Pyrroloquinoline quinone protected autophagy-dependent apoptosis induced by mono(2-ethylhexyl) phthalate in INS-1 cells

Author:

Shi L1,Jiang L2,Zhang X1,Yang G1,Zhang C1,Yao X3,Wu X4,Fu M4,Sun X3,Liu X1ORCID

Affiliation:

1. Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People’s Republic of China

2. Preventive Medicine Laboratory, College of Public Health, Dalian Medical University, Dalian, People’s Republic of China

3. Department of Occupational and Environmental Health, College of Public Health, Dalian Medical University, Dalian, People’s Republic of China

4. Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China

Abstract

Mono(2-ethylhexyl) phthalate (MEHP) is the main metabolite of di(2-ethylhexyl) phthalate (DEHP) in organisms and is commonly used as a plasticizer. Exposure to DEHP impairs the function of islet beta cells (INS-1 cells), which is related to insulin resistance and type 2 diabetes. At present, some research data have also confirmed that MEHP has a certain damage effect on INS-1 cells. In our experiment, we found that MEHP would lead to the increase of reactive oxygen species (ROS) and the upregulation of autophagy. And downregulated ROS production by N-acetyl-L-cysteine could also reduce autophagy. In addition, MEHP-induced lysosomal membrane permeability (LMP) subsequently released cathepsin D. Additionally, MEHP induced the collapse of mitochondrial transmembrane potential and release of cytochrome c. Addition of autophagy inhibitor 3-methyladenine relieved MEHP-induced apoptosis as assessed by the expression of cleaved caspase 3, cleaved caspase 9, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, indicating that MEHP-induced apoptosis was autophagy dependent. Cathepsin D inhibitor, pepstatin A, suppressed MEHP-induced mitochondria release of cytochrome c and apoptosis as well. Meanwhile, pyrroloquinoline quinone (PQQ), a new B vitamin, improved the above phenomenon. Taken together, our results indicate that MEHP induces autophagy-dependent apoptosis in INS-1 cells by lysosomal–mitochondrial axis. PQQ improved this process by downregulating ROS and provided a degree of protection. Our study provides a new perspective for MEHP on the cytotoxic mechanism and PQQ protection in INS-1 cells.

Publisher

SAGE Publications

Subject

Health, Toxicology and Mutagenesis,Toxicology,General Medicine

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