Modulation of different stress pathways after styrene and styrene-7,8-oxide exposure in HepG2 cell line and normal human hepatocytes.
Styrene is one of the most important monomers produced worldwide. IARC classified styrene as a possible carcinogen to humans (group 2B). Styrene-7,8-oxide (SO) is the main reactive metabolite of styrene, and it is found to be genotoxic in several in vitro test systems. Styrene and styrene-7,8-oxide (SO) toxicity to HepG2 cells was investigated by evaluating end-points such as heat shock proteins (Hsps), metallothioneins (MT), apoptosis-related proteins, accumulation of styrene within the cells and expression of two isoforms of cytochrome P450. The potential activity of styrene and styrene-7,8-oxide in modulating gene expression was also investigated. The results showed induction of Hsp70, metallothioneins, BclX(S/L) and c-myc expression and a decrease in Bax expression in HepG2 after treatments, confirming that these compounds activated protective mechanisms. Moreover, up-regulation of TGFbeta2 and TGFbetaRIII in HepG2 cells was found after exposure to styrene, while in human primary hepatocytes these genes were down-regulated after both treatments. Finally, it was found that styrene and SO treatments did not induce CYP1A2 and CYP2E1 protein expression. In conclusion, both compounds caused toxic stress in HepG2 cells, with SO being more toxic; in the meantime, a different effect of the two compounds in HepG2 cells and primary human hepatocytes was observed regarding their activity in gene modulation.
Diodovich
Cristina
C
ECVAM, Institute for Health and Consumer Protection, JRC, Ispra, Italy.
Urani
Chiara
C
Maurici
Daniela
D
Malerba
Ilaria
I
Melchioretto
Pasquale
P
Orlandi
Marco
M
Zoia
Luca
L
Campi
Valentina
V
Carfi'
Maria
M
Pellizzer
Cristian
C
Gribaldo
Laura
L
D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008668:Metallothionein / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020058:Styrene / Q000378:metabolism / Q000633:toxicity*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D002273:Carcinogens; D004852:Epoxy Compounds; D018840:HSP70 Heat-Shock Proteins; C489427:MYC protein, human; D011509:Proteoglycans; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D051020:bcl-X Protein; C071736:betaglycan; D020058:Styrene; D008668:Metallothionein; C013690:styrene oxide; D019392:Cytochrome P-450 CYP2E1; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2