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Intrauterine hyperglycemia impairs memory across two generations.

ABSTRACT: Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcriptome profiling of F1 and F2 hippocampi revealed that differentially expressed genes (DEGs) were enriched in neurodevelopment and synaptic plasticity. The reduced representation bisulfite sequencing (RRBS) of sperm in F1 adult males showed that the intrauterine hyperglycemia exposure caused altered methylated modification of F1 sperm, which is a potential epigenetic mechanism for the intergenerational neurocognitive effects of GDM.

SUBMITTER: Zou K

PROVIDER: S-EPMC8379206 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Intrauterine hyperglycemia impairs memory across two generations.

Zou Kexin K Ren Jun J Luo Sisi S Zhang Junyu J Zhou Chengliang C Tan Chengxi C Lv Pingping P Sun Xiao X Sheng Jianzhong J Liu Xinmei X Huang Hefeng H Ding Guolian G

Translational psychiatry 20210820 1

Studies on humans and animals suggest associations between gestational diabetes mellitus (GDM) with increased susceptibility to develop neurological disorders in offspring. However, the molecular mechanisms underpinning the intergenerational effects remain unclear. Using a mouse model of diabetes during pregnancy, we found that intrauterine hyperglycemia exposure resulted in memory impairment in both the first filial (F1) males and the second filial (F2) males from the F1 male offspring. Transcr ...[more]

PMID: 34417446

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Project description:Maternal protein deficiency during the critical development period of the progeny disturbs mitochondrial metabolism in the brainstem, which increases the risk of developing cardiovascular diseases in the first-generation (F1) offspring, but is unknown if this effect persists in the second-generation (F2) offspring. The study tested whether mitochondrial health and oxidative balance will be restored in F2 rats. Male and female rats were divided into six groups according to the diet fed to their mothers throughout gestation and lactation periods. These groups were: (1) normoprotein (NP) and (2) low-protein (LP) rats of the first filial generation (F1-NP and F1-LP, respectively) and (3) NP and (4) LP rats of the second filial generation (F2-NP and F2-LP, respectively). After weaning, all groups received commercial chow and a portion of each group was sacrificed on the 30th day of life for determination of mitochondrial and oxidative parameters. The remaining portion of the F1 group was mated at adulthood and fed an NP or LP diet during the periods of gestation and lactation, to produce progeny belonging to (5) F2R-NP and (6) F2R-LP group, respectively. Our results demonstrated that male F1-LP rats suffered mitochondrial impairment associated with an 89% higher production of reactive species (RS) and 137% higher oxidative stress biomarkers, but that the oxidative stress was blunted in female F1-LP animals despite the antioxidant impairment. In the second generation following F0 malnutrition, brainstem antioxidant defenses were restored in the F2-LP group of both sexes. However, F2R-LP offspring, exposed to LP in the diets of the two preceding generations displayed a RS overproduction with a concomitant decrease in mitochondrial bioenergetics. Our findings demonstrate that nutritional stress during the reproductive life of the mother can negatively affect mitochondrial metabolism and oxidative balance in the brainstem of F1 progeny, but that restoration of a normal diet during the reproductive life of those individuals leads toward a mitochondrial recovery in their own (F2) progeny. Otherwise, if protein deprivation is continued from the F0 generation and into the F1 generation, the F2 progeny will exhibit no recovery, but instead will remain vulnerable to further oxidative damage.

Project description:Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and fetus. Although some studies have examined these changes in the placenta, the differences resulting from fetal sex remain unelucidated. In this study, we established an intrauterine hyperglycemic model using ICR mice. We collected placental specimens before birth for histological observation using Hematoxylin and Eosin (HE) staining, along with Tandem Mass Tag (TMT) labeled proteomic analysis which was stratified by sex. In both male and female fetuses of the GDM group, body weight and placental weight were significantly lower compared to the control group. Additionally, the placenta-to-body weight ratio was higher, suggesting potential placental insufficiency. Histological analysis revealed smaller sizes and reduced thickness of the junctional zone and labyrinth in diabetic placentas at E18.5, along with ectopic accumulation of spongiotrophoblasts in the labyrinth. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratifying by sex, the male subgroup displayed 209 upregulated and 111 downregulated proteins, while the female subgroup exhibited 97 upregulated and 75 downregulated proteins. Among these, 64 differentially expressed proteins showed consistent trends across both sexes, primarily enriched in the JAK-STAT signaling pathway, complement and coagulation cascades, and metabolism-related modifications. The male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. The intrauterine hyperglycemic environment affects both placental morphology and proteomics, leading to shifts in energy metabolism, oxidative stress responses, and immune processes. Our study suggests that the observed differences in placental protein expression specific to each sex may provide an explanation for the varying impacts of GDM on offspring.

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Intrauterine hyperglycemia impairs memory across two generations.

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Intrauterine hyperglycemia impairs memory across two generations.

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