Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter

Abstract

Recent increases in fructose consumption have raised concerns about the potential adverse intergenerational effects of excess fructose intake. In the present study, we investigated whether excess maternal fructose intake affects hippocampal function in offspring. Female Sprague-Dawley rats were divided into 3 experimental groups: one group received distilled water, one group received 20% fructose water, and one group received 20% glucose water in addition to standard chow during gestation and lactation. Hippocampal function of offspring was evaluated by using novel object recognition and fear conditioning tests. Impaired cognitive performance was observed in the offspring of fructose-fed dams at postnatal d 60, potentially a result of decreased hippocampal neurogenesis. Real-time PCR analysis demonstrated that offspring from fructose-fed dams exhibited decreased brain-derived neurotrophic factor ( BDNF) gene expression, whereas pyrosequencing assays revealed increased DNA methylation at the BDNF promoter. The potential association between BDNF transcription and levels of DNA methylation was confirmed on the basis of luciferase activity. Furthermore, longitudinal analysis revealed that increased methylation of the BDNF promoter region was maintained at least until rats reached maturity. These results indicate that epigenetic changes associated with BDNF may underlie hippocampal dysfunction that is induced by early-life exposure to excess maternal fructose consumption.-Yamazaki, M., Yamada, H., Munetsuna, E., Ishikawa, H., Mizuno, G., Mukuda, T., Mouri, A., Nabeshima, T., Saito, K., Suzuki, K., Hashimoto, S., Ohashi, K. Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter.

Maternal fructose–induced oxidative stress occurs via Tfam and Ucp5 epigenetic regulation in offspring hippocampi

“…In agreement with our previous study, our present results suggest that maternal fructose-induced alterations to hippocampal Tfam and Ucp5 expression could be mediated by changes in epigenetic modifications (17). Specifically, maternal fructose intake led to the increased DNA methylation of a putative SP1 binding sequence in the gene promoter, resulting in the suppression of its transcription.…”

“…Specifically, it was found to up-regulate the methylation of hepatic peroxisome proliferator-activated receptor a and carnitine palmitoyltransferase 1A promoters and decrease the methylation of mtDNA in adult rats (4,5). It should be noted that the transgenerational epigenetic effects of fructose occurred in offspring (17,28). Similar to our previous results, current findings showed that DNA methylation is highly sensitive to high fructose consumption.…”

“…We previously reported that maternal high fructose consumption impairs hippocampal function and neurogenesis (17). This phenomenon might be explained by the enhanced oxidative stress and reduced O 2 consumption in the hippocampi of the offspring from maternal rat dams fed high fructose.…”

“…Then, total protein concentration was determined using a BCA Protein Assay Kit (Thermo Fisher Scientific) with bovine serum albumin as the standard. SDS-PAGE and Western blotting were carried out as we previously reported (17). The membrane was incubated overnight at 4°C with primary antibodies against Total Oxphos Rodent WB Antibody (Abcam, Cambridge, United Kingdom) and b-actin (Abcam).…”

“…To date, we have demonstrated the effect of maternal fructose on hippocampal gene expression and function (15)(16)(17). Specifically, maternal fructose induces impaired hippocampal function and a reduction in hippocampal neurogenesis in offspring (17), indicating the effect of maternal fructose consumption on brain function. The negative effects of fructose on human health have been demonstrated by epidemiologic studies.…”