API

Aop: 31

AOP Title

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Oxidation of iron in hemoglobin leading to hematotoxicity

Short name:

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Hemoglobin oxidation leading to hematotoxicity

Authors

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Mitchell Wilbanks, Kurt Gust, Youping Deng, Sharon Meyer, and Edward Perkins

Point of Contact: Mitchell Wilbanks, Mitchell.S.Wilbanks@usace.army.mil

Point of Contact

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Mitchell S. Wilbanks

Contributors

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  • Mitchell S. Wilbanks

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.16 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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Revision dates for related pages

Page Revision Date/Time
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leading to oxidation of heme iron(II) in hemoglobin to iron(III) December 03, 2016 16:37
Altered regulation, Alpha hemoglobin September 16, 2017 10:14
Propagation, Oxidative stress September 16, 2017 10:14
Damaging, Red blood cells; hemolysis September 16, 2017 10:14
Formation, Formation of hemoglobin adducts September 16, 2017 10:14
Down Regulation, Gulcose-6-phosphate dehydrogenase September 16, 2017 10:14
Increase, RBC congestion in liver September 16, 2017 10:14
Increase, Liver and splenic hemosiderosis September 16, 2017 10:14
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number September 16, 2017 10:14
N/A, Cyanosis occurs December 03, 2016 16:33
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Propagation, Oxidative stress December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Damaging, Red blood cells; hemolysis December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Formation, Formation of hemoglobin adducts December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to Increase, RBC congestion in liver December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37
Damaging, Red blood cells; hemolysis leads to Increase, Liver and splenic hemosiderosis December 03, 2016 16:37
Propagation, Oxidative stress leads to Down Regulation, Gulcose-6-phosphate dehydrogenase December 03, 2016 16:37
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Altered regulation, Alpha hemoglobin December 03, 2016 16:37
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number leads to N/A, Cyanosis occurs December 03, 2016 16:37
Increase, RBC congestion in liver leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37
Propagation, Oxidative stress leads to Damaging, Red blood cells; hemolysis December 03, 2016 16:37
Increase, Liver and splenic hemosiderosis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number December 03, 2016 16:37

Abstract

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Studies have shown that aniline, 2,4,6-trinitrotoluene (TNT) and 2,4-dinitrotoluene (2,4-DNT) are converted to the reactive metabolite and form free radicals leading to oxidization of heme Iron(II) in hemoglobin to Iron(III), a molecular initiating event. Damage then occurs to red blood cells (RBCs) and methemoglobinemia ensues which is characterized by reduced RBCs, hemoglobin concentration, and Heinz body formation (Ellis et al. 1985, Lee et al. 1976, 1978, Hazleton Laboratories 1977, 1982, Kozuka et al. 1978, 1979, Bolt et al. 2006). The adverse outcome due to such hematological effects is cyanosis with possible death if methemoglobin levels become severe. Hemoglobin adducts are also formed by these chemicals (Sabbioni et al. 2006). Sinusoidal congestion was noted in animals who were exposed to 2,4-DNT or 2,6-DNT (Deng et al. 2011) while hemosiderosis was reported in another study involving DNT (Lee et al. 1978) and in aniline studies. A compensatory response to possible anemic effects has been observed in animals including increased peripheral reticulocytes (Deng et al. 2011) and induction of genes associated with heme biosynthesis (CPOX and UROS) (Rawat et al. 2010). Oxidative stress is also induced upon this interaction with the RBC which may lead to DNA damage and cell death to not only the RBC but other cells such as hepatocytes (Deng et al. 2011). Glucose-6-phosphate dehydrogenase (G6pd) was found to be significantly down-regulated in animals treated with 2,4-DNT for 14 d which leads to decreased levels of NADPH, a coenzyme used to properly maintain glutathione levels and therefore protect cells, especially RBC, from oxidative damage (Wilbanks, et al., unpublished observations). In response to increased oxidative stress, protective mechanisms such as the Nrf2 mediated oxidative stress response may be induced (Deng et al. 2011). While this AOP specifically shows effects of 2,4-DNT and 2,6-DNT, the principal adverse pathways of oxidation of Fe(II) to Fe(III) leading to methemoglobinemia and its downsteam effects and oxidative stress formation leading to its downstream effects are shared with the more well characterized structurally similar compound group of N-hydroxyl anilines.


Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leading to oxidation of heme iron(II) in hemoglobin to iron(III) N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin

Key Events

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Title Short name
Altered regulation, Alpha hemoglobin Altered regulation, Alpha hemoglobin
Propagation, Oxidative stress Propagation, Oxidative stress
Damaging, Red blood cells; hemolysis Damaging, Red blood cells; hemolysis
Formation, Formation of hemoglobin adducts Formation, Formation of hemoglobin adducts
Down Regulation, Gulcose-6-phosphate dehydrogenase Down Regulation, Gulcose-6-phosphate dehydrogenase
Increase, RBC congestion in liver Increase, RBC congestion in liver
Increase, Liver and splenic hemosiderosis Increase, Liver and splenic hemosiderosis
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number

Adverse Outcome

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Title Short name
N/A, Cyanosis occurs N/A, Cyanosis occurs

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Propagation, Oxidative stress Directly leads to Moderate
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Damaging, Red blood cells; hemolysis Directly leads to Strong
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Formation, Formation of hemoglobin adducts Directly leads to Strong
Damaging, Red blood cells; hemolysis leads to Increase, RBC congestion in liver Directly leads to Moderate
Damaging, Red blood cells; hemolysis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number Directly leads to Strong
Damaging, Red blood cells; hemolysis leads to Increase, Liver and splenic hemosiderosis Directly leads to Strong
Propagation, Oxidative stress leads to Down Regulation, Gulcose-6-phosphate dehydrogenase Directly leads to Weak
N/A, Parent compound is converted to the reactive metabolite and forms free radicals leadin leads to Altered regulation, Alpha hemoglobin Indirectly leads to Weak
N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number leads to N/A, Cyanosis occurs Directly leads to Strong
Increase, RBC congestion in liver leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number Directly leads to Moderate
Propagation, Oxidative stress leads to Damaging, Red blood cells; hemolysis Directly leads to Strong
Increase, Liver and splenic hemosiderosis leads to N/A, Methemoglobinemia, decreased hemoglobin, hematocrit, red blood cell number Directly leads to Moderate

Network View

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Life Stage Applicability

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Taxonomic Applicability

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Term Scientific Term Evidence Link
Mus musculus Mus musculus Strong NCBI
Rattus norvegicus Rattus norvegicus Strong NCBI

Sex Applicability

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Graphical Representation

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Click to download graphical representation template

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Overall Assessment of the AOP

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This AOP is constructed using data from human, rat, mouse, avian, and fish based studies.

Domain of Applicability

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Essentiality of the Key Events

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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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Bolt HM, Degen GH, Dorn SB, Plöttner S, Harth V (2006) Genotoxicity and potential carcinogenicity of 2,4,6-TNT trinitrotoluene: structural and toxicological considerations. Reviews on environmental health. Oct-Dec; 21(4):217-28.

Deng Y, Meyer SA, Guan X, Escalon BL, Ai J, et al. (2011) Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds. PLoS ONE. 6(2): e14662.

Ellis HV, Hong CB, Lee CC, et al. 1985. Subchronic and chronic toxicity studies of 2,4-dinitrotoluene. Part I. Beagle dog. J Am Co11 Toxicol. 4:233-242.

Jones, C.R., Liu, Y., Sepai, O., Yan, H., and Sabbioni, G. (2005). Hemoglobin adducts in workers exposed to nitrotoluenes. Carcinogenesis. 26(1):133-143.

Kozuka H, Mori M., Katayama K, Matsuhashi T, Miyahara T, Mori Y, and Nagahara S. 1978. Studies on the metabolism and toxicity of dinitrotoluenes-Metabolism of dinitrotoluenes by Rhodotorula glutinis and rat liver homogenate. Eisei Kagaku, 24: 252-259.

Kozuka H, Mori M, and Yoshifumi, N. 1979. Studies on the metabolism and toxicity of dinitrotoluenes: Toxicological study of 2,4-dinitrotoluene (2,4-DNT) in rats in long term feeding. The Journal of Toxicological Sciences. 4:221-228.

La, D.K. and Froines, J.R. (1992). Comparison of DNA adduct formation between 2,4 and 2,6-dintirotoluene by 32P-postlabelling analysis. Archives of Toxicology. 66(9):633-640.

Lee CC, Ellis HV, Kowalski JJ, et al. 1976. Mammalian toxicity of munitions compounds. Phase II: Effects of multiple doses. Part IIh 2,6-Dinitrotoluene. Progress report no. 4. Midwest Research Institute Project no. 3900-B. Contract no. DAMD-17-74-C-4073. From ASTDR.

Lee CC, Ellis HV, Kowalski JJ, et al. 1978. Mammalian toxicity of munitions compounds. Phase II: Effects of multiple doses. Part Il: 2,4-Dinitrotoluene. Progress report No. 3. Midwest Research Institute, Kansas City, MO. Contract no. DAMD 17-74-C-4073. From ASTDR.

Hazleton Laboratories. 1977. A thirty-day toxicology study in Fischer-344 rats given dinitrotoluene, technical grade. Full report. Submitted to Chemical Industry Institute of Toxicology, Research Triangle Park, NC.

Hazleton Laboratories. 1982. 104-week chronic study in rats. Dinitrotoluene. Final report Volume I of II. Submitted to Chemical Industry Institute of Toxicology, Research Triangle Park, NC.

Rawat A, Gust KA, Deng Y, Garcia-Reyero N, Quinn MJ Jr, Johnson MS, Indest KJ, Elasri MO, Perkins EJ. From raw materials to validated system: the construction of a genomic library and microarray to interpret systemic perturbations in Northern bobwhite. Physiol Genomics. 42: 219–235, 2010.

Sabbioni G, Jones CR, Sepai O, et al. 2006. Biomarkers of exposure, effect, and susceptibility in workers exposed to nitrotoluenes. Cancer Epidemiol Biomarkers. Prev 15(3):559-66.

Wintz H, Yoo LJ, Loguinov A, Wu Y, Steevens JA, Holland RD, Beger RD, Perkins EJ, Hughes O, Vulpe CD. Gene expression profiles in fathead minnow exposed to 2,4-DNT: correlation with toxicity in mammals. Toxicol Sci. 94: 71–82, 2006.