Gender- and age-related distinctions for the in vivo prooxidant state in Fanconi anaemia patients

Abstract

Some selected oxidative stress parameters were measured in 56 Fanconi anaemia (FA) patients (42 untransplanted and 14 transplanted), 54 FA heterozygotes (parents) and 173 controls. Untransplanted FA patients showed a highly significant increase in leukocyte 8-hydroxy-2′-deoxyguanosine (8-OHdG) ( P = 0.00003) and a borderline increase ( P = 0.076) in urinary levels of 8-OHdG versus child controls. These increases were more pronounced in female FA patients ( P = 0.00005 for leukocyte 8-OHdG and P = 0.021 for urinary 8-OHdG). Female FA patients also displayed a highly significant excess of spontaneous chromosomal breaks versus male patients ( P = 0.00026), in the same female:male ratio (∼1.4) as detected for both leukocyte and urine 8-OHdG levels. Plasma methylglyoxal (MGlx) levels were increased in untransplanted FA patients versus child controls ( P = 0.032). The increases in leukocyte and urinary 8-OHdG and in MGlx levels were detected in young FA patients (≤15 years), whereas patients aged 16–29 years failed to display any differences versus controls in the same age group. A significant increase in oxidized:reduced glutathione (GSSG:GSH) ratio was observed ( P = 0.046) in the FA patients aged ≤15 years, whereas those aged 16–29 years, both untransplanted and transplanted, displayed a decrease ( P = 0.06) in the GSSG:GSH ratio versus the controls of the respective age groups. No significant changes were detected in plasma levels of vitamin C, vitamin E or uric acid. Transplanted FA patients showed lesser alterations in leukocyte 8-OHdG and in GSSG:GSH ratio versus untransplanted patients. The parents of FA patients displayed a significant increase in plasma MGlx levels ( P = 0.0014) versus adult controls. The results suggest a gender- and age-related modulation of oxidative stress in FA patients. The observed increase in urinary 8-OHdG in untransplanted FA patients suggests a proficient removal of oxidized DNA bases.

BPDS, bathophenanthroline disulfonic acid, CHES, 2-( N -cyclohexylamine)ethanesulphonic acid , DEB, diepoxybutane, dG, deoxyguanosine, FA, Fanconi anaemia, f:m ratio, female:male ratio, HD, healthy donors, HSD, honest significant difference, MGlx, methylglyoxal, MMC, mitomycin C, MPA, metaphosphoric acid, 8-OHdG, 8-hydroxy- 2′-deoxyguanosine, PC, pathology controls, PCA, perchloric acid, TG, total glutathione