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Title: 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 ( 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 exhibited a net increase in diacylglycerol and plasmalogens, and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resultingmore » 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.« less

Authors:
; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1375370
Report Number(s):
PNNL-SA-123734
Journal ID: ISSN 0022-2828; 49677
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular and Cellular Cardiology; Journal Volume: 108; Journal Issue: C
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory

Citation Formats

Muralimanoharan, Sribalasubashini, Li, Cun, Nakayasu, Ernesto S., Casey, Cameron P., Metz, Thomas O., Nathanielsz, Peter W., and Maloyan, Alina. Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction. United States: N. p., 2017. Web. doi:10.1016/j.yjmcc.2017.06.006.
Muralimanoharan, Sribalasubashini, Li, Cun, Nakayasu, Ernesto S., Casey, Cameron P., Metz, Thomas O., Nathanielsz, Peter W., & Maloyan, Alina. Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction. United States. doi:10.1016/j.yjmcc.2017.06.006.
Muralimanoharan, Sribalasubashini, Li, Cun, Nakayasu, Ernesto S., Casey, Cameron P., Metz, Thomas O., Nathanielsz, Peter W., and Maloyan, Alina. Sat . "Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction". United States. doi:10.1016/j.yjmcc.2017.06.006.
@article{osti_1375370,
title = {Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction},
author = {Muralimanoharan, Sribalasubashini and Li, Cun and Nakayasu, Ernesto S. and Casey, Cameron P. and Metz, Thomas O. and Nathanielsz, Peter W. and Maloyan, Alina},
abstractNote = {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 ( 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 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.},
doi = {10.1016/j.yjmcc.2017.06.006},
journal = {Journal of Molecular and Cellular Cardiology},
number = C,
volume = 108,
place = {United States},
year = {Sat Jul 01 00:00:00 EDT 2017},
month = {Sat Jul 01 00:00:00 EDT 2017}
}
  • Previous studies of sexual size dimorphism (SSD) use a variety of size dimorphism indices (SDI's) to quantify SSD. We propose that a useful SDI should meet four criteria as follows; (1) it should be properly scaled, (2) it should have high intuitive value, (3) it should produce values with one sign, (positive) when sex A is larger than sex B, and the opposite sign when sex B is larger, and (4) it should produce values that are symmetric around a central value, preferably zero. Many previously published SDI's do not meet any of these criteria, and none meet more thanmore » three. We present an alternative SDI based on the mean size of the larger sex divided by the mean size of the smaller sex with the result arbitrarily defined as positive (minus one) when females are larger and negative (plus one) in the converse case. Careful selection of a primary size variable is crucial to meaningful interpretation of sexual size differences.« less
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