Editorial
NMR Metabolomics in Ionizing Radiation
Jian Zhi Hu*, Xiongjie Xiao and Mary Hu Y
Division of Earth and Biological Science, Pacific Northwest National Laboratory, USA
*Corresponding author: Jian Zhi Hu, Division of Earth and Biological Science, Pacific Northwest National Laboratory, WA 99354, USA
Published: 08 Sep, 2016
Cite this article as: Hu JZ, Xiao X, Mary Hu Y. NMR
Metabolomics in Ionizing Radiation. Clin
Oncol. 2016; 1: 1080.
Editorial
Ionizing radiation is an invisible threat that cannot be seen, touched or smelled and exists either
as particles or waves. Particle radiation can take the form of alpha, beta or neutrons, as well as high
energy space particle radiation such as high energy iron, carbon and proton radiation, etc [1]. Nonparticle
radiation includes gamma- and x-rays. Publically, there is a growing concern about the
adverse health effects due to ionizing radiation mainly because of the following facts. (a) The X-ray
diagnostic images are taken routinely on patients. Even though the overall dosage from a single
X-ray image such as a chest X-rays scan or a CT scan, also called X-ray computed tomography
(X-ray CT), is low, repeated usage can cause serious health consequences, in particular with the
possibility of developing cancer [2,3]. (b) Human space exploration has gone beyond moon and
is planning to send human to the orbit of Mars by the mid-2030s. And a landing on Mars will
follow. ("Obama PromisesRenewedSpace Program". The New York Times. Retrieved April 15, 2010).
Completely shield the high energy space radiation in outer space is a big challenging [4,5]. (c) The
impact of past nuclear disasters such as Chernobyl disaster (1986/4/26) and Fukushima Daiichi
nuclear disaster (2011/3/12) are long lasting, including leaving behand radiation contaminated sites
that are very difficult to clean [6,7]. And (d) Radiological hazards are likely to be employed by
terrorists via nuclear detonation, radiological dispersion devices, and covert placement/distribution
of radioactive substances [8]. The worst case scenario for a radiation incident would involve a
nuclear detonation-either from an improvised nuclear device or an actual warhead.
All cells can be damaged by ionizing radiation, but actively dividing cells are far more
radiosensitive than cells that are neither meiotically nor mitotically active. The most radiosensitive
cells in the human body include the bone marrow stem cells, gastrointestinal villi cells, and the
gametes in the ovaries and testes. Acute Radiation Syndrome (ARS) is an illness caused by partial
or whole-body exposure to high doses of ionizing radiation over a short period of time (usually
a few minutes or less). According to American military radiologists, the pathophysiology effects
dependence upon the irradiation doses are summarized in Table 1 [9]. Although the manifestations
of radiation injury vary depending on total absorbed radiation dose and the preexisting health of the
victim, it is clear from Table 1 that in most radiation scenarios, injury to the hematopoietic system
and GI tract are the main determinants of survival. If left untreated, a victim exposed to a total dose
of 3.5Gy (LD50 is about 4.0 Gy) and above is unlikely to survive.
The classical model of molecular injury involves immediate cellular damage following irradiation,
which can result in membrane and intracellular injury, i.e, inflammation, DNA single and double
strand break that subsequently turn on various genes and lead to cell proliferation, fibrosis, cancer
or cell death [10-12]. Significant investigations at molecular level have been done at the genetic
and protein levels by studying changes associated with DNA, RNA and proteins extracted from
cells and animal tissues using genomic [13,14] and proteomic [15,16] methods. Although expensive
and labor intensive, genomic and proteomic methods, may have potential as powerful tools for
studying different levels of the biological response to radiation-induced injury, including searching
for radiation specific molecular biomarkers. However, careful studies have generally shown a low
correlation between the pattern of gene expression and the pattern of protein expression [17,18].
Moreover, even in combination, genomic and proteomic methods still do not provide the range of
information needed for understanding integrated cellular function in a living system, since both
ignore the dynamic metabolic status of the whole organism.
It is well-known that alterations in DNA, RNA and protein are associated with changes in
metabolic profiles. Metabolites are chemical compounds that participate as reactants, intermediates,
or byproducts in a cellular metabolic pathway, and include carbon compounds with a molecular
weight typically in the range of 100-1000 Da. Radiation exposure will disturb the ratios and
concentrations of endogenous metabolites, either by direct chemical reaction or by binding to
key enzymes or nucleic acids that control metabolism. If these disturbances are of sufficient
magnitude, toxic effects will result. Therefore, metabolomics, defined
as a comprehensive and quantitative analysis of all metabolites in a
biological system [19-21], will be an important new systems biology
tool for elucidating the molecular mechanisms of radiation.
Metabolomics is a new technique and has only been recently
applied in the field of radiation, emerging as a field of great
significance for both translational and basic research [22-25]. Unlike
approaches in which biomolecules/metabolites are selected and
analyzed one or a few at a time, metabolomics focuses on broad
identification and analysis of multiple metabolites simultaneously.
The state of metabolome cumulatively reflects the stages of gene
expression, protein expression, and the cellular environment as well
as multidirectional interactions among these elements. Metabolomic
information is complementary, yet distinct, from that generated
by genomic and proteomic approaches. Moreover, metabolic
changes are among the earliest cellular responses to environmental
or physiological changes. It is well-known that there are estimated
30,000-40,000 genes (genome) associated with DNA, more than
100,000 transcripts (transcriptome) associated with RNA, and more
than 1,000,000 proteins (proteome) yet there are only approximately
5000 metabolites (metabolome) in human cells [26,27]. It is clear that
complexity is greatly simplified with metabolomics which, although
in its infancy, has already proven capable of detecting and diagnosing
a disease and evaluating the efficacy of therapy in an early stage
[22,23,25,28]. Therefore, it is highly likely that metabolomics will
provide valuable new information about the impact of radiation on
human health.
Nuclear Magnetic Resonance (NMR) spectroscopy is a
quantitative, non-destructive method that requires no or minimal
sample preparation, and is one of the leading analytical tools for
metabonomic research [19,29-33]. Unlike mass spectrometry
based methods, where the peak intensity depends on the efficiency
of ionization of the molecules that are different for different
types of molecules and the ion suppression issues when multiple
species coelute, the peak intensity in an NMR spectrum is directly
proportional to the number or concentration of molecules. The
easy quantification associated with NMR is a big advantage over
other techniques. 1H NMR is especially attractive because protons
are present in virtually all metabolites and its NMR sensitivity is
high, enabling the simultaneous identification and monitoring of
a wide range of low molecular weight metabolites, thus providing
a biochemical fingerprint of an organism “without prejudice”. It
is expected that NMR metabolomics will play an important role in
understanding the damage at molecular level by ionizing radiation as
have demonstrated recently by us [34,35].
Figure 1 shows an example [35] of applying 1H NMR
metabolomics to study the changes in metabolic profile in the
spleen of C57BL/6 mouse after 4 days whole body exposure to 3.0
Gy and 7.8 Gy gamma radiations. As an integrated part of NMR
metabolomics, principal component analysis (PCA) [36], an
unsupervised statistical method, and orthogonal projection to latent
structures analysis (OPLS) [37], a supervised statistical method, are
employed for classification and identification of potential biomarkers
associated with gamma irradiation. The results from the PCA and
OPLS analysis have shown [35] that the exposed groups can be well
separated from the control group. Leucine, 2-aminobutyrate, valine,
lactate, arginine, glutathione, 2-oxoglutarate, creatine, tyrosine,
phenylalanine, π-methylhistidine, taurine, myo-inositol, glycerol and
uracil are significantly elevated while ADP is decreased significantly.
These significantly changed metabolites are associated with multiple
metabolic pathways and may be considered as potential biomarkers
in the spleen exposed to gamma irradiation.
Table 1
Figure 1
Figure 1
Example of applying 1H NMR metabolomics to study the changes in metabolic profile in the spleen of C57BL/6 mouse after 4 days whole body exposure
to 3.0 Gy and 7.8 Gy gamma radiations.
Acknowledgement
The preparation of this editorial note was supported by the National Institute of Environmental Health Sciences of the National Institute of Health (NIH) under Award Number R01ES022176, and was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the DOE's Office of Biological and Environmental Research, and located at Pacific Northwest National Laboratory (PNNL). PNNL is a multi-program national laboratory operated for the DOE by Battelle Memorial Institute under Contract DE-AC06-76RLO 1830.
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