No abstract

Acrylamide (AA) is the potential carcinogen, which can induce multiple toxic effects in laboratory animals and humans. So far, increasing attention have been paid to toxical mechanism and intervention measures of AA, however, these details and methods are still obscure. MicroRNAs (miRNAs) have been demonstrated to be involved in toxical functional mechanisms induced by chemicals in vivo or vitro. To explore novel target and mechanism of AA toxicity, a more detailed miRNA expression profiling study is needed. In this study, we established the short‐term high‐dose model of rats with the treatment of 35 mg/kg·b.w./day AA for 17 days, analyzed the miRNAs expression profiling in AA and control groups, and discovered the altered miRNA profiles in 11 tissues with AA treatment. Interestingly enough, the expression of miR‐27a‐5p were significantly up‐regulated in AA group, especially in bladder and hepar. Furthermore, we found miR‐27a‐5p increased in 11 tissues of long‐term low‐dose AA‐treated rats (3.5 mg/kg·b.w./day for 68 days). Therefore, these results revealed that AA changed miRNAs profiles in multiple tissues of SD rats for the first time and suggested that miR‐27a‐5p could be used as the target biomarker for the detection and interference of AA toxicity.

Autophagy‐lysosomal pathway (ALP), a lysosome‐mediated self‐renewal process, is crucial for cell survival and death. Acrylamide (AA) is a neurotoxic compound produced during food thermal processing, and the mechanism underlying AA‐induced neurotoxicity remains elusive. In this study, we explored whether dysregulated ALP was involved in AA‐induced neurotoxicity and the underlying mechanism. We first evaluated the toxic effects of AA on the activation of apoptosis and NLRP3 pathway in human glioma U251 cells. We found that AA‐induced autophagy activation with the accumulation of an autophagy substrate P62, which implies the occurrence of autophagy‐lysosomal disorders. By using autophagy agonist PP242 and siRNA interfering ATG5, we demonstrated that ALP dysregulation contributed to AA‐induced apoptosis and NLRP3 inflammasome pathway activation. In addition, AA triggered ALP dysfunction by decreasing the expression of transcription factor EB (TFEB), and TFEB overexpression restored the lysosomal‐associated proteins and protected against AA‐induced apoptosis and inflammasome activation. Moreover, the autophagy agonist rapamycin restored AA‐induced ALP dysfunction by upregulating TFEB and prevented neurotoxicity. Overall, our study provides novel insights into the role of disrupted ALP in AA‐induced neurotoxicity and highlights that TFEB can be developed as a promising intervention target against AA‐induced neurotoxicity.