Thioredoxin overexpression in mice, model of attenuation of oxidative stress, prevents benzene-induced hemato-lymphoid toxicity and thymic lymphoma.
OBJECTIVE
Reactive oxygen species (ROS), generated following benzene exposure, are considered to trigger the development of hematopoietic neoplasms, although little supporting evidence has been found. In this study, we examined whether the experimental elimination of ROS generated following benzene exposure prevents the development of benzene-induced hematopoietic disorders to clarify the mechanism underlying the development of benzene-induced hematopoietic disorders.


METHODS
C57BL/6 mice, overexpressing human thioredoxin (h-Trx-Tg), were used to examine the possible nullification of ROS induction following benzene exposure. The experimental group was exposed to 300 ppm benzene 6 hours/day, 5 days/week, for 26 weeks, and lifetime observation followed by molecular and histopathological examinations were carried out.


RESULTS
The present study using h-Trx-Tg mice showed a complete suppression of the development of thymic lymphoma induced by benzene inhalation (0% in h-Trx-Tg vs 30% in wild-type (Wt) mice). This was associated with a 48% decrease in the incidence of clastogenic micronucleated reticulocyte induction in the h-Trx-Tg mice compared with the Wt control after 2 weeks of inhalation. As underlying mechanisms, the attenuation of oxidative stress was accompanied by a complete abrogation of hemato-lymphoid toxicity, as shown by the upregulation of the activity of superoxide-dismutase, and a consequently stable ROS level, as determined by cell sorting using 2', 7'-dichlorodihydrofluorescein diacetate, along with a significant attenuation of the overexpression of a cell cycle-dependent kinase inhibitor, p21.


CONCLUSIONS
The attenuation of benzene-induced oxidative stress and that of the consequent lymphomagenesis were observed for the first time, and these indicate a role of oxidative stress in benzene-induced clastogenesis and lymphomagenesis. (These attenuations were not seen in nonthymic lymphomas, and no leukemias developed in C57BL/6 used in this study.) During the constitutive overexpression of h-Trx, the expression of aryl-hydrocarbon receptor in h-Trx-Tg mice was downregulated, which may also contribute to the attenuation.
Li
Guang-Xun
GX
Division of Cellular and Molecular Toxicology, Biological Safety and Research Center, National Institute of Health Sciences, Tokyo, Japan.
Hirabayashi
Yoko
Y
Yoon
Byung-Il
BI
Kawasaki
Yasushi
Y
Tsuboi
Isao
I
Kodama
Yukio
Y
Kurokawa
Yuji
Y
Yodoi
Junji
J
Kanno
Jun
J
Inoue
Tohru
T
D000818:Animals; D001554:Benzene / Q000633:toxicity; D002051:Burkitt Lymphoma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D002273:Carcinogens / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D015536:Down-Regulation; D005838:Genotype; D006402:Hematologic Diseases / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015996:Survival Rate; D013879:Thioredoxins / Q000096:biosynthesis / Q000235:genetics*; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D013879:Thioredoxins; D019392:Cytochrome P-450 CYP2E1; D001554:Benzene