2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) induces gene expression changes in JAK/STAT and MAPK pathways related to inflammation, diabetes and cancer

Abstract

Background2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a heterocyclic aromatic amine (HCA) formed in meat that is cooked at high temperatures and then ingested, can potentially be retained in human adipose tissues.MethodsTo determine if PhIP is bioactive in the adipocyte, we exposed a human adipocyte cell line,HepG2 and Caco-2 cells to low dose PhIP. Uptake and retention of PhIP was determined and cytotoxicity was assessed by the TUNEL assay. Relative expression of PhIP-activating genes (CYP1A1, CYP1A2, SULT1A1 and UGT1A1) was determined by RT-PCR and global expression changes were also examined.ResultsThe percent retention of 0.1 μCi [14C]-PhIP over a 24 h period was significantly higher in the adipocyte than the HepG2 (p = 0.0001) and Caco-2 (p = 0.0007) cell lines. Cytotoxicity rates were 14.4 and 2.6 % higher compared to controls in Caco-2 and HepG2 cells (p < 0.001 and 0.054, respectively); no significant differences were detected in adipocyte cells (p = 0.18). Caco-2 and HepG2 cells, respectively, had significantly higher basal expression of CYP1A1 (p = 0.001, p = 0.003), SULT1A1 (p = 0.04, p < 0.001) and UGT1A1 (p < 0.001, p = 0.01) compared to the adipocyte. Exposure to 5nM PhIP did not significantly induce expression of these genes in any of the cell lines. Global gene expression analysis of mature adipocytes exposed to 5nM PhIP for 72 h resulted in statistically significant changes in 8 genes (ANGPTL2, CD14, CIDEA, EGR1, FOS, IGFBP5, PALM and PSAT1). Gene-gene interaction and pathway analysis indicates that PhIP modulates genes controlled by the STAT3 transcriptional factor and initiates leptin signaling via the JAK/STAT and MAPK pathway cascades. Early growth response 1 (EGR1) and prostaglandin synthase 2 (COX-2) were down-regulated via c-Fos, while insulin binding protein 5 (IBP5) was up regulated. Expression of transcription factors (ANGPTL2, HP, LEP, SAA1, SAA2), genes related to inflammation (SAA1, LEP), diabetes (IGFBP5) and cancer risk (SAA2) were also elevated upon exposure to 5 nM PhIP..ConclusionsPhIP mediates gene expression changes within the adipocyte, and the pathways most affected are related to cancer and other chronic diseases. Further studies are needed on the relationship between dietary carcinogens such as PhIP with cancer, obesity and diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0111-0) contains supplementary material, which is available to authorized users.

Meat Cooking Methods and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies

“…Although the exact mechanisms underlying the observed associations remain unknown, some studies have suggested that certain hazardous chemicals including HAAs, PAHs, nitrosamines, and AGEs, which are produced during hightemperature cooking of meats, might be involved in the development of diabetes (14,16,19). A recent in vitro study by Rogers et al (16) demonstrated that low-dose HAA exposure could induce gene expression changes in JAK/STAT and MAPK pathways linked with inflammation and diabetes.…”

“…Moreover, accumulating evidence has suggested that cooking meats at high temperature can produce several hazardous chemicals, including heterocyclic aromatic amines (HAAs), polycyclic aromatic hydrocarbons (PAHs), and advanced glycation end products (AGEs) (12)(13)(14), which are known carcinogens or can impact inflammation and insulin sensitivity (15)(16)(17)(18)(19). Cooking temperature, duration, and doneness level can significantly affect the levels of these chemicals in cooked meats (12)(13)(14).…”

In vitro exposure of simulated meat-cooking fumes to assess adverse biological effects

“…This might be caused by cell type-dependent toxic effects of PhIP. A previous report proved this phenomenon based on genotoxic DNA fragmentation by comparing cytotoxicities between carcinoma cells (HepG2 and Caco2 cells) and normal adipocytes 26 . On the other hand, remarkable cytotoxic effects could not be seen in particulate PhIP and PhIP@OA samples even after the 48-h incubation.…”

The SLC27A1 Gene and Its Enriched PPAR Pathway Are Involved in the Regulation of Flavor Compound Hexanal Content in Chinese Native Chickens

“…VEGFA was found to contribute to increasing adiposity in Iberian pig [ 37 ]. According to the report, EGR1 was down-regulated via c-Fos in mature adipocytes [ 38 ]. CACNB1 gene was reported associated with growth in chicken [ 39 ].…”