Accumulation of 8-Oxoguanine in Liver DNA During Hyperoxic Resuscitation of Newborn Mice

Abstract

Supplementary oxygen during resuscitation of the asphyxiated newborn is associated with long-term detrimental effects including increased risk of childhood cancer. It is suspected that the resuscitation procedure results in accumulated DNA damage and mutagenesis. Base excision repair (BER) is the major pathway for repair of premutagenic oxidative DNA lesions. This study addresses DNA base damage and BER in brain, lung, and liver in neonatal mice (P7) after hyperoxic resuscitation. Mice were randomized to 8% oxygen or room air for 60 min in a closed chamber and subsequent reoxygenation with 100% oxygen for 0 to 90 min. During this treatment, 8-oxoguanine accumulated in liver but not in lung or cerebellum. We observed a linear relation between 8-oxoguanine and reoxygenation time in liver DNA from hypoxic animals (n ϭ 28; B ϭ 0.011 [0.001, 0.020]; p ϭ 0.037). BER activity was not significantly changed during resuscitation. Our data suggest that after hypoxia, the capacity for immediate repair in liver tissue is inadequate to meet increasing amounts of DNA damage. The duration of supplementary oxygen use during resuscitation should be kept as short as justifiable to minimize the risk of genetic instability.

Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation

“…After 120 min of hypoxia, pH in the whole blood (mean (SEM)) lowered to 7.23 (0.04) (n = 6) as compared with 7.42 (0.1) (n = 5) when exposed to air (P < 0.001). pH lowered with 0.13 from 60 to 120 min of hypoxia (17). Furthermore, base excess (mmol/l) lowered from 4.2 (1.1) in air to −13.3 (1.7) (P < 0.001) after 120-min hypoxia, and pCO 2 lowered from 6.0 (0.2) to 3.4 (0.2) (P < 0.001).…”

“…Our group has previously reported that increasing FiO 2 during resuscitation of newborn pigs results in increasing levels of 8-oxodG in urine, which is a marker of oxidative stress (5). Moreover, there is a positive correlation between reoxygenation time and 8-oxoguanine in mouse liver DNA after hypoxia (17).…”

“…Furthermore, base excess (mmol/l) lowered from 4.2 (1.1) in air to −13.3 (1.7) (P < 0.001) after 120-min hypoxia, and pCO 2 lowered from 6.0 (0.2) to 3.4 (0.2) (P < 0.001). Base excess lowered with 3.9 mmol/l from 60 to 120 min of hypoxia (17).…”

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

“…Hyperoxia per se defined a unique gene expression pattern compared with when hyperoxia was preceded by hypoxia, thus disclosing different transcriptional activations due to these distinct stimuli. Our aim was to mimic a global hypoxic insult followed by subsequent reoxygenation, to be able to study the sudden reintroduction of different FiO 2 to hypoxic brain tissue, as done previously (19). We therefore avoided ligation of the carotid artery as used in the Vanucci model, producing a focal brain injury.…”

Oxygenation of the Newborn: A Molecular Approach

“…Guanine has a low reduction potential and is readily oxidized to 8-oxoguanine (8-oxoG), a highly mutagenic base lesion due to its preferential base pairing with adenine and the subsequent transversion from G:C to T:A during the replication process [52]. We have previously shown that experimental hyperoxic resuscitation increases the levels of 8-oxoG both in urine and tissue [40,53], providing evidence that oxygen may act as a carcinogenic agent in the newborn, but a causal relationship remains to be established. Future studies should take advantage of DNA repair-deficient models, discussed below, to investigate the mechanisms underlying the association between oxygen and malignant disease.…”