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Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.

ABSTRACT: Methyl donor deficiency (MDD) during pregnancy influences intrauterine development. Ghrelin is expressed in the stomach of fetuses and influences fetal growth, but MDD influence on gastric ghrelin is unknown. We examined the gastric ghrelin system in MDD-induced intrauterine growth retardation. By using specific markers and approaches (such as periodic acid-Schiff, bromodeoxyuridine, homocysteine, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunostaining, reverse transcription-polymerase chain reaction), we studied the gastric oxyntic mucosa cellular organization and ghrelin gene expression in the mucosa in 20-day-old fetuses and weanling pups, and plasma ghrelin concentration in weanling rat pups of dams either normally fed or deprived of choline, folate, vitamin B6, and vitamin B12 during gestation and suckling periods. MDD fetuses weighed less than controls; the weight deficit reached 57% at weaning (P < 0.001). Both at the end of gestation and at weaning, they presented with an aberrant gastric oxyntic mucosa formation with loss of cell polarity, anarchic cell migration, abnormal progenitor differentiation, apoptosis, and signs of surface layer erosion. Ghrelin cells were abnormally located in the pit region of oxyntic glands. At weaning, plasma ghrelin levels were decreased (-28%; P < 0.001) despite unchanged mRNA expression in the stomach. This decrease was associated with lower body weight. Taken together, these data indicate that one mechanism through which MDD influences fetal programming is the remodeling of gastric cellular organization, leading to dysfunction of the ghrelin system and dramatic effects on growth.

SUBMITTER: Bossenmeyer-Pourie C

PROVIDER: S-EPMC2797889 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.

Bossenmeyer-Pourié Carine C Blaise Sébastien S Pourié Grégory G Tomasetto Catherine C Audonnet Sandra S Ortiou Sandrine S Koziel Violette V Rio Marie-Christine MC Daval Jean-Luc JL Guéant Jean-Louis JL Beck Bernard B

The American journal of pathology 20091130 1

Methyl donor deficiency (MDD) during pregnancy influences intrauterine development. Ghrelin is expressed in the stomach of fetuses and influences fetal growth, but MDD influence on gastric ghrelin is unknown. We examined the gastric ghrelin system in MDD-induced intrauterine growth retardation. By using specific markers and approaches (such as periodic acid-Schiff, bromodeoxyuridine, homocysteine, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunostaining, reverse transc ...[more]

PMID: 19948829

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Project description:Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Project description:Fetal programming by hypercaloric intake leads to food addiction-like behavior and brain pro-inflammatory gene expression in offspring. The role of methylome modulation during programming on central immune activation and addiction-like behavior has not been characterized. We employed a nutritional programming model exposing female Wistar rats to chow diet, cafeteria (CAF), or CAF-methyl donor's diet from pre-pregnancy to weaning. Addiction-like behavior in offspring was characterized by the operant training response using Skinner boxes. Food intake in offspring was determined after fasting-refeeding schedule and subcutaneous injection of ghrelin. Genome-wide DNA methylation in the nucleus accumbens (NAc) shell was performed by fluorescence polarization, and brain immune activation was evaluated using real-time PCR for pro-inflammatory cytokines (IL-1β, TNF-1α, and IL-6). Molecular effects of methyl modulators [S-adenosylmethionine (SAM) or 5-azatidine (5-AZA)] on pro-inflammatory cytokine expression and phagocytosis were identified in the cultures of immortalized SIM-A9 microglia cells following palmitic acid (100 μM) or LPS (100 nM) stimulation for 6 or 24 h. Our results show that fetal programming by CAF exposure increases the number of offspring subjects and reinforcers under the operant training response schedule, which correlates with an increase in the NAc shell global methylation. Notably, methyl donor's diet selectively decreases lever-pressing responses for reinforcers and unexpectedly decreases the NAc shell global methylation. Also, programmed offspring by CAF diet shows a selective IL-6 gene expression in the NAc shell, which is reverted to control values by methyl diet exposure. In vitro analysis identified that LPS and palmitic acid activate IL-1β, TNF-1α, and IL-6 gene expression, which is repressed by the methyl donor SAM. Finally, methylation actively represses phagocytosis activity of SIM-A9 microglia cells induced by LPS and palmitic acid stimulation. Our in vivo and in vitro data suggest that fetal programming by methyl donors actively decreases addiction-like behavior to palatable food in the offspring, which correlates with a decrease in NAc shell methylome, expression of pro-inflammatory cytokine genes, and activity of phagocytic microglia. These results support the role of fetal programming in brain methylome on immune activation and food addiction-like behavior in the offspring.

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Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.

Publications

Methyl donor deficiency affects fetal programming of gastric ghrelin cell organization and function in the rat.

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