New biomarkers for 1,1-dimethylhydrazine

Cover Page

Cite item

Full Text

Abstract

Introduction. Despite the large-scale use of asymmetric dimethylhydrazine (UDMH) in the domestic rocket and space industry, its biomarkers of exposure in blood plasma and urine, as well as biomarkers of cardiotoxic effects, have not yet been described.

Material and methods. The study of blood and urine samples of rats after a single injection of 10 mg/kg UDMH (1/16 LD50) was carried out by HPLC-MS. The determination of the non-metabolized form of UDMH was also carried out using the method of gas chromatography with mass-selective detection with preliminary derivatization with 4-pyridinecarboxyaldehyde. The cardiotoxic effect of UDMH was assessed on a model of an isolated rat heart with subchronic intragastric administration for 28 days at doses of 0,02; 0,2; 2,0 mg/kg.

Results. It has been established that the main metabolites of UDMH are dimethylhydrazones of pyridoxal (vitamin B6) and pyruvic acid (pyruvate). The possibility of determining the non-metabolized form of UDMH in blood and urine by HPLC-MS was shown, concentrations reach 10–60 ng/ml of blood plasma and 200–2000 ng/ml. The use of UDMH leads to an increase in the mass coefficient of the heart at a dose of 2,0 mg/kg. In ex vivo experiments on the rat heart, the cardiotoxic effect of UDMH was shown at subchronic use at a dose of 0,2 mg/kg and above, expressed in significant dilatation of the coronary bloodstream and left ventricle, the development of pronounced negative inotropic and chronotropic effects, and a decrease in the maximum rate of contraction and relaxation of the left ventricle. ventricle, reflecting the inhibition of myocardial energy metabolism.

Limitations. In the work, biomarkers were detected after a single intragastric injection of NDMG, the toxicokinetic characteristics of biomarkers and their retrospectivity were not evaluated. 

Conclusion. The main metabolites of UDMH with intravenous administration of 1/16 DL50 are dimethylhydrazones of pyridoxal (vitamin B6) and pyruvic acid (pyruvate). With subchronic administration, UDMH has cardiotoxicity at a dose of 0,02 mg/kg and above.

About the authors

Anton Igorevich Ukolov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Author for correspondence.
Email: antonukolov@gmail.com
ORCID iD: 0000-0002-2911-1260

PhD, deputy head of toxicological department FSUE 'Research Institute of Hygiene, Occupational Pathology and Human Ecology", FMBA of Russia, g.p. Kuzmolovskii, 188663, Leningrad region, Russian Federation.

e-mail: AntonUkolov@gmail.com

Scopus Author ID: 25321116600, Researcher ID: S-2545-2016 

Russian Federation

Denis Sergeevich Laptev

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: lapden@mail.ru
ORCID iD: 0000-0002-3960-3058

Кандидат биол. наук, заведующий лабораторией экстремальной физиологии ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: lapden@mail.ru

Russian Federation

Evgeny Yurievich Karmanov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: karmanov@gpech.ru

Научный сотрудник лаборатории общей токсикологии и гигиенического регламентирования ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: karmanov@gpech.ru

Russian Federation

Georgy Vasilyevich Karakashev

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: karakashev@gpech.ru

Кандидат биол. наук, ведущий научный сотрудник лаборатории аналитической токсикологии ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: karakashev@gpech.ru

Russian Federation

Denis Viktorovich Krivorotov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: krivorotov.dv@gpech.ru
ORCID iD: 0000-0002-6077-2534

Кандидат хим. наук, заведующий лабораторией химического моделирования ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: krivorotov.dv@gpech.ru

Russian Federation

A. S. Bogachenkov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: noemail@neicon.ru
Russian Federation

Olga Valeryevna Nechaikina

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: olga2278@mail.ru
ORCID iD: 0000-0001-7151-7240

Старший научный сотрудник лаборатории экстремальной физиологии ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: olga2278@mail.ru

Russian Federation

Dmitry Vladimirovich Bobkov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: bdv21@yandex.ru
ORCID iD: 0000-0002-1823-4361

Старший научный сотрудник лаборатории экстремальной физиологии ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: bdv21@yandex.ru

Russian Federation

Sergey Gervasievich Petunov

FSUE «Research Institute of Hygiene, Occupational Pathology and Human Ecology» FMBA of Russia

Email: sergey-petunov@mail.ru
ORCID iD: 0000-0001-6781-8315

Кандидат мед. наук, доцент, заведующий научно-организационным отделом ФГУП «НИИ ГПЭЧ» ФМБА России, 188663, г.п. Кузьмоловский, Ленинградская область, Российская Федерация.

e-mail: sergey-petunov@mail.ru

Russian Federation

References

  1. Ivanov S.D., Kolbasov S.E., Yamshanov V.A., Kovan’ko E.G., Monahov A.S., Melihova M.V. et al. Express assessment of toxicogenomic effects of asymmetric dimethylhydrazine. Toksikologicheskij vestnik. 2009; 3(96): 11–7. (in Russian)
  2. Bugaev P.A., Antushevich A.E., Rejnyuk V.L., Basharin V.A., Zacepin V.V. Hydrazine and its derivatives: toxicological characteristics. Sovremennye problemy nauki i obrazovaniya. 2017; 4: 31. (in Russian)
  3. U.S. Environmental Protection Agency. Health and Environmental Effects Profile for 1,1-Dimethylhydrazine. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Cincinnati, OH. EPA/600/x-84/134.1984.
  4. Antushevich A.E., Basharin V.A., Rejnyuk V.L., Bugaev P.A. Efficacy of inosine glycyl-cysteinyl-glutamate disodium and pyridoxine hydrochloride in acute poisoning with asymmetric dimethylhydrazine. Vestnik Rossijskoj Voenno-medicinskoj akademii. 2018; 1(61): 164–7. (in Russian).
  5. Environmental health criteria 155. Biomarkers and Risk Assessment: Concepts and Principles. Moscow; 1996.
  6. Yаguzhinskij L.S., Manuhov I.V., Vagapova E.R. Experimental studies of the effect of low concentrations of heptyl and its hydrolysis products on water and biological objects [Experimentalnye issledovaniya vliyaniya nnizkikh konzentratsii geptila I produktov ego gidroliza na vodu I biologicheskie ob’tkty]. Mezhdisciplinarnyj Centr Fundamental’nyh Issledovanij (MFTI), g. Dolgoprudny. 2016. (in Russian)
  7. Laptev D.S, Petunov S.G, Bobkov D.V, Radilov A.S. The influence of β-endorphin on the functional activity of the isolated heart of rat. The role δ-opioid receptors. Regionarnoe Krovoobrashhenie i Mikrocirkuljacija. 2015; 3(55): 66–71. (in Russian)
  8. Zenkevich I.G., Ukolov A.I., Kushakova A.S., Gustyleva L.K. Identification of isomeric alkylarenes with the use of additive relations for the evaluation of gas-chromatographic retention indices. Zhurnal Аnaliticheskoj Himii. 2011; 66(12): 1165–72. (in Russian)
  9. Zenkevich I.G., Ukolov A.I. Coding of the structural features of organic compounds for the estimation of chromatographic retention indices with the use of additive schemes. Zhurnal Strukturnoy Himii. 2010; 51(4): 642–51. (in Russian)
  10. Ukolov A.I., Radilov A.S. Determination of hydroxylamine in blood plasma and urine by gas chromatography mass spectrometry. Vestnik SPbGU. Fizika i himiya. 2017; 4(62): 337–45. (in Russian)
  11. Ukolov A.I., Radilov A.S. Toxic metabolomics of hydroxylamine. Medicina ekstremal’nyh situacij. 2019; 21(1): 184–92. (in Russian)
  12. Kucenko S.A. Basics of toxicology [Osnovy toxikologii]. SPb.: Voenno-medicinskaya akademiya im. S.M. Kirova; 2002. (in Russian)
  13. Minasyan S.M., Galagudza M.M., Sonin D.L., Bobrova E.A., Zverev D.A., Korolev D.V. et al. Perfusion technique of isolated rat heart. Regionarnoe Krovoobrashchenie i Mikrocirkulyaciya. 2009; 4(32): 54–9. (in Russian)

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2022 Ukolov A.I., Laptev D.S., Karmanov E.Y., Karakashev G.V., Krivorotov D.V., Bogachenkov A.S., Nechaikina O.V., Bobkov D.V., Petunov S.G.


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 81728 от 11 декабря 2013.