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. 2023 Apr 4;74(1):22-33.
doi: 10.2478/aiht-2023-74-3692. Print 2023 Mar 1.

Different damaging effects of volatile anaesthetics alone or in combination with 1 and 2 Gy gamma-irradiation in vivo on mouse liver DNA: a preliminary study

Vesna Benković  1 , Mirta Milić  2 , Nada Oršolić  1 , Anica Horvat Knežević  1 , Gordana Brozović  3   4 , Nikola Borojević  5
Affiliations

Different damaging effects of volatile anaesthetics alone or in combination with 1 and 2 Gy gamma-irradiation in vivo on mouse liver DNA: a preliminary study

Vesna Benković et al. Arh Hig Rada Toksikol. .

Abstract
in English, Croatian

As the number of radiotherapy and radiology diagnostic procedures increases from year to year, so does the use of general volatile anaesthesia (VA). Although considered safe, VA exposure can cause different adverse effects and, in combination with ionising radiation (IR), can also cause synergistic effects. However, little is known about DNA damage incurred by this combination at doses applied in a single radiotherapy treatment. To learn more about it, we assessed DNA damage and repair response in the liver tissue of Swiss albino male mice following exposure to isoflurane (I), sevoflurane (S), or halothane (H) alone or in combination with 1 or 2 Gy irradiation using the comet assay. Samples were taken immediately (0 h) and 2, 6, and 24 h after exposure. Compared to control, the highest DNA damage was found in mice receiving halothane alone or in combination with 1 or 2 Gy IR treatments. Sevoflurane and isoflurane displayed protective effects against 1 Gy IR, while with 2 Gy IR the first adverse effects appeared at 24 h post-exposure. Although VA effects depend on liver metabolism, the detection of unrepaired DNA damage 24 h after combined exposure with 2 Gy IR indicates that we need to look further into the combined effects of VA and IR on genome stability and include a longer time frame than 24 h for single exposure as well as repeated exposure as a more realistic scenario in radiotherapy treatment.

Kako se broj radioterapijskih i radioloških dijagnostičkih postupaka iz godine u godinu povećava, tako raste i primjena hlapljivih anestetika za opću anesteziju. Iako se smatralo sigurnim, izlaganje hlapljivim anesteticima može izazvati različite štetne učinke, a u kombinaciji s ionizirajućim zračenjem može izazvati i sinergijske učinke. Međutim, malo se zna o oštećenju DNA koje uzrokuje ova kombinacija u dozama primijenjenima u jednom izlaganju u radioterapiji. Kako bismo saznali više o tome, alkalnim komet-testom analizirali smo oštećenje DNA i odgovor na popravak u jetrenom tkivu muških Swiss albino miševa nakon izlaganja samo izofluranu, sevofluranu ili halotanu, odnosno u kombinaciji sa zračenjem od 1 ili 2 Gy. Uzorci su uzeti odmah (0 h) te 2, 6 i 24 sata nakon izlaganja. U usporedbi s kontrolom, najveća oštećenja DNA utvrđena su u miševa koji su primili halotan, sam ili u kombinaciji sa zračenjem od 1 ili 2 Gy. Sevofluran i izofluran pokazali su zaštitne učinke nakon izlaganja zračenju od 1 Gy, a pri 2 Gy prve nuspojave pojavile su se 24 sata nakon izlaganja. Iako učinci hlapljivih anestetika ovise o metabolizmu jetre, otkrivanje nepopravljenog oštećenja DNA 24 sata nakon kombinirane izloženosti sa zračenjem od 2 Gy upućuje na to da trebamo nastaviti istraživati kombinirane učinke hlapljivih anestetika i ionizirajućega zračenja na stabilnost genoma i obuhvatiti šire razdoblje nakon jednokratne izloženosti (duže od 24 sata). Također treba obuhvatiti višekratna izlaganja kao realističniji scenarij u liječenju radioterapijom.

Keywords: alkaline comet assay; alkalni komet test; halotan; halothane; ionising irradiation; ionizirajuće zračenje; isoflurane; izofluran; sevofluran; sevoflurane.

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Figures

Figure 1
Figure 1
Scheme of the experiment. Male Swiss albino mice (n=240) were divided into 12 groups (control; 1 or 2 Gy irradiated; exposed to only halothane, sevoflurane or isoflurane; exposed to a combination of 1 or 2 Gy and either halothane, sevoflurane or isoflurane) and further each group was divided into 4 subgroups (according to the liver sampling time after the exposure- 0, 2, 6 and 24 hours) with 5 animals in each subgroup. Alkaline Comet assay was used for DNA damage and cellular repair index assessment
Figure 2a
Figure 2a
Tail length values in liver cells of non-irradiated male Swiss albino mice anaesthetised solely with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. C-control. Samples were compared to control 0 h (C 0h), statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 2b
Figure 2b
Tail intensity values in liver cells of non-irradiated male Swiss albino mice anaesthetised solely with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24h after treatment were analysed from five animals per group for 200 comets. C-control. Samples were compared to control 0 h (C 0h), statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 2c
Figure 2c
Tail moment values in liver cells of non-irradiated male Swiss albino mice anaesthetised solely with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. C-control. Samples were compared to control 0 h (C 0h), statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 3a
Figure 3a
Tail length values in liver cells of 1 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 1 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 3b
Figure 3b
Tail intensity values in liver cells of 1 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 1 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 3c
Figure 3c
Tail moment values in liver cells of 1 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 1 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 4a
Figure 4a
Tail length values in liver cells of 2 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 2 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range).
Figure 4b
Figure 4b
Tail intensity values in liver cells of 2 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 2 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle), and standard deviation (SD, range)
Figure 4c
Figure 4c
Tail moment values in liver cells of 2 Gy irradiated male Swiss albino mice previously anaesthetised with halothane (H), sevoflurane (S) or isoflurane (I). Samples taken immediately after (0 h), 2, 6 or 24 h after treatment were analysed from five animals per group for 200 comets. Samples were compared to 2 Gy 0 h, statistical differences (*) were analysed with the Mann-Whitney U test. The values represented here are mean (square), median (triangle) and standard deviation (SD, range)
Figure 5
Figure 5
CRI index (percentage of repair) for tail length (TL) and tail intensity (TI) parameter measured in liver cells of mice for 24 hours. 0 h-immediately after, 2 h, 6 h and 24 h after combined exposure to anaesthetics and: 1 Gy (A, B) or 2 Gy (C, D) γ-irradiation (60Co). H-halothane, S-sevoflurane, I-isoflurane
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