced obesity; however, the implications for later NAFLD development and progression are still unclear. Although some models show increased NAFLD incidence and progression in offspring, development of nonalcoholic steatohepatitis with fibrosis may be model dependent. Multigenerational programming of NAFLD phenotypes occurs after maternal obesogenic diet exposure; however, the mechanisms for such programming remain poorly understood. Likewise, emerging data on the role of paternal obesity in offspring NAFLD development reveal incomplete mechanisms. This review will explore the impact of parental obesity and obesogenic diet exposure on offspring NAFLD and areas for further investigation, including the impact of parental diet on disease progression, and consider potential interventions in preclinical models.

Grillin’ with My Grandchild©: multigenerational programming for grandfathers and grandchildren

ABSTRACTThis article describes the Grillin’ with My Grandchild© multigenerational relationship education program which is designed to encourage the enhancement and maintenance of a meaningful grandfather-grandchild relationship. During this multi-session program, grandfather and grandchild participants engage in several activities which include creating an electronic memory book as well as grilling and eating food together. They learn through facilitated discussion and by sharing personal experiences what it means to be a grandfather and a grandchild. Facilitated discussion about nutritional grilling practices and safe food grilling are implemented at each session. Grandfather-grandchild dyads interact with other familial dyads in their group and experience a sense of community and familiarity. Future research into the relational and psychological benefits of the program are suggested.

Generations learning together: pilot study for a multigenerational program

ABSTRACTGenerations need to spend time in meaningful activities to facilitate more healthy interactions. An interdisciplinary team worked together to implement an enriching, intergenerational project with 4 year olds, college students, and older adults. College students played an active role in planning/facilitating activities. The overall objective of the research was assessing perceptional change between the generations using pre/posttests with college students, pre-post interviews with older adults, and pre-post teacher led discussions with children. Findings suggest that older adults and college students had improved perceptions. Children’s perceptions remained negative with some positive perceptions.

Multigenerational impact of maternal overnutrition/obesity in the sheep on the neonatal leptin surge in granddaughters.

Background/ObjectivesWe have reported that maternal overnutrition/obesity (OB) in sheep resulting from feeding 150% of National Research Council (NRC) requirements throughout gestation, leads to maternal hyperglycemia and hyperinsulinemia. Further, newborn lambs born to OB vs. control-fed (CON, 100% of NRC) ewes exhibited greater adiposity, increased blood cortisol, insulin and glucose and the elimination of the postnatal leptin spike seen in lambs born to CON ewes. This early postnatal leptin peak is necessary for development of hypothalamic circuits which program appetite in later life. This study evaluated the multigenerational impact of OB on insulin:glucose dynamics of mature female F1 offspring fed only to requirements throughout gestation, and on their lambs (F2 generation).Design and MethodsAdult F1 female offspring born to OB (n=10) or CON (n=7) ewes were utilized. All F1 ewes were subjected to a glucose tolerance test at midgestation and late gestation. Jugular blood was obtained from F2 lambs at birth (day 1) through postnatal day 11, and plasma glucose, insulin, cortisol and leptin concentrations determined. Dual Energy X-ray Absorptiometry (DEXA) was utilized to determine bone mineral density (BMD), bone mineral content (BMC), lean tissue mass, and fat tissue mass.ResultsFasted blood glucose and insulin concentrations were greater (P < 0.05) in OBF1 than CONF1 ewes at mid- and late gestation. Further, after glucose infusion, both glucose and insulin concentrations remained higher in OBF1 ewes (P < 0.05) than CONF1 ewes demonstrating greater insulin resistance. Blood concentrations of glucose, insulin, and cortisol, and adiposity were higher (P < 0.01) in OBF2 lambs than CONF2 lambs at birth. Importantly, OBF2 lambs failed to exhibit the early postnatal leptin peak exhibited by CONF2 lambs.ConclusionsThese data suggest that these OBF2 lambs are predisposed to exhibit the same metabolic alterations as their mothers, suggesting a multi-generational programming effect.

Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids

Synthetic glucocorticoid administration to women threatening preterm delivery increases neonatal survival. However, mounting evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation adversely programs offspring development. We examined fetal synthetic glucocorticoid multigenerational metabolic effects on F1 and F2 female offspring. At 0.7 gestation, pregnant F0 ewes received 4 injections of dexamethasone (2 mg, approximately 60 ug.kg(-1) day(-1) 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal pancreatic β-cell function was tested in F1 and F2 by intravenous glucose tolerance test. F1 and F2 ewe lambs showed reduced birthweight and morphometrics, and similar increased fasting glucose and decreased intravenous glucose tolerance test β-cell response. This is the first demonstration of multigenerational programming of later life β-cell response by clinically relevant doses of synthetic glucocorticoid indicating the need for study of long-term effects of fetal exposure to synthetic glucocorticoid.

Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects

Exposure to an adverse early life environment is associated with increased cardio-metabolic disease risk, a phenomenon termed "programming." The effects of this are not limited to the exposed first (F1) generation but can be transmissible to a second generation (F2) through male and female lines. Using a three generation animal model of programming by initial prenatal glucocorticoid overexposure we have identified effects on fetal and placental weight in both the F1 and F2 offspring. However, the expression of candidate imprinted genes in the fetus and placenta differed between the F1 and F2, with marked parent-of-origin effects in F2. Since DNA methylation at imprinted genes is maintained at fertilization, they are potential templates for the transmission of programming effects across generations. Although we detected alterations in DNA methylation at differentially methylated regions (DMRs) of the key prenatal growth factor Igf2 in F1 and F2 fetal liver, the changes in DNA methylation at these DMRs do not appear to underlie the transmission of effects on Igf2 expression through sperm. Thus, multigenerational programming effects on birth weight and disease risk is associated with different processes in F1 and F2. These findings have implications for the pathogenesis and future attempts to stratify therapies for the ‘developmental component’ of cardiometabolic disease.