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Sun Feb 11, 2018, 11:53 AM

Mass Spectrometry of DNA Adducts: Resolving the Mechanism of How Air Pollution Induces Cancer.

Last edited Sun Feb 11, 2018, 03:53 PM - Edit history (2)

Leafing through my files today, I came across a review article that I'm sure I read, or partially read, in the past, but which is a pleasure to read again.

It is here: Mass Spectrometry of Structurally Modified DNA (Natalia Tretyakova, Peter W. Villalta, and Srikanth Kotapati, Chem. Rev., 2013, 113 (4), pp 23952436)

Although this is basically a scientific post, it is on a political website and it is therefore worth noting that all three authors of this paper then (and perhaps still) working at the University of Minnesota are immigrants, one from Canada, one from India, and one from Russia.

This is worth noting in the time of Hair Fuhrer, the uneducated nepotist criminal unintelligent moronic nativist bankruptcy king who lounges in the White House trying to destroy his country with the help his Spokesperson Paul Ryan working in the House, and his equally stupid bigoted apologist in the Senate, Mitch McConnell. All three of these puerile, horrible fools are far worse traitors to both the spirit, promise, and legal structures of this country than these three fine scientists could ever be. The self declared "Real Genius" in the White House would be barely qualified to wash glassware in these people's lab, not that stupid people should be allowed in labs at all in any capacity.

Sorry, I couldn't resist.

The science:

As an advocate of the rapid expansion of nuclear power, I am often confronted with people who want to prattle on about Fukushima (or Chernobyl) as if they were the worst energy disasters of all time. I point out that this is absurd since, for example, the Banqiao dam disaster killed close to 200,000 people, possibly even more in 1976 in a matter of days, not that anyone gives a shit about these deaths. (The death toll varies depending on where you read about it, and the real number will almost certainly never be known.) But the Banqiao dam disaster, is still not the greatest energy disaster of all time, not at least in my book.

The greatest energy disaster of all time is the on going and continuous disaster of air pollution, which as I often point out using the following link, kills approximately 7 million people a year, every year:

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 19902010: a systematic analysis for the Global Burden of Disease Study 2010 (Lancet 2012, 380, 222460: For air pollution mortality figures see Table 3, page 2238 and the text on page 2240.)

This does not include deaths owing to the other effect of air pollution, climate change.

Air pollution kills in a variety of ways: A large fraction of the deaths take place in children under the age of 5, because of their poorly developed respiratory systems coupled with other environmental insults to their physiology, but the DALY (disability adjusted lost years) of life also involves lung cancer among the adult lives lost to air pollution, which develops over a number of years, and before killing its victims, seriously disables them and leaves them in great pain.

The scientific review article cited above explains how air pollutants cause cancer, that it, it explores the analytical chemistry elucidating the mechanism by which air pollutants are carcinogenic.

The mechanism is basically this: Many air pollutants are fairly flat molecules that fit into the grooves (minor and major) that characterize the famous helical structure of DNA. Once there, they are in a position to chemically bond directly to the functional groups associated with DNA molecules. This is in contrast to the epigenetic modification of DNA (and RNA) which is the natural biochemical modification of the 5 nucleobases that make up these molecules for purposes of affecting cellular biology.

In their introduction the authors briefly describe epigenetic modifications:

Epigenetic DNA modifications such as 5-methylcytosine (MeC) are important regulators of cell function that influence chromatin structure and control the levels of gene expression. DNA methyltransferases (DMTs) catalyze the addition of the C-5 methyl group to cytosine nucleobases.(1) DMTs preferentially recognize hypomethylated 5′-CG-3′ sequences, producing epigenetic modifications which preserve DNA methylation patterns. C-5 cytosine methylation controls gene expression by mediating the binding of specific proteins (methyl-CpG binding proteins) to MeCG sites, followed by the recruitment of histone-modifying enzymes that promote chromatin remodeling.(2) Recent studies have discovered additional cytosine modifications, e.g., 5-hydroxymethyl-C, 5-formyl-C, and 5-carboxyl-C; these modifications have been hypothesized to be demethylation intermediates or they may have their own unique epigenetic functions within cells.(3-5)


Continuing they then describe the difference between normal epigenetic modifications of nucleobases to describe the odious effects of air pollution:

In contrast to epigenetic modifications, chemical DNA damage including nucleobase alkylation, oxidation, deamination, and cross-linking occurs at a variety of sites, including the N-7, O-6, C-8, and N-2 of guanine; the N-1, N-3, and N-7 of adenine; the O-2 and O-4 of thymine; and the O-2 and N-4 of cytosine (Scheme 1 and Chart 1).(6) Some carcinogens are inherently reactive toward DNA, while others must first be metabolically activated to electrophilic intermediates (e.g., epoxides, quinone methides, diazonium ions, and nitrenium ions), which subsequently bind to DNA, producing nucleobase adducts (Figure 1).(6) All living cells contain extensive DNA repair systems responsible for removing nucleobase lesions. If structurally modified DNA bases escape repair, they may induce base mispairing during DNA replication; in this case, the chemical damage is converted into permanent genetic damage (mutations).(6) Accumulation of mutations in genes controlling cell growth, proliferation, programmed cell death, and cell differentiation is likely to cause cancer.(7-10)


The bold is mine.

Here, from the paper, is a graphic describing sites where the nucleobases are subject to modification.



(Uracil, desmethyl cytosine, associated with RNA is not shown here.)


They immediately show some of the adducts they will discuss in the paper:



Chart 1. Structures of Representative DNA Adductsa
a1,N6-etheno-2′-deoxyadenosine (εAdo); 3,N4-etheno-2′-deoxycytosine (εdCyd); O6-methyl-2′-deoxyguanosine (O6-Me-dG); N7-methylguanine (N7-Me-G); 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxo-dG); 8-oxo-7,8-dihydro-2′deoxyadenosine (8-oxo-dA); N7-ethylguanine (N7-ethyl-G); 1, 1,N6-(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2′-deoxyadenosine (1,N6 -αHMHP-dA); 1,N6-(2-hydroxy-3-hydroxymethyl-propan-1,3-diyl)-2′-deoxyadenosine (1,N6 -γHMHP-dA).


Then there's a little cartoon about how this all works:



The caption:

Figure 1. Central role of DNA adducts in chemical carcinogenesis. Adapted with permission from Reference 55. Copyright 2011 American Chemical Society.


The point made here is that sometimes, probably most of the time cells with damaged DNA either repair the DNA or die, which is a usually a good thing. However sometimes the cells survive, and, particularly if the damaged DNA is involved in the regulation of cell division, mutate into cancer cells. Reference 55 is here: Quantitation of DNA Adducts by Stable Isotope Dilution Mass Spectrometry (Natalia Tretyakova, Melissa Goggin, Dewakar Sangaraju, and Gregory Janis, Chem. Res. Toxicol., 2012, 25 (10), pp 20072035)

Further down they give an even broader picture of DNA modified by air pollutants, a picture that is rather scary actually:



The caption:

Chart 4. Structures of DNA Adducts Highlighted in Section 5.5a
aN7-(2′-Hydroxyethyl)guanine (N7-HEG); 5-hydroxymethyl-2′-deoxyuridine (HmdU); 3,N4-ethenocytosine (εCyt); 7-(1′,2′-dihydroxyheptyl)-3H-imidozo(2,1-i)purine (DHH- εAde); 1,N6-ethenoadenine (εAde); N2,3-ethenoguanine (N2,3-εGua); 1,N2-ethenoguanine (1,N2- εGua); 4-hydroxyestrogen-1-N3-adenine (4-OH-E-1-N3Ade); 1,N6-etheno-2′-deoxyadenosine (εdAdo); 3,N4-etheno-2′-deoxycytidine (εdCyt); 1,N2- etheno-2′-deoxyguanosine (1,N2- εdGuo); O2-ethylthymidine (O2-edT); O4-ethylthymidine (O4-edT); 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD); 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD); N2-hydroxymethyl-2′-deoxyguanosine (N2-HOMe-dG); N7-ethylguanine (N7-Ethyl-G); N-(deoxyguanosin-8-yl)-PhIP (C8-dG-PhIP); 10-(deoxyguanosin-N2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N2-B[a]P); 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AL-I); 7-deoxyguanosin-N2-yl aristolactam I (dG-AL-I).


To be fair to people who don't give a shit about the worst energy disaster of all time, air pollution, but would rather engage in the use of electricity that almost certainly involves the combustion of dangerous fossil fuels to go on their computers to whine about Fukushima and Chernobyl, it does seem to me that a few of these adducts probably derive from pollutants other than air pollutants. For example, dG-C84-ABP probably derives from a water pollutant like a partially dehalogenated PCB. Others are almost certainly derived from air pollutants, for example dG-AI-I looks like it comes from a lignin derived combustion product of that wonderful "renewable" fuel wood, which is a large participant (along with straw) in about half of the 7 million air pollution deaths that take place each year, mostly among poor people, although wood burning is very popular, and, as Valentine's day approaches, considered very "romantic" in the first world.

Cigarette smoking is the combustion of biomass, just saying...

The review article is of interest to the analytical chemist, and there's a very nice overview of various types of mass spectrometry instruments, triple quads, orbitraps, Q-traps, TOF instruments etc, etc, as well as wonderful descriptions of sample preparation.

The mass spectrometer is clearly one of the most important tools ever invented for investigating the world, whether the topic is carcinogenisis, therapeutics, air and water pollution, extraterrestrial chemistry, what have you. It is very unlikely that J.J. Thompson, genius that he was, could imagine where the discovery of the electron would take science.

Unbelievable.

In any case, this paper should represent a subtle warning to anyone who actually cares about environmental science about what is clearly - if not to everyone else, at least to me - the worst energy disaster of all time, air pollution. This disaster has been taking place for a long time, and it will not stop until we clear our minds and think anew, until we pay attention..

Not so long I had an unpleasant discussion on the internet with one of those "FUKUSHIMA!!! FUKUSHIMA!!! FUKUSHIMA!!!" assholes who insist on contemplating their navels while the planet dies.

This person, who informed me that he or she was a "heavy ion physicist" (as opposed to a nuclear physicist, since "nuclear" is apparently a bad word) said that Fukushima was the worst disaster of the 21st century because, to paraphrase, "one could calculate the excess cancers from it."

He or she felt qualified to inform me of this fact because he or she claimed to have a Ph.D. As someone who has met thousands of Ph.D's, if not tens of thousands, over a long life, I have a perspective on what that degree qualifies one to say or do on any variety of subjects, but no matter, famously:



Happily for me, I will never interact with this person again.

Nevertheless, I, for example, could be a greeter at a Walmart who never graduated from elementary school, but it has no bearing whatsoever on the truth or falsity of any of the above.

To Wit: Donald Trump was awarded an MBA from the Wharton School of Business, but apparently that only qualifies him to drive businesses, and apparently whole countries into bankruptcy.

Having a Ph.D. doesn't prevent you from being an asshole, even an ignorant asshole.

Some simple arithmetic with some very basic assumptions:

If Fukushima were to cause 10,000 "eventual" cancers - it won't but if it did - and if only 10% of the 7 million air pollution deaths involved lung (or other) cancer, then the total cancer loss from Fukushima would be on the order of about 5 or 6 days worth of air pollution cancer deaths.

Fukushima is the result of a massive earthquake which by the way also killed 20,000 people, not from radiation, but because they happened to live in a coastal city not that anyone is interested in banning coastal cities.

Air pollution, by contrast to the reactor failures at Fukushima, does not require an earthquake to kill people. It kills people when its primary source, dangerous fossil fuel and biomass combustion operates normally.

This bears repeating. If we pay only selective attention to energy disasters as opposed to full attention involving risk/benefit calculations - because no decision of any kind will ever lead to risk free situations - we subject ourselves to the greater risk doing great harm to the future of humanity, and not just humanity, but to the very beautiful world to which we have had the good fortune to see.

I wish you a pleasant Sunday afternoon.



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