Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

Abstract

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

Three-Generation Study of Male Rats Gestationally Exposed to High Butterfat and Bisphenol A: Impaired Spermatogenesis, Penetrance with Reduced Severity

“…Studies from our laboratory found that in the rat prostate gland [ 58 ], neonatal exposure to estradiol/BPA alters the transcriptional program of factors involved in DNA methylation (DNMT3A/B and MBD2/4) and hypomethylation of the promoter of nucleosome binding protein-1 (NSBP1), an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life. Additionally, maternal high-fat diets in mice have been found to be associated with altered gene expression, chromatin marks, and DNA methylation changes [ 82 , 83 , 84 ] in male and female offspring. However, in our present study, we did not observe any consistent changes in transcripts for the DNA methyl transferases, or for the methyl-CpG-binding domain proteins MBD1, MBD2 , or MBD4 between the various groups in the F1- and F3-generation offspring.…”

Environmental Alterations during Embryonic Development: Studying the Impact of Stressors on Pluripotent Stem Cell-Derived Cardiomyocytes

“…Likewise, rodent cardiac morphogenesis as well as adult cardiac structures are similar to those of human beings [57]. The early period of foetal development is sensitive in rodents, as several studies show blastocyst abnormalities and cardiovascular alterations in undernutrition or HFD models [58,59,65]. Nutritional deficiencies in rodents not only affect the foetal program-ming period but may also induce various pregnancy complications, negatively affecting the foetal environment and possibly triggering the development of CVD in offspring [60].…”

“…Data supporting DOHAD: Undernutrition [32][33][34][35][36][37] Overnutrition [38][39][40][41][42] Birth weight [23,[43][44][45] Paternal contribution [1,2,[46][47][48][49][50][51][52][53] ART technique [2,54,55] Easier handling/housing and genetic manipulation [17,56] High sequence conservation with humans [57] Data supporting nutrition and pregnancy complications [58][59][60][61][62][63][64][65] Similarities with human [56,66] Data supporting nutrition and pregnancy complications [67][68][69][70][71][72] Unlimited supply of genetically well-defined material [73] Recapitulate embryonic development [31,…”

Epigenetics in Male Infertility

“…Similarly, high fat diet (HFD) alters sperm cells epigenome of sperm cells reprograming, thereby affecting metabolic tissues of offspring throughout two generations [132]. Through such effect, HFD can modulate spermatogenesis via increasing chromatin compaction and affecting the transcription profile of the spermatozoid [133]. Within this context, HFD-induced obesity provides a link with disease related phenotypes in male infertility, i.e.…”