Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction

Abstract

Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR s. Expression of cardiac fibrotic markers TGFβ, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and. females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4α, and NFκB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.

Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart

“…Interestingly, there was no difference in COL3A mRNA expression between the Control and LGUN groups; however, the increase in COL1A:COL3A in the LGUN group suggests decreased cardiac contractility and compliance (Wei et al 1999). Furthermore, despite the previously reported sex effect, our results are consistent with an increased prevalence of myocardial fibrosis in the hearts of IUGR male non-human primates (Muralimanoharan et al 2017). These data along with the changes to contractility proteins (PLB and Troponin I) in the present study may explain the emergence of dysfunction in the right ventricle after birth in the IUGR non-human primate (Kuo et al 2017a).…”

“…Furthermore, despite the previously reported sex effect, our results are consistent with an increased prevalence of myocardial fibrosis in the hearts of IUGR male non‐human primates (Muralimanoharan et al . ). These data along with the changes to contractility proteins (PLB and Troponin I) in the present study may explain the emergence of dysfunction in the right ventricle after birth in the IUGR non‐human primate (Kuo et al .…”

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

“…The placenta influences the sex-specific embryonic responses to the maternal environment, [81][82][83][84] and has a role in conferring biased susceptibility to gestational insults. [80,85,86] In humans, for example, male fetuses exposed to intrauterine adversity are more vulnerable than females [87] and are 4-8 times more likely than females to present neurodevelopmental disorders.…”

‘Stiffening the sinews of the heart’

“…The nature of these postnatal changes fit with the fibrosis demonstrated in the article reviewed here and Muralimanoharan et al . (). The pattern of vascular distribution observed in IUGR offspring is reminiscent of the changes that occur in fetuses challenged by hypoxia or undernutrition (Cohn et al .…”

“…Unfortunately, the study was not able to determine sexually dimorphic differences. A study of left ventricular (LV) myocardial tissue in IUGR fetuses of baboons fed 70% of control diet found that in males, but not females, LV fibrosis inversely correlated with birth weight (Muralimanoharan et al 2017). It found differences in expression of fetal myocardial microRNAs (miRNAs) between male and female fetuses within both control and IUGR baboon groups.…”