Shaping the future heart: transgenerational outcomes of maternal metabolic syndrome

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the world, accounting for 17.3 million deaths per year and expected to grow to greater than 23.6 million by 2030 (10). Among numerous nonmodifiable and modifiable risk factors associated with CVD, obesity has reached epidemic proportions worldwide. Recent statistics have underscored that preconceptional maternal obesity is associated with early pregnancy loss, development of gestational diabetes mellitus (DM) and preeclampsia, and an increased risk of congenital fetal malformations; furthermore, increasing data supports that subsequent generations born to obese mothers are at risk for DM and CVD (8). Yet, the precise mechanisms by which maternal lifestyle potentiates these cardiometabolic diseases in future offspring later in life remain largely unknown.

The concept of developmental plasticity first emerged from the Barker hypothesis in “Fetal Origins of Adult Disease” and later expanded to the “Developmental Origins of Health and Disease,” and it posits that chronic, degenerative conditions during adulthood may be triggered by poor environmental exposures during embryonic and fetal life (2). Increasing evidence from several model organisms has demonstrated that environmental insults, including exposure to maternal hyperglycemia, obesity, or dyslipidemia during critical periods of fetal development, drive structural and metabolic alterations leading to an increased risk of short- and long-term cardiac complications (3). The effect of in utero and early-life conditions on adult health and disease requires stable modulation of gene expression by non-DNA sequence-based mechanisms. These are further classified as genome-dependent (e.g., chromosomal alterations, posttranslational modification of histones, DNA methylation, noncoding and coding RNAs) or genome-independent (altered mitochondrial dynamics, metabolite and microbiome transfer) mechanisms (3, 7). Briefly, transgenerational inheritance (TGI) refers to the transmission of information that passes to more than one future generation in the absence of original trigger on either the embryo or germ cells that will eventually become the fetus. Unlike TGI, intergenerational epigenetic inheritance (IGI) spans a shorter timescale and describes the transfer of epigenetic code from parent to offspring via the germline (Fig. 1). Given the well-conserved nature of epigenetic mechanisms, TGI and IGI depend on the type and dosage of environmental stress and degree of epigenetic reprogramming between generations (7).

Fig. 1.

Influence of parental (F0) environmental stressors on the mode of transmission to subsequent generations (F1–F3).

Preconceptional and gestational maternal obesity, with its associated alterations in fetal environment, is known to increase the risk of obesity, type 2 DM, and CVD in the offspring (6). Several rodent and nonhuman primate models have demonstrated that offspring exposed to maternal obesity are prone to endothelial dysfunction, hypertension, cardiac hypertrophy, left ventricular (LV) dysfunction, and cardiac fibrosis (6). In this issue of the American Journal of Physiology-Heart and Circulatory Physiology (1), Ferey et al. report the transgenerational effects of maternal obesity on the cardiovascular health of offspring using a high-fat/high-sucrose (HFHS) or “Western” diet. The authors examined the morphology, oxygen flux, and expression of electron transport chain and dynamics proteins in the mitochondria of LV from male and female F1 offspring exposed to HFHS-fed versus control (Con)-fed dams. Similar phenotypic characterization was carried out using in vitro fertilization (IVF) methodology in which embryo-transfer (ET) offspring were generated using obesity-exposed (F0) oocytes, which allowed the investigators to mitigate effects of the gestational environment (1). Their results indicated that although HFHS and Con-fed F0 dams neither exhibited mitochondrial structural abnormalities nor functional deficits, F1–F3 descendant males and females had disorganized and less electron dense cardiac mitochondria with rarefaction of cristae and reduced oxygen consumption rate (1). While this provided evidence of TGI, there were inconsistent and conflicting patterns of mitochondrial protein expression in cardiac tissues across generations and between males and female progenies as noted by the investigators, and it was postulated that this could be due to the effect of diluted obesogenic exposure or nuclear epigenetic modifications (1). These studies did rule out maternal mitochondrial inheritance as the key mode of transmission, and this conclusion was further corroborated by the examination of paternal F2 (PF2) offspring of HFHS exposed F0 dams, which demonstrated similar mitochondrial defects, suggesting that the effects of paternal obesity could also be transmitted via the male germline (1). Similar studies by this investigative group have previously demonstrated that diet-induced metabolic syndrome (MetS) before and during pregnancy altered mitochondrial dynamics in the oocyte and skeletal muscle, and this was transmitted through the female germline to the F3 generation (9). Likewise, this study also detected altered mitochondrial morphology and metabolism, misexpression of mitochondrial dynamic proteins in HFHS-fed F1–F3 offspring, suggesting the mitochondrial phenotype in the oocytes as well as in somatic tissue is due to imbalance of fission and fusion through the maternal germline (9). Additionally, there are numerous reports which suggest that the transmittance of disease susceptibility in presence of an external stressor can infiltrate through both maternal and paternal germlines. The reason for this variability in TGI is conflicting and may be explained by broad programming events at imprinted loci, opposing DNA-methylome patterns and differential correlation between methylation and gene expression levels in oocyte and sperm genomes (5).

In this study, the effect of maternal obesity on cardiac structure and function was also assessed in 8-wk-old C57BL6 mice. Echocardiographic analysis on HFHS-fed versus Con-fed offspring displayed sexually dimorphic cardiac anomalies, including abnormal LV diameters and fractional shortening, in the F1 generation but only increased LV mass in subsequent F2 and F3 generations as well as in ET and PF2 offspring (1). One interesting aspect of the echocardiography data that went unnoted is the dichotomous behavior of the LV chamber dimension between male and female offspring. The F1 females born to HFHS-fed dams exhibited a mild LV chamber dilation associated with a mild impairment in fractional shortening, which switched to a smaller dimension in F2 generation and was resolved by F3 generation. In contrast, F1 males born to HFHS-fed dams displayed inward LV chamber dimension, which switched to mild LV dilation in F2 generation and was resolved by F3 generation. LV mass remained elevated across generations regardless of sex (1). Interestingly, a similar maternal diet-induced obesity model revealed that exposure to HFHS alone is sufficient to trigger pathological changes and programmed hypertension, LV hypertrophy, ventricular dysfunction including increased cardiomyocyte area, and upregulation of fetal genes in the male offspring of obese dams (6). Together, these data suggest a potentially important sex-specific transgenerational differences in myocardial structure in response to F0 maternal obesity.

Maternal MetS, which includes obesity, is a detrimental nongenetic risk factor and is associated with cardiovascular dysfunction including hypertension and DM in the adult offspring. Development of preconceptional maternal obesity primarily dictates the metabolic/epigenetic programming in the exposed offspring leading to cardiac abnormalities. This effect can be further amplified by the postweaning diet of the offspring because an additional exposure to an obesogenic diet was shown to increase the susceptibility to MetS (6). Since epigenetic modifications occur at the interface between a fluctuating environment and gene programming, this can also result in a more rapid escalation in phenotypes in subsequent generations. Interestingly, the current study and previous report from this group have highlighted altered mitochondrial dynamics and function between cardiac tissue and skeletal muscle between generations, further strengthening the role of epigenetic mechanisms for tissue-specific gene-expression during differentiation and that these mechanisms underlie the processes of “developmental plasticity” (1, 9). This high level of epigenetic heritability can be further determined by high-throughput phenotyping, quantitative genomics, and in-depth epigenetic profiling at single-cell resolution. Impairments in myocardial structure and function have been observed in offspring born to obese mothers or those with manifestations of MetS. Consistent with the current study, other groups have reported that neonates born to late-trimester obese mothers displayed thicker LV walls and larger stroke volumes, findings that were corroborated in a mini-pig animal model and were associated with alterations in glucose uptake and metabolism (4, 6). These studies suggest that the cardiac phenotype of offspring is not only affected by maternal obesity but also the timing of maternal obesity.

The robust reprogramming of mammalian germline and varying dose of environmental/metabolic exposure within each generation has the potential to significantly impact postnatal health and development of disease (7). Given the tremendous clinical and public health implications, studies examining the existence of epigenetic inheritance of metabolic risk in humans are limited to date, and the major constraints lay in the paucity of data from multigenerational pedigrees, the dynamic nature of the epigenome, and the relative inaccessibility of germ cells and key metabolic tissues. Additional confounders include not only the environmental and dietary risk factors, which aggravate CVD risk, but also genetic factors and ethnicity that may lead to unfavorable cardiovascular profile. Overall, further investigation is needed to address the underlying mechanistic basis of this observed phenotypic variability using multiple experimental models, in addition to well-characterized human patient cohorts. Recognizing that there is a complex interplay between genetic, epigenetic, and environmental factors, a focus on elucidating the key signaling pathways active in maternal obesity-induced CVD in later generations, is warranted, and the identification of these factors will offer insights into the development of novel intervention methods.

GRANTS

This work was supported by National Institutes of Health Grants R01-HL-121797 and R01-HL-132801 (to V. Garg) and R00-HL-116769 and R21-EB-026518 (to A. J. Trask), and American Heart Association and the Children's Heart Foundation Grant 18CDA34110330 (to M. Basu).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.B. prepared figures; M.B. drafted manuscript; M.B., A.J.T., and V.G. edited and revised manuscript; M.B., A.J.T., and V.G. approved final version of manuscript.