Transgenic Mouse Development for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure

Abstract

Human albumin is a commonly used protein for studying human exposure to various pharmacologically and toxicologically important chemicals including therapeutic drugs and environmental pollutants. Very often the reactivity of albumin with xenobiotics is studied ex vivo with commercial human albumin or plasma/serum samples. Some studies have characterized the reactivity of albumin with chemicals in rodent models; however differences between the sequences of human and rodent serum albumins can result in formation of different adducts or peptide adducts with different sequences. Our goal is to create a human albumin transgenic mouse model that can be used to establish human protein biomarkers of hazardous xenobiotics for human risk assessment. We have developed a human albumin transgenic mouse model by pronuclear injection and its transgenic genotype and phenotype were characterized by genomic PCR, RT‐PCR, immunochemistry, and UPLC‐MS/MS methods. The transgenic human albumin protein was found to be a full‐length mature protein that coexisted with the endogenous mouse albumin in transgenic mouse serum. The transgenic human albumin protein formed ex vivo adducts with genotoxic metabolites of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine, a procarcinogenic heterocyclic aromatic amine formed in cooked meat. Studies with human albumin transgenic mouse models can greatly advance our understanding of the reactivity of human albumin with hazardous chemicals in the environment and facilitate the development of analytical methods to measure albumin‐carcinogen adducts in humans.