[Abstract Title]. - Society for Neuroscience

Topic: E.06.e. Early life experience
Support: DK 064086
UPenn-SOM
Title: Epigenetic modulation of dopamine gene expression by prenatal and postnatal diet
Authors: *Z. VUCETIC 1 , K. TOTOKI 2 , T. M. REYES 2 ;
1 Univ. of Pennsylvania, Philadlephia, PA; 2 Univ. of Pennsylvania, Philadelphia, PA
Abstract: A growing body of research, both in humans and in animal models, is linking prenatal
and postnatal environmental factors including chemical agents, diet, and lifestyle with an
increased risk of developing cancer, diabetes, obesity and behavioral disorders. The molecular
mechanism underlying the onset of disease following environmental insult may involve
epigenetic dysregulation of key genes involved in disease pathogenesis. Epigenetic changes (e.g.,
DNA methylation and chromatin modifications) can induce persistent alteration of gene
expression as a response to environmental insults. We aimed to explore if either prenatal or
postnatal nutritional manipulations have the potential to induce permanent molecular changes
involving epigenetic regulation of gene expression and result in altered behavior. We studied
nutritionally challenged mice; either during prenatal period (low protein (LP) diet to pregnant
dams) or in adult life (high fat (HF) diet fed from weaning). Mice exposed to either gestational
low protein diet or long-term postnatal high fat diet have significantly lowered preference for
natural reward, sucrose, (n=5, p< 0.02) compared to controls. Additionally, both prenatal LP and
postnatal HF diet led to increased expression of genes involved in the synthesis and transmission
of dopamine signal in the hypothalamus (TH, DARPP-32, DAT). Both prenatal and postnatal
dietary alterations resulted in 20% lower content of cytosine-methylated DNA in the
hypothalamus compared to animals fed standard chow. Global hypomethylation of hypothalamic
genomic DNA was accompanied with 2-fold up-regulation of nucleic acid demethylating
enzyme, Fto in the case of LP animals and 35% reduction in mRNA levels of MeCP2 and Dnmt1
in postnatal HF group. Additionally, methylated DNA immunoprecipitation (MeDIP) assay
showed that prenatal and postnatal dietary alterations affected promoter DNA methylation of
distinct gene targets. Animals on postnatal HF diet showed decreased enrichment of methylated
DNA in the proximal promoter region of Th and DAT compared to controls and prenatal LP. In
contrast, animals exposed to prenatal LP diet had reduced levels of Cdkn1c promoter
methylation and increased expression of a subset of Cdkn1c-Igf2 locus imprinted genes (Cdkn1c,
Tssc4, Igf2) important for dopamine neuron differentiation. Taken together data suggest that
prenatal and postnatal dietary alterations have the ability to modulate expression of dopamine
related genes through diverse epigenetic mechanisms.
Disclosures: Z. Vucetic, None; K. Totoki, None; T.M. Reyes, None.
Poster