Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR rats

Abstract

Intrauterine growth retardation (IUGR) increases the risk of neuroendocrine reprogramming. In the rat, IUGR leads to persistent changes in cerebral mRNA levels. This suggests lasting alterations in IUGR cerebral transcriptional regulation, which may result from changes in chromatin structure. Candidate nutritional triggers for these changes include altered cerebral zinc and one-carbon metabolite levels. We hypothesized that IUGR affects cerebral chromatin structure in neonatal and postnatal rat brains. Rats were rendered IUGR by bilateral uterine artery ligation; controls (Con) underwent sham surgery. At day of life 0 (d0), we measured cerebral DNA methylation, histone acetylation, expression of chromatin-affecting enzymes, and cerebral levels of one-carbon metabolites and zinc. At day of life 21 (d21), we measured cerebral DNA methylation and histone acetylation, as well as the caloric content of Con and IUGR rat breast milk. At d0, IUGR significantly decreased genome-wide and CpG island methylation, as well as increased histone 3 lysine 9 (H3/K9) and histone 3 lysine 14 (H3/K14) acetylation in the hippocampus and periventricular white matter, respectively. IUGR also decreased expression of the chromatin-affecting enzymes DNA methyltransferase 1 (DNMT1), methyl-CpG binding protein 2 (MeCP2), and histone deacetylase (HDAC)1 in association with increased cerebral levels of zinc. In d21 female IUGR rats, cerebral CpG DNA methylation remained lower, whereas H3/K9 and H3/K14 hyperacetylation persisted in hippocampus and white matter, respectively. In d21 male rats, IUGR decreased acetylation of H3/K9 and H3/K14 in these respective regions compared with controls. Despite these differences, caloric, fat, and protein content were similar in breast milk from Con and IUGR dams. We conclude that IUGR results in postnatal changes in cerebral chromatin structure and that these changes are sex specific.

Embryo–Placento–Maternal Interaction and Biomarkers: From Diagnosis to Therapy – A Workshop Report

“…Direct sequencing of the NET and 11β-HSD2 promoters is underway. This may represent a novel form of placental gene silencing seen in other tissues [15,16]. This gene-environment interaction suggests an important molecular mechanism for long-term programming.…”

Sexual Dimorphism in Non-Mendelian Inheritance

“…These differences may result from the sex-specific programming of imprinted gene expression within the preimplantation embryo itself (58 -60). Postnatal changes in cerebral chromatin associated with bilateral uterine artery ligation in rats with IUGR are also sex-specific (43). Birth weight was low for the offspring of either sex of males exposed prenatally to dexamethasone mated with control females, but only for the male offspring of female rats exposed prenatally to dexamethasone, but not during their own pregnancy (46).…”

“…Prenatal and suckling exposure to a diet rich in animal fat leads to whole body insulin resistance and pancreatic beta-cell dysfunction in adulthood, which is preceded by reduced tissue mtDNA content and altered mitochondrial gene expression (11). The epigenetic alterations are thus both sex-and tissue-specific (43). The mechanisms involved are not mutually exclusive and the different types of sequence may be involved simultaneously (43).…”

“…The epigenetic alterations are thus both sex-and tissue-specific (43). The mechanisms involved are not mutually exclusive and the different types of sequence may be involved simultaneously (43).…”

Pre-birth origins of allergy and asthma

“…In rodent models of PR, fetal 1-carbon donor abundance is decreased, 1-carbon pathway enzyme expression is altered and this is associated with hypomethylation of DNA and increased histone acetylation in multiple tissues (MacLennan et al 2004, Ke et al 2006, Park et al 2008. Consistent with the hypothesis that reduced placental methyl donor transport to the fetus protects against allergy in the PR sheep, when we supplemented PR ewes with methyl donors and cofactors in the last month of their five month gestation, the protective effects of PR against cutaneous delayed-type hypersensitivity after allergen sensitisation were partially lost (Wooldridge et al, unpublished).…”