Molecular Mechanism Of Hazardous Food Product Acrylamide Affecting On Circadian Rhythm

Circadian rhythm is a type of oscillator with a cycle of approximately 24 h.Acquired by natural selection during the evolution process,circadian rhythm sets and mediates the physiological functions of the organism and maintains synchrony with the environmental cycles of light and nutrients.The circadian clock consists of the suprachiasmatic nucleus(SCN)located in the hypothalamus and the peripheral clock located in the liver,kidney and intestine.Food signals play a vital role in regulating circadian clock.However,whether the hazardous food product could influence the circadian were still unknown.Acrylamide(ACR),a vinyl monomer,has many applications in the chemical industry and laboratories.It can also be formed in thermally treated foods via Maillard reaction and shows neurotoxicity,genotoxicity and carcinogenicity.With this background,acrylamide was selected as the research object to investigate the effects of ACR on circadian clock.(1)The present study showed that ACR treatment induced circadian disorder and suppressed the circadian-related protein Bmal1 and Clock expressions in mice brain.Furthermore,ACR diet aggravated the cognitive dysfunction and spatial memory loss at night phase via Morris water maze test.Consistent with these results,ACR caused cognitive defects in the night period by ERK/CREB/BDNF signaling pathways and the expression of synaptosomal-related protein SNAP-25 and PSD-95.Moreover,excessive autophagy phenomenon also occurred in mice hippocampus in the night phase under ACR administration.Of note,ACR stimulated the brain inflammatory reaction via gut-brain axis.(2)The aim of this research is to investigate whether the circadian clock is involved in the toxicity mechanisms of acrylamide in mice liver.Our results revealed that acrylamide markedly induced circadian gene oscillation disorder and blocked circadian-related protein in mice liver and HepG2 cells.Simultaneously,the balance of the daily oscillation of the antioxidant enzymes such as GSH and SOD were impeded under acrylamide treatment.Furthermore,acrylamide treatment elevated the mitochondrial dynamic gene expressions and influenced the mitochondrial morphology at the night phase.Acrylamide blocked circadian protein Bmal1 and Sirt1 expressions via repressing the phosphorylation of AKT or inducing oxidative stress.(3)The objective of this chapter is to investigate the mechanism of High-fat diet aggravates acrylamide hepatotoxicity via circadian clock.The present study revealed that acrylamide treatment at ZT12 caused a more serious liver injury and mitochondria dysfunction such as mitochondrial swelling and the decrease of mitochondrial complex enzymes in HFD mice.The potential reason for this phenomenon was the lower glutathione(GSH)contents and higher cytochrome P450 2E1(CYP2E1)expressions at ZT12 in HFD mice liver.Furthermore,acrylamide administration at ZT12 broken the intestinal barrier and lead intestinal endotoxin enter the systemic circulation and further induced systemic inflammation.Moreover,core circadian gene cryptochrome1(Cry1)played a critical role in acrylamide induced chronotoxicity on HFD mice.Taken together,our current study reveals that acrylamide administration at ZT12 exhibited a higher toxicity on HFD mice.(4)The aim of this part is to explore the protective effects of resveratrol on ACR-induced circadian disorder and mitochondrion dysfunction via circadian gene Bmal1.The present research revealed that resveratrol(RES)could reverse the relatively circadian genes transcription and protein expressions in primary hepatocytes triggered by acrylamide.Furthermore,resveratrol pretreatment ameliorated acrylamide-induced mitochondria impairment via recovering the expressions of mitochondrial respiration complex I-IV and activating Nrf2/NQO1 pathway in Bmal1-dependend manner.Moreover,resveratrol relieved acrylamide-elicited intracellular inflammatory response through circadian genes Cry1.Taken together,our findings proved that ACR blunted the circadian protein in mice brain and induced cognitive dysfunction.Furthermore,ACR induced liver circadian disorder and mitochondria impairment.The mechanism of liver injury induced by acrylamide was further explored by HFD pattern.This present work could spur a new discovery of ACR toxicity via circadian-related mechanisms and also establishe a theoretical foundation for development of natural functional food components combating circadian dysfunction.