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Metabolic Activation of Benzo[ a ]pyrene by Human Tissue Organoid Cultures.
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- Additional Information
- Source:
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
- Publication Information:
Original Publication: Basel, Switzerland : MDPI, [2000-
- Subject Terms:
- Abstract:
Organoids are 3D cultures that to some extent reproduce the structure, composition and function of the mammalian tissues from which they derive, thereby creating in vitro systems with more in vivo-like characteristics than 2D monocultures. Here, the ability of human organoids derived from normal gastric, pancreas, liver, colon and kidney tissues to metabolise the environmental carcinogen benzo[ a ]pyrene (BaP) was investigated. While organoids from the different tissues showed varied cytotoxic responses to BaP, with gastric and colon organoids being the most susceptible, the xenobiotic-metabolising enzyme (XME) genes, CYP1A1 and NQO1 , were highly upregulated in all organoid types, with kidney organoids having the highest levels. Furthermore, the presence of two key metabolites, BaP- t -7,8-dihydrodiol and BaP-tetrol-l-1, was detected in all organoid types, confirming their ability to metabolise BaP. BaP bioactivation was confirmed both by the activation of the DNA damage response pathway (induction of p-p53, pCHK2, p21 and γ-H2AX) and by DNA adduct formation. Overall, pancreatic and undifferentiated liver organoids formed the highest levels of DNA adducts. Colon organoids had the lowest responses in DNA adduct and metabolite formation, as well as XME expression. Additionally, high-throughput RT-qPCR explored differences in gene expression between organoid types after BaP treatment. The results demonstrate the potential usefulness of organoids for studying environmental carcinogenesis and genetic toxicology.
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- Grant Information:
C98/A24032 United Kingdom CRUK_ Cancer Research UK; MR/N013700/1 United Kingdom MRC_ Medical Research Council
- Contributed Indexing:
Keywords: 3D culture; CYP1A1; DNA adducts; DNA damage response; NQO1; RT-qPCR; benzo[a]pyrene; carcinogen; human tissue organoid
- Accession Number:
3417WMA06D (Benzo(a)pyrene)
EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
0 (DNA Adducts)
- Publication Date:
Date Created: 20230108 Date Completed: 20230112 Latest Revision: 20230112
- Publication Date:
20231215
- Accession Number:
PMC9820386
- Accession Number:
10.3390/ijms24010606
- Accession Number:
36614051
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