TY - JOUR
T1 - Deregulation of Cancer-Related Pathways in Primary Hepatocytes Derived from DNA Repair-Deficient Xpa(-/-)p53(+/-) Mice upon Exposure to Benzo[a]pyrene
AU - van Kesteren, Petra C. E.
AU - Zwart, Edwin P.
AU - Pennings, Jeroen L. A.
AU - Gottschalk, W. H. Ralph
AU - Kleinjans, Jos C. S.
AU - van Delft, Joost H.
AU - van Steeg, Harry
AU - Luijten, Mirjam
PY - 2011/9
Y1 - 2011/9
N2 - The current method to predict carcinogenicity of chemicals or drugs is the chronic 2-year rodent bioassay, which has disadvantages in duration, animal use, and specificity. An attractive alternative is the DNA repair-deficient Xpa(-/-)p53(+/-) mouse model that is sensitive to both genotoxic and nongenotoxic carcinogens. A next step in alternative carcinogenicity testing is the development of reliable in vitro systems. We investigated the use of primary hepatocytes, isolated from wild-type (WT) and Xpa(-/-)p53(+/-) mice, in combination with transcriptome analyses for their usefulness to predict carcinogenic features of compounds. As a proof of principle, we studied the response of hepatocytes to the genotoxic carcinogen benzo[a]pyrene (B[a]P). Upon treatment, both WT and Xpa(-/-)p53(+/-) hepatocytes appeared to be metabolically active. However, Xpa(-/-)p53(+/-) hepatocytes were more sensitive than WT hepatocytes to B[a]P treatment in terms of cell survival. In B[a]P-treated WT hepatocytes, DNA repair and cell cycle control genes were transcriptionally activated. Xpa(-/-)p53(+/-) hepatocytes were more responsive to B[a]P exposure, resulting in the downregulation of cancer-related pathways. Deregulation of mitogen-activated protein kinase signaling seems to play an essential role in this and might be the underlying reason for the increased susceptibility of Xpa(-/-)p53(+/-) mice toward carcinogens. Our conclusion is that primary hepatocytes combined with transcriptomics are promising to identify the carcinogenic features of chemicals. Furthermore, these cells seem suitable to gain further insight into the molecular mechanisms of the increased sensitivity of Xpa(-/-)p53(+/-) mice toward both genotoxic and nongenotoxic carcinogens.
AB - The current method to predict carcinogenicity of chemicals or drugs is the chronic 2-year rodent bioassay, which has disadvantages in duration, animal use, and specificity. An attractive alternative is the DNA repair-deficient Xpa(-/-)p53(+/-) mouse model that is sensitive to both genotoxic and nongenotoxic carcinogens. A next step in alternative carcinogenicity testing is the development of reliable in vitro systems. We investigated the use of primary hepatocytes, isolated from wild-type (WT) and Xpa(-/-)p53(+/-) mice, in combination with transcriptome analyses for their usefulness to predict carcinogenic features of compounds. As a proof of principle, we studied the response of hepatocytes to the genotoxic carcinogen benzo[a]pyrene (B[a]P). Upon treatment, both WT and Xpa(-/-)p53(+/-) hepatocytes appeared to be metabolically active. However, Xpa(-/-)p53(+/-) hepatocytes were more sensitive than WT hepatocytes to B[a]P treatment in terms of cell survival. In B[a]P-treated WT hepatocytes, DNA repair and cell cycle control genes were transcriptionally activated. Xpa(-/-)p53(+/-) hepatocytes were more responsive to B[a]P exposure, resulting in the downregulation of cancer-related pathways. Deregulation of mitogen-activated protein kinase signaling seems to play an essential role in this and might be the underlying reason for the increased susceptibility of Xpa(-/-)p53(+/-) mice toward carcinogens. Our conclusion is that primary hepatocytes combined with transcriptomics are promising to identify the carcinogenic features of chemicals. Furthermore, these cells seem suitable to gain further insight into the molecular mechanisms of the increased sensitivity of Xpa(-/-)p53(+/-) mice toward both genotoxic and nongenotoxic carcinogens.
KW - primary hepatocytes
KW - benzo[a]pyrene
KW - toxicogenomics
KW - DNA repair
KW - Xpa
KW - p53
KW - cancer
U2 - 10.1093/toxsci/kfr169
DO - 10.1093/toxsci/kfr169
M3 - Article
C2 - 21715664
SN - 1096-6080
VL - 123
SP - 123
EP - 132
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -