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

Angela L Caipa Garcia, Jill E Kucab, Halh Al-Serori, Rebekah S S Beck, Franziska Fischer, Matthias Hufnagel, Andrea Hartwig, Andrew Floeder, Silvia Balbo, Hayley Francies, Mathew Garnett, Meritxell Huch, Jarno Drost, Matthias Zilbauer, Volker M Arlt, David H Phillips

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

4 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
TijdschriftInternational journal of molecular sciences
Volume24
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 29 dec. 2022

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