Enhanced levels in neonatal rat liver of 7,8-dihydro-8-oxo-2'- deoxyguanosine (8-hydroxydeoxyguanosine), a major mutagenic oxidative DNA lesion

Abstract

The purpose of this study was to determine whether the level of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxy-2'-deoxyguanosine) (8-oxo-dG), a major mutagenic DNA oxidation product, is enhanced in newborn rat liver DNA as a consequence of oxidative stress incurred during the early postnatal period. 32P-postlabeling showed this adduct to increase approximately 2-fold from the 20th day of gestation (2 days before birth) to a peak level at 50-53 h after birth. Postnatal levels exceeded fetal levels at all time points investigated, i.e. 0.5-1, 8, 24, 50-53, 100, 216 and 432 h after birth. Increased formation of this mutagenic DNA lesion during the critical postnatal phase when there is rapid cell proliferation in all tissues is proposed to contribute to carcinogenesis in susceptible tissues later in life.

Age and Organ Dependent Spontaneous Generation of Nuclear 8-Hydroxydeoxyguanosine in Male Fischer 344 Rats

“…The data thus indicate that rats are indeed confronted with early-postnatal oxidative stress (Gunther et al, 1993;Krukowski and Smith, 1976;Yoshimura et al, 1988). The discrepancy between our findings and those of Randerath et al (1997) may be, at least partly, due to the differences in detection methods (they apply 32 P-postlabeling) and the possible presence of mitochondrial DNA contamination. Fraga et al (1990) reported aging-dependent increase of 8-OHdG in the liver, kidney and intestine, but not brain or testis, of male Fischer 344 rats from 1 to 24 months of age.…”

“…With regard to the pre-and postnatal changes in 8-OHdG steady-state levels in rat organs, Randerath et al (1997) demonstrated liver increase within 1 hour after birth, a peak at the 53rd hour and decrease by the 100th hour in neonatal Fischer 344 rats. We could not detect any elevation of nuclear 8-OHdG levels in the assessed organs during the prenatal and postnatal/preweaning period up to 2 weeks of age using HPLC-ECD, with the single exception of a small increase in the liver at 7 days.…”

“…Since its first discovery by Kasai and Nishimura's group , 8-OHdG levels have been determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD), gas chromatography with mass spectrometry, 32 P-postlabelling, or assays based on the use of repair endonucleases specific for the lesion, but good agreement has not been obtained among values given by different techniques (Collins et al, 1997). Furthermore, 8-OHdG levels appear to be altered in age-and organ-specific fashions, but again there is no good consensus among values (Fraga et al, 1990;Hirano et al, 1996;Kaneko et al, 1996;Randerath et al, 1997;Sai et al, 1992). Finally, while the conventional methods listed above are applicable for analysis of 8-OHdG levels on a whole organ basis, they do not allow for its localization within tissues.…”

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

“…We speculate that the proposed alterations in mitochondrial function during hypoxia further enhance production of ROS upon reoxygenation, which might explain the current findings in hypoxic animals as opposed to controls. Furthermore, the sudden surge in partial oxygen pressure at birth has been reported to increase the amount of 8-oxoG in rat liver DNA (32), indicating a finely tuned equilibrium under physiological conditions. Mitochondrial dysfunction and defective translocation of OGG1, as seen with increasing oxidative stress in older mice (33), may cause disruption and a progressive accumulation of oxidative DNA damage.…”

Extended longevity mechanisms in short-lived progeroid mice: Identification of a preservative stress response associated with successful aging

“…The rapid postnatal onset suggests that birth stress, which involves an increase in ROS levels (Randerath et al, 1997a;Randerath et al, 1997b) may trigger it and that rapid postnatal growth may further exacerbate it. Combined with the inability to repair certain endogenous lesions as in SIRT6 or NER deficiency, oxidative genotoxic stress may trigger an adaptive response intended to reduce generation of ROS through mitochondrial respiration and thus prevent further damage.…”