TY - JOUR
T1 - Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure
AU - Sheng, Jonathan
AU - Wang, Yi
AU - Turesky, Robert J.
AU - Kluetzman, Kerri
AU - Zhang, Qing Yu
AU - Ding, Xinxin
N1 - Funding Information:
This research was supported by NIH grant nos. R01CA122320 (R.J.T.), R01CA092596 (X.D.), and R01ES020867 (X.D.) and by National Cancer Institute Cancer Center Support grant no. CA077598 (R.J.T.).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/5/16
Y1 - 2016/5/16
N2 - Albumin is a commonly used serum protein for studying human exposure to xenobiotic compounds, including therapeutics and environmental pollutants. Often, the reactivity of albumin with xenobiotic compounds is studied ex vivo with human albumin or plasma/serum samples. Some studies have characterized the reactivity of albumin with chemicals in rodent models; however, differences between the orthologous peptide sequences of human and rodent albumins can result in the formation of different types of chemical-protein adducts with different interaction sites or peptide sequences. Our goal is to generate a human albumin transgenic mouse model that can be used to establish human protein biomarkers of exposure to hazardous xenobiotics for human risk assessment via animal studies. We have developed a human albumin transgenic mouse model and characterized the genotype and phenotype of the transgenic mice. The presence of the human albumin gene in the genome of the model mouse was confirmed by genomic PCR analysis, whereas liver-specific expression of the transgenic human albumin mRNA was validated by RT-PCR analysis. Further immunoblot and mass spectrometry analyses indicated that the transgenic human albumin protein is a full-length, mature protein, which is less abundant than the endogenous mouse albumin that coexists in the serum of the transgenic mouse. The transgenic protein was able to form ex vivo adducts with a genotoxic metabolite of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a procarcinogenic heterocyclic aromatic amine formed in cooked meat. This novel human albumin transgenic mouse model will facilitate the development and validation of albumin-carcinogen adducts as biomarkers of xenobiotic exposure and/or toxicity in humans.
AB - Albumin is a commonly used serum protein for studying human exposure to xenobiotic compounds, including therapeutics and environmental pollutants. Often, the reactivity of albumin with xenobiotic compounds is studied ex vivo with human albumin or plasma/serum samples. Some studies have characterized the reactivity of albumin with chemicals in rodent models; however, differences between the orthologous peptide sequences of human and rodent albumins can result in the formation of different types of chemical-protein adducts with different interaction sites or peptide sequences. Our goal is to generate a human albumin transgenic mouse model that can be used to establish human protein biomarkers of exposure to hazardous xenobiotics for human risk assessment via animal studies. We have developed a human albumin transgenic mouse model and characterized the genotype and phenotype of the transgenic mice. The presence of the human albumin gene in the genome of the model mouse was confirmed by genomic PCR analysis, whereas liver-specific expression of the transgenic human albumin mRNA was validated by RT-PCR analysis. Further immunoblot and mass spectrometry analyses indicated that the transgenic human albumin protein is a full-length, mature protein, which is less abundant than the endogenous mouse albumin that coexists in the serum of the transgenic mouse. The transgenic protein was able to form ex vivo adducts with a genotoxic metabolite of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a procarcinogenic heterocyclic aromatic amine formed in cooked meat. This novel human albumin transgenic mouse model will facilitate the development and validation of albumin-carcinogen adducts as biomarkers of xenobiotic exposure and/or toxicity in humans.
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U2 - 10.1021/acs.chemrestox.5b00529
DO - 10.1021/acs.chemrestox.5b00529
M3 - Article
C2 - 27028147
AN - SCOPUS:84969771866
SN - 0893-228X
VL - 29
SP - 797
EP - 809
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 5
ER -