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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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MDS produced in the guinea pigs are irreversible.(Panel A) Differential staining showing persistent changes in blood and bone marrow cell morphology of MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. A, a–d, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, e–h, represent MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in d and h; (magnification 400×). (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Geimsa-stained metaphase spread showing aneuploidy in MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day; (magnification 1000×). (Panel D) NQO1 Activity of bone marrow cells. Bars over the respective columns represent means ± SD (n = 4); * indicates significant difference (p<0.05, n = 4) with respect to air exposed guinea pigs. (Panel E) NQO1 and p53 status in the bone marrow cells.
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pone-0020590-g005: MDS produced in the guinea pigs are irreversible.(Panel A) Differential staining showing persistent changes in blood and bone marrow cell morphology of MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. A, a–d, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, e–h, represent MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in d and h; (magnification 400×). (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Geimsa-stained metaphase spread showing aneuploidy in MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day; (magnification 1000×). (Panel D) NQO1 Activity of bone marrow cells. Bars over the respective columns represent means ± SD (n = 4); * indicates significant difference (p<0.05, n = 4) with respect to air exposed guinea pigs. (Panel E) NQO1 and p53 status in the bone marrow cells.

Mentions: It is known that MDS is an irreversible condition caused in some cases by genotoxicity. Here we show that MDS produced in the guinea pigs are irreversible, as evidenced by bone marrow cell morphology and cytogenetic examination. Six guinea piga were fed 0.5 mg vitamin C and 3 mg DC/animal/day and exposed to CS. Another 6 guinea pigs were fed 0.5 mg vitamin C/animal/day and exposed to air (sham controls). After exposure to CS for 21 days, 2 out of the 6 guinea pigs were sacrificed and MDS diagnosed by morphology and cytogenetic examination described before in the text. CS exposure was discontinued in the remaining 4 guinea pigs and they were fed 15 mg vitamin C/animal/day. Supplementation of DC (3 mg/day) was continued for maintaining NQO1 deficiency. After 6 days, there was drastic fall in the food intake and loss of body weight. At that stage, the animals were sacrificed and blood smear, bone marrow cell morphology, CD34(+) cell count and cytogenetic examination were performed. We have also measured NQO1 activity and the p53 status in the bone marrow. Figure 5A a, b, c, d show normal morphology in blood and bone marrow cells. In contrast to these, Figure 5A e and f depict poor functioning large platelets and dyserythropoietic changes in bone marrow cells. Figure 5A g and h show micromegakaryocyte and ring sideroblast. The percentage of CD34(+) cells in the bone marrow increased significantly (p<0.05, n = 4) about 22% over that observed in the sham controls (Figure 5B). Here we have also observed anuploidy, the number varied from 104 to 120 (Figure 5C). A critical analyses of 100 metaphases revealed that 62% metaphases represented normal karyotype, (Figure 5C) whereas 38% metaphases represented anuploidy (Figure 5C). All these aforesaid results indicate that the animals had persistent changes confirming irreversibility of MDS produced in the guinea pigs. Figure 5D shows 90% inhibition of NQO1 activity in the bone marrow without any change in the NQO1 gene expression at the protein level (Figure 5E, row 1). However, the p53 level was markedly low in the MDS guinea pigs fed 15 mg vit C (Figure 5E, row 2).


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)

MDS produced in the guinea pigs are irreversible.(Panel A) Differential staining showing persistent changes in blood and bone marrow cell morphology of MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. A, a–d, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, e–h, represent MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in d and h; (magnification 400×). (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Geimsa-stained metaphase spread showing aneuploidy in MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day; (magnification 1000×). (Panel D) NQO1 Activity of bone marrow cells. Bars over the respective columns represent means ± SD (n = 4); * indicates significant difference (p<0.05, n = 4) with respect to air exposed guinea pigs. (Panel E) NQO1 and p53 status in the bone marrow cells.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105086&req=5

pone-0020590-g005: MDS produced in the guinea pigs are irreversible.(Panel A) Differential staining showing persistent changes in blood and bone marrow cell morphology of MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. A, a–d, represent sham controls (fed 0.5 mg vitamin C/day and exposed to air); A, e–h, represent MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day. Blood smear - Leishman stain; bone marrow aspirate - Wright Geimsa stain, except Perls' stain in d and h; (magnification 400×). (Panel B) Measurement of CD34(+) cells in bone marrow by flow cytometry. (Panel C) Geimsa-stained metaphase spread showing aneuploidy in MDS guinea pigs followed by discontinuation of CS exposure and feeding 15 mg vitamin C/day; (magnification 1000×). (Panel D) NQO1 Activity of bone marrow cells. Bars over the respective columns represent means ± SD (n = 4); * indicates significant difference (p<0.05, n = 4) with respect to air exposed guinea pigs. (Panel E) NQO1 and p53 status in the bone marrow cells.
Mentions: It is known that MDS is an irreversible condition caused in some cases by genotoxicity. Here we show that MDS produced in the guinea pigs are irreversible, as evidenced by bone marrow cell morphology and cytogenetic examination. Six guinea piga were fed 0.5 mg vitamin C and 3 mg DC/animal/day and exposed to CS. Another 6 guinea pigs were fed 0.5 mg vitamin C/animal/day and exposed to air (sham controls). After exposure to CS for 21 days, 2 out of the 6 guinea pigs were sacrificed and MDS diagnosed by morphology and cytogenetic examination described before in the text. CS exposure was discontinued in the remaining 4 guinea pigs and they were fed 15 mg vitamin C/animal/day. Supplementation of DC (3 mg/day) was continued for maintaining NQO1 deficiency. After 6 days, there was drastic fall in the food intake and loss of body weight. At that stage, the animals were sacrificed and blood smear, bone marrow cell morphology, CD34(+) cell count and cytogenetic examination were performed. We have also measured NQO1 activity and the p53 status in the bone marrow. Figure 5A a, b, c, d show normal morphology in blood and bone marrow cells. In contrast to these, Figure 5A e and f depict poor functioning large platelets and dyserythropoietic changes in bone marrow cells. Figure 5A g and h show micromegakaryocyte and ring sideroblast. The percentage of CD34(+) cells in the bone marrow increased significantly (p<0.05, n = 4) about 22% over that observed in the sham controls (Figure 5B). Here we have also observed anuploidy, the number varied from 104 to 120 (Figure 5C). A critical analyses of 100 metaphases revealed that 62% metaphases represented normal karyotype, (Figure 5C) whereas 38% metaphases represented anuploidy (Figure 5C). All these aforesaid results indicate that the animals had persistent changes confirming irreversibility of MDS produced in the guinea pigs. Figure 5D shows 90% inhibition of NQO1 activity in the bone marrow without any change in the NQO1 gene expression at the protein level (Figure 5E, row 1). However, the p53 level was markedly low in the MDS guinea pigs fed 15 mg vit C (Figure 5E, row 2).

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