Repair of Retrorsine-Induced DNA Damage in Rat Livers: Insights Gained from Transcriptomic and Proteomic Studies
Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Toxins |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6651/16/12/538 |
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| Summary: | Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal of PA-derived DNA adducts remains largely unexplored. In the present study, Sprague Dawley (SD) rats were exposed to retrorsine (RTS), a representative PA, at a human-relevant dose of 3.3 mg/kg/day for 28 days. The rats were divided into three groups: control, RTS-28 (sacrificed after continuous RTS exposure), and RTS-161 (sacrificed at 133 days post-RTS-exposure). The multi-omics analyses demonstrated the involvement of homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways as a response to PA-induced DNA damage. Additionally, the characteristic guanine adducts induced by RTS exposure were in accordance with the higher expression of XPA and XPC, indicating that nucleotide excision repair (NER) and base excision repair (BER) also contributed to repairing RTS-induced DNA damage. Furthermore, we also showed that DNA damage persisted after PA exposure, and mutagenically related repair errors might occur due to the prolonged genotoxic effects. The present study lays the foundation for bridging PA-derived DNA adducts, DNA damage, DNA repair, and the follow-up mutagenesis and carcinogenesis associated with PA exposure. |
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| ISSN: | 2072-6651 |