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The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis.

ABSTRACT: Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.

SUBMITTER: Nowrouzi A

PROVIDER: S-EPMC3594025 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis.

Nowrouzi Ali A Cheung Wing T WT Li Tingting T Zhang Xuegong X Arens Anne A Paruzynski Anna A Waddington Simon N SN Osejindu Emma E Reja Safia S von Kalle Christof C Wang Yoahe Y Al-Allaf Faisal F Gregory Lisa L Themis Matthew M Holder Maxine M Dighe Niraja N Ruthe Alaine A Buckley Suzanne Mk SM Bigger Brian B Montini Eugenio E Thrasher Adrian J AJ Andrews Robert R Roberts Terry P TP Newbold Robert F RF Coutelle Charles C Schmidt Manfred M Themis Mike M

Molecular therapy : the journal of the American Society of Gene Therapy 20121113 2

Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the live ...[more]

PMID: 23299800

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Project description:1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or three months (5000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.

Dataset Information

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis.

Publications

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis.

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