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NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes.

Das A, Dey N, Ghosh A, Das T, Chatterjee IB - PLoS ONE (2011)

Bottom Line: Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein.However, after the onset of MDS vitamin C becomes ineffective.Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.

ABSTRACT

Background: The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs.

Methodology and principal findings: Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective.

Conclusions and significance: CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

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Identification of MDS in guinea pigs by blood and bone marrow cell morphology, measurement of CD34(+) cells and cytogenetic studies.(Panel A) Differential staining showing some typical changes in blood and bone marrow cell morphology of MDS guinea pigs and its prevention by feeding the animals 15 mg vitamin C/day. A, I–IV, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, V–XVI, represent MDS guinea pigs (CS-exposed fed DC and 0.5 mg vitamin C/day); A, XVII–XX, represent CS-exposed guinea pigs fed DC and 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in X and XIV; (magnification 400×, except I, V, VI, IX, XIII, XVII; 1000× magnification). → indicates dysplastic cells. Vit C means vitamin C. (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Quantitative evaluation of CD34(+) cells; bars (means ± SD, n = 6) over the respective columns represent CD34(+) cells, * significantly different (p<0.05) with respect to 1–7 samples. (Panel D) Geimsa-stained metaphase spread showing aneuploidy in II; (magnification 1000×).
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pone-0020590-g002: Identification of MDS in guinea pigs by blood and bone marrow cell morphology, measurement of CD34(+) cells and cytogenetic studies.(Panel A) Differential staining showing some typical changes in blood and bone marrow cell morphology of MDS guinea pigs and its prevention by feeding the animals 15 mg vitamin C/day. A, I–IV, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, V–XVI, represent MDS guinea pigs (CS-exposed fed DC and 0.5 mg vitamin C/day); A, XVII–XX, represent CS-exposed guinea pigs fed DC and 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in X and XIV; (magnification 400×, except I, V, VI, IX, XIII, XVII; 1000× magnification). → indicates dysplastic cells. Vit C means vitamin C. (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Quantitative evaluation of CD34(+) cells; bars (means ± SD, n = 6) over the respective columns represent CD34(+) cells, * significantly different (p<0.05) with respect to 1–7 samples. (Panel D) Geimsa-stained metaphase spread showing aneuploidy in II; (magnification 1000×).

Mentions: One important method of diagnosis of MDS relies on morphologic assessments based on World Health Organization (WHO) classification [32]. Here we have diagnosed MDS in guinea pigs on the basis of bone marrow cell morphology, histology and cytogenetic examinations. The guinea pigs were divided into 8 groups (6 animals/group): (i) 0.5 mg vitamin C and exposed to air (sham controls), (ii) 0.5 mg vitamin C and exposed to CS, (iii) 0.5 mg vitamin C fed DC and exposed to air, (iv) 0.5 mg vitamin C fed DC and exposed to CS, (v) 15 mg vitamin C and exposed to air, (vi) 15 mg vitamin C and exposed to CS, (vii) 15 mg vitamin C fed DC and exposed to air, and (viii) 15 mg vitamin C fed DC and exposed to CS. All the guinea pigs of groups (i–iii) and (v–viii) were fed with respect to the average food consumption of the guinea pigs of group (iv). After exposure to CS for 21 days, MDS were produced only in the guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. Figure 2A, V and IX show that in comparison to normal segmented neutrophils (Figure 2AI), there are hyper segmented neutrophils (7 lobes) in the blood film of MDS guinea pigs. These observations indicate dysgranulopoiesis, as reported by others [33]. Figure 2AXIII depicts poorly functioning large platelets in the MDS guinea pigs, as compared to the platelets observed in the blood film of guinea pigs fed 0.5 mg vitamin C/day and exposed to air (Figure 2AI). In contrast to all other experimental groups there was significant decrease in the number of platelets in the MDS guinea pigs (Table S1). All these various changes were observed in the MDS guinea pigs, but not in any of the guinea pigs other than MDS, including vitamin C-sufficient guinea pigs fed 15 mg vitamin C/day (Figure 2A XVII).


NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes.

Das A, Dey N, Ghosh A, Das T, Chatterjee IB - PLoS ONE (2011)

Identification of MDS in guinea pigs by blood and bone marrow cell morphology, measurement of CD34(+) cells and cytogenetic studies.(Panel A) Differential staining showing some typical changes in blood and bone marrow cell morphology of MDS guinea pigs and its prevention by feeding the animals 15 mg vitamin C/day. A, I–IV, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, V–XVI, represent MDS guinea pigs (CS-exposed fed DC and 0.5 mg vitamin C/day); A, XVII–XX, represent CS-exposed guinea pigs fed DC and 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in X and XIV; (magnification 400×, except I, V, VI, IX, XIII, XVII; 1000× magnification). → indicates dysplastic cells. Vit C means vitamin C. (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Quantitative evaluation of CD34(+) cells; bars (means ± SD, n = 6) over the respective columns represent CD34(+) cells, * significantly different (p<0.05) with respect to 1–7 samples. (Panel D) Geimsa-stained metaphase spread showing aneuploidy in II; (magnification 1000×).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105086&req=5

pone-0020590-g002: Identification of MDS in guinea pigs by blood and bone marrow cell morphology, measurement of CD34(+) cells and cytogenetic studies.(Panel A) Differential staining showing some typical changes in blood and bone marrow cell morphology of MDS guinea pigs and its prevention by feeding the animals 15 mg vitamin C/day. A, I–IV, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, V–XVI, represent MDS guinea pigs (CS-exposed fed DC and 0.5 mg vitamin C/day); A, XVII–XX, represent CS-exposed guinea pigs fed DC and 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in X and XIV; (magnification 400×, except I, V, VI, IX, XIII, XVII; 1000× magnification). → indicates dysplastic cells. Vit C means vitamin C. (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Quantitative evaluation of CD34(+) cells; bars (means ± SD, n = 6) over the respective columns represent CD34(+) cells, * significantly different (p<0.05) with respect to 1–7 samples. (Panel D) Geimsa-stained metaphase spread showing aneuploidy in II; (magnification 1000×).
Mentions: One important method of diagnosis of MDS relies on morphologic assessments based on World Health Organization (WHO) classification [32]. Here we have diagnosed MDS in guinea pigs on the basis of bone marrow cell morphology, histology and cytogenetic examinations. The guinea pigs were divided into 8 groups (6 animals/group): (i) 0.5 mg vitamin C and exposed to air (sham controls), (ii) 0.5 mg vitamin C and exposed to CS, (iii) 0.5 mg vitamin C fed DC and exposed to air, (iv) 0.5 mg vitamin C fed DC and exposed to CS, (v) 15 mg vitamin C and exposed to air, (vi) 15 mg vitamin C and exposed to CS, (vii) 15 mg vitamin C fed DC and exposed to air, and (viii) 15 mg vitamin C fed DC and exposed to CS. All the guinea pigs of groups (i–iii) and (v–viii) were fed with respect to the average food consumption of the guinea pigs of group (iv). After exposure to CS for 21 days, MDS were produced only in the guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. Figure 2A, V and IX show that in comparison to normal segmented neutrophils (Figure 2AI), there are hyper segmented neutrophils (7 lobes) in the blood film of MDS guinea pigs. These observations indicate dysgranulopoiesis, as reported by others [33]. Figure 2AXIII depicts poorly functioning large platelets in the MDS guinea pigs, as compared to the platelets observed in the blood film of guinea pigs fed 0.5 mg vitamin C/day and exposed to air (Figure 2AI). In contrast to all other experimental groups there was significant decrease in the number of platelets in the MDS guinea pigs (Table S1). All these various changes were observed in the MDS guinea pigs, but not in any of the guinea pigs other than MDS, including vitamin C-sufficient guinea pigs fed 15 mg vitamin C/day (Figure 2A XVII).

Bottom Line: Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein.However, after the onset of MDS vitamin C becomes ineffective.Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, Kolkata, West Bengal, India.

ABSTRACT

Background: The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs.

Methodology and principal findings: Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective.

Conclusions and significance: CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

Show MeSH
Related in: MedlinePlus