Epigenetic Dysregulation of Dopaminergic System by Maternal Cafeteria Diet During Early Postnatal Development

Abstract

Dopamine is a neurotransmitter crucial for motor, motivational, and reward-related functions. Our aim was to determine the effect of a palatable maternal diet on the transcriptional regulation of dopaminergic-related genes during perinatal development of the offspring. For that, female offspring from dams fed with a control (CON) or a cafeteria (CAF) diet were sacrificed on embryonic day 21 (E21) and postnatal day 10 (PND10). Using micropunch techniques, ventral tegmental area (VTA) and nucleus accumbens(NAc) were isolated from brain´s offspring. Bioinformatic analysis of the promoter regions, mRNA quantification and methylation studies were done. The increase in tyroxine hidroxylase (TH), dopamine receptor (DRD) 1 and ghrelin receptor (GHSR) expression in VTA and NAc from E21 to PND10 was correlated with changes in DNA methylation of their promoter regions. Maternal diet did not affect the expression patterns in E21.At PND10, maternal CAF diet decreased the transcription of TH, GHSR, DRD2 and dopamine transporter (DAT) in VTA. Interestingly, the changes in TH, DRD2 and DAT expression were related to the methylation status of their promoters. In NAc, maternal CAF diet reduced DRD1, DRD2 and DAT expression in the offspring at PND10, although alternations in the methylation patterns were only detectedin DAT promoter. These results show the importance of maternal nutrition and provide novel insights into the mechanisms through which maternal junk-food feeding can affect reward system during development and early postnatal life. Particularly important is the expression decline of DRD2 given its physiological implication in obesity and addiction. Highlights 1. Maternal cafeteria diet decreased the transcription of TH, DRD2 and DAT in the ventral tegmental area of neonatal offspring. 2. In nucleus accumbens, maternal cafeteria diet reduced DRD1, DRD2 and DAT expression at postnatal day 10.

Fetal Programming by Methyl Donors Modulates Central Inflammation and Prevents Food Addiction-Like Behavior in Rats

“…In agreement with these data, we found that programming by CAF diet substantially increases global DNA methylation in the NAc shell of addict offspring that are no longer exposed to CAF diet. Recent evidence have identified that CAF programming promotes D2 dopamine receptor DNA methylation in NAc of the offspring (Rossetti et al, 2020), which potentially might explain the impulsiveness for unhealthy eating. Notably, methyl donors revert the percentage of global DNA methylation and block addiction-like behavior in the offspring.…”

Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity

“…Dopamine is a neurotransmitter regulating motivational and reward-related functions. A recent preclinical study showed that consumption of cafeteria diets during pregnancy induced epigenetic changes in the dopamine receptor (DAT), dopamine transporter 1 (DRD1) and dopamine transporter 2 (DRD2) genes in the nucleus accumbens (NAc) and VTA, two key regions of the dopaminergic pathway [ 86 ]. In the VTA and NAc, DRD1, DRD2 and DAT expression was decreased at embryonic day 2 and postnatal day 10 in rat female offspring.…”

Epigenetic Changes Associated With Exposure to Glyphosate-Based Herbicides in Mammals

“…When these sites are methylated, transcription factors are not able to bind to the promoter regions, and the gene expression decreased. On the contrary, if these sites are demethylated, transcription is activated and gene expression is increased (9,44).…”

“…The epigenome is influenced by both genetic (e.g. single nucleotide polymorphisms) and environmental factors (8)(9)(10). In this sense, several studies indicate that pesticides can exert toxicity through epigenetic changes [reviewed in (11)].…”