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Metabolic Activation of Benzo[a]pyrene by Human Tissue Organoid Cultures.

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Caipa Garcia, Angela L 
Kucab, Jill E 
Al-Serori, Halh 
Beck, Rebekah SS 
Fischer, Franziska 


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.


Peer reviewed: True

Funder: King’s College London

Funder: National Institute for Health Research (NIHR)


Article, carcinogen, 3D culture, benzo[a]pyrene, human tissue organoid, CYP1A1, NQO1, DNA adducts, RT-qPCR, DNA damage response

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Int J Mol Sci

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UK Medical Research Council (MR/N013700/1)
Cancer Research UK Grand Challenge Award “Mutographs of Cancer” (C98/A24032)