Abstract
Betaine serves as a methyl donor for DNA methylation. Here, the effects of betaine on hippocampal expression of neurogenesis genes and their DNA methylation status across three generations are investigated. Pregnant rats (F0) are fed control and betaine-supplemented diets throughout gestation and lactation. Female F1 and F2 offspring at weaning, together with the F0 dams, are used in the study. Hippocampal expression of aromatase, estrogen receptor α, and estrogen-related receptor β is downregulated in F1, together with the estrogen-responsive insulin-like growth factor 2/insulin-like growth factor binding protein 2 (IGF-2/IGFBP2) genes. However, all these genes are upregulated in F2, which follows the same pattern of F0. In agreement with changes in mRNA expression, the imprinting control region (ICR) of IGF-2 gene is hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all the affected genes is hypermethylated in F1 but hypomethylated in F2 and F0. Methyl transfer enzymes, such as betaine homocysteine methyltransferase and DNA methyltransferase 1, follow the same pattern of transgenerational inheritance. These results indicate that betaine exerts a transgenerational effect on hippocampal expression of estrogen-responsive genes in rat offspring, which is associated with corresponding alterations in DNA methylation on ICR of IGF-2 gene and the promoter of affected genes.
Highlights
Hippocampus is the key structure governing many important functions including learning and memory, as well as navigation and spatial orientation [1]
Epigenetic transgenerational inheritance is defined as the phenotypic change across generations and germline transmission of epigenetic information without direct genetic manipulation or environmental exposure
We sought to investigate the effects of betaine on rat hippocampal expression of neurogenesis genes and their DNA methylation status across three generations
Summary
Hippocampus is the key structure governing many important functions including learning and memory, as well as navigation and spatial orientation [1]. Accumulated studies have shown that estrogen enhances synaptic plasticity, such as enhances long-term potentiation (LTP), the electrophysiological parameter of memory, and improves performance on hippocampus-dependent cognitive behavior [2, 3]. Aromatase (CYP19A1), the final enzyme of estradiol biosynthesis, is a key mammalian microsomal enzyme in the process of the conversion of androgens to estrogens [7]. Numerous studies have shown that estradiol upregulates synaptic proteins in the hippocampal CA1 region [8, 9]. Inhibition of aromatase activity significantly reduced the expression of synaptic proteins, which was associated with synapse loss in hippocampal slice cultures and in female mice [10]. The beneficial effects of estrogens on memory are mediated through classical estrogen receptors (ERs), such as ERα and ERβ, which are expressed throughout the brain [11]
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