ENVIRONMENTAL TOXICITY (Another Look)

[OddDuck]

Hi, folks!

Well........I'm off today (holiday), so needless to say I'm researching again. Get this! (I stumble onto the strangest things!)

We all know of my previous and continuing research regarding the drug desipramine. So, this morning, I thought I'd check to see what new items of interest might be coming down the pike regarding desipramine. (Please stay with me here........this is another of my "here's how I put it together" scenarios.) I'll highlight, as usual. Blue for my comments, red for what was "interesting".

First..........here is what I found regarding desipramine that I had not known before.


Free Radic Res. 2004 Jun;38(6):613-21. Related Articles, Links

Involvement of ceramide in the mechanism of Cr(VI)-induced apoptosis of CHO cells.

Muranaka S, Kanno T, Fujita H, Kobuchi H, Akiyama J, Yasuda T, Utsumi K.

Institute of Medical Science, Kurashiki Medical Center, Kurashiki 710-8522, Japan.

Mitochondria reduce Cr(VI) to Cr(V) with concomitant generation of reactive oxygen species, thereby exhibiting cytotoxic effects leading to apoptosis in various types of cells. To clarify the mechanism by which Cr(VI) induces apoptosis, we examined the effect of Cr(VI) on Chinese hamster ovary (CHO) cells. Cr(VI) increased cellular levels of ceramide by activating acid sphingomyelinase (ASMase) and inhibiting the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt). Cr(VI) also induced cyclosporin A- and trifluoperazine-sensitive depolarization of mitochondria and activated caspase-3, 8 and 9, thereby causing fragmentation of cellular DNA. The presence of desipramine, an inhibitor of ASMase, and membrane permeable pCPT-cAMP suppressed the Cr(VI)-induced activation of caspases and DNA fragmentation. These results suggested that accumulation of ceramide play an important role in the Cr(VI)-induced apoptosis of CHO cells through activation of mitochondrial membrane permeability transition.

PMID: 15346652 [PubMed - in process]

I thought, Ok....cool! We all know how activation of caspases and DNA fragmentation may (i.e. probably) is very integral in MS (hence why minocycline may help MS via inhibition of activation of caspase 3). My first thought, was GREAT! Another beneficial substantiation for desipramine's use in MS! THEN my next thought was, "Ok, what the heck is CRVI?" A general search told me this:

...."Chromium-VI is the basis of the movie, 'Erin Brockovich.'

Chromium-VI is a bad one, one of these metals the EPA (Environmental Protection Agency) doesn't like floating around in groundwater," Strongin said.

Chromium-VI attacks the respiratory tract in humans, leading to coughing, wheezing, shortness of breath, pneumonia and asthma.

It also injures the gastrointestinal tract, causing vomiting, abdominal pains and hemorrhaging. In addition, chromium-VI may damage the liver, kidneys, immune system, brain and spine, and possibly the blood, as well as potentially triggering complications during pregnancy and childbirth. Chromium-VI is used often in the chrome-plating and stainless steel industries. ...."

Then I find:

"....Chromium hexavalent (CrVI) compounds, often called hexavalent chromium, exist in several forms. Chromates are often used as pigments for photography, and in pyrotechnics, dyes, paints, inks, and plastics. They can also be used for stainless steel production, textile dyes, wood preservation, leather tanning, and as anti-corrosion coatings."

Ok....here's what I say to myself.......WHAT???? It's hexavalent chromium??? You've got to be kidding me!! This is something I know quite a bit about due DIRECTLY to the type of work I am in, and part of what I am familiar with!

"....October 24, 2002

According to a new study conducted by consumer interest group Public Citizen, many blue-collar employers are continuing to expose their workers to hexavalent chromium, a known carcinogen and industrial by-product of several manufacturing processes, including the production of steel, chrome plating and certain pigments. As part of its study, published in next month's issue of the American Journal of Industrial Medicine, Public Citizen monitored a number of companies, determining that over 20 percent violated the Occupational Safety and Health Administration's (OSHA) eight-hour permissible exposure limit (PEL) for hexavalent chromium.
In March, the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE), along with Public Citizen, filed a lawsuit asking a United States Court of Appeals to order OSHA to lower the PEL for the by-product. The case will be argued November 5. ...."

"....Hexavalent chromium is an industrial by-product of several manufacturing processes, including those to make steel, chrome plating and certain pigments. The element is considered highly toxic and has been labeled a potent lung carcinogen by several health organizations. According to the Occupational Safety and Health Administration (OSHA), one million workers are exposed to hexavalent chromium each year. Medical officials say hundreds of laborers will die of lung cancer due to contact with the toxic substance.
Recently, the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE), along with the watchdog group Public Citizen, filed a lawsuit asking a United States Court of Appeals to order OSHA to lower the permissible exposure limit (PEL) for hexavalent chromium. Public Citizen and PACE claim to have detected dangerously high levels of hexavalent chromium at several workplaces across the country. The substance made news recently when it was featured in a popular movie, "Erin Brockovich," the fact-based story of one woman's fight to win compensation for residents exposed to hexavalent chromium."

"April 11, 2003

4/2/03 ORDER (Chief Judge Becker, Authoring Judge, McKee and *Hill, Circuit Judges)
This 2nd day of April, 2003, upon consideration of the Report and Recommendation by the Honorable Walter K. Stapleton who was appointed as mediator, and the comments of the parties thereon, and for the reasons set forth in this court's opinion of December 24, 2002, It is ordered that:
1. The Occupational Safety and Health Administration ("OSHA") and the Secretary of Labor ("the Secretary") shall pursue on an expedited basis the rule-making process initiated on December 4, 2002, directed to the permissible exposure limit for hexavalent chromium.
2. OSHA and the Secretary shall publish a proposed rule on or before October 4, 2004.
3. OSHA and the Secretary shall publish a final rule on or before January 18, 2006.
4. The compliance dates set forth above will be altered by the court only in the event of materially altered circumstances that cannot currently be anticipated.
5. Within one week of each of the following dates: August 4, 2003, December 4, 2003, April 4, 2004 July 4, 2004, October 4, 2004, January 4, 2005 May 4, 2005, August 4, 2005, November 4, 2005 and February 4, 2006, OSHA shall provide to the court, to counsel for the petitioner, and to counsel for the intervenors, a written report describing its progress in the rulemaking.
The Court shall retain jurisdiction over this matter and the implementation of this order.
*The Honorable James C. Hill, United States Circuit Judge for the Eleventh Circuit, sitting by designation, filed. (tyw)"

Ok, I say.....I'm not mistaken about my familiarity with it. As a matter of fact, due to a recent industrial accident just a few months ago, the Director of Safety and Health where I work brought up his overwhelming concern about all of the "hexavalent chromium" that was released in the air!! And not long ago, we were working with Brokovich's law firm on another unrelated water contamination case here in Dickson County. I talked to them myself and they visited! So, then I say to myself.........how in the world does or MIGHT this correlate with MS? So....off I go on THAT search! Here's what I found:


Am J Forensic Med Pathol. 1989 Sep;10(3):213-5. Related Articles, Links


Clustering of multiple sclerosis in Galion, Ohio, 1982-1985.

Ingalls TH.

School of Public Health, Boston University School of Medicine, Massachusetts.

Epidemiologic evidence indicates that the outbreak of 30-40 cases of multiple sclerosis and other demyelinating syndromes in Galion, Ohio, USA, during 1982-1985 was related to an excess concentration of heavy-metal wastes, especially of cadmium and chromium in sewage and river water. Both multiple sclerosis and myasthenia gravis were diagnosed by board-certified neurologists.
PMID: 2782299 [PubMed - indexed for MEDLINE]
*****************************

Sci Total Environ. 1989 Aug;84:45-59. Related Articles, Links

Geotoxicology of multiple sclerosis: the Henribourg, Saskatchewan, Cluster Focus. I. The water.

Irvine DG, Schiefer HB, Hader WJ.

Toxicology Research Centre, University of Saskatchewan, Saskatoon, Canada.

Some childhood-related, geographically-linked factor predisposes towards (or protects against) multiple sclerosis (MS). It is quite plausible that this factor could be one or more chemicals in the environment, and that chemical study of the environment or "focus" of an MS cluster might maximize the chances of detecting such an etiological link. The water chemistry of such a focus (Henribourg, Saskatchewan) was compared with North American norms, and with the chemistry of water from a nearby control area with a near-zero incidence of MS and of childhood homes of MS cases. Overall, the results suggest that an environment predisposing to MS may have a number of water chemistry characteristics such as: relative deficiency of selenium and sulfate, but relative abundance of barium, calcium, chloride, chromium, magnesium, manganese, molybdenum, nitrate plus nitrite, strontium and zinc. Possible explanations for the apparent link between the excess rate of MS and the water geochemistry findings at Henribourg are discussed.

PMID: 2772624 [PubMed - indexed for MEDLINE]

Well, ........isn't that interesting, I say. Didn't they find and don't you always read about an "unexplainable" higher level of MS in the more "industrialized" geographical locations? hmmmmmmmmmmm............ I wonder why they dropped this particular investigation? So, ok.........I went on to see if I could find any recent scientific studies regarding this. Here's what I found:


Toxicol Appl Pharmacol. 2004 Jun 1;197(2):96-106. Related Articles, Links

Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells.

Hayashi Y, Kondo T, Zhao QL, Ogawa R, Cui ZG, Feril LB Jr, Teranishi H, Kasuya M.

Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.

It has been reported that the hexavalent chromium compound (Cr(VI)) can induce both p53-dependent and p53-independent apoptosis. While a considerable amount of information is available on the p53-dependent pathway, only little is known about the p53-independent pathway. To elucidate the p53-independent mechanism, the roles of the Ca(2+)-calpain- and mitochondria-caspase-dependent pathways in apoptosis induced by Cr(VI) were investigated. When human lymphoma U937 cells, p53 mutated cells, were treated with 20 microM Cr(VI) for 24 h, nuclear morphological changes and DNA fragmentation were observed. Production of hydroxyl radicals revealed by electron paramagnetic resonance (EPR)-spin trapping, and increase of intracellular calcium ion concentration monitored by digital imaging were also observed in Cr(VI)-treated cells. An intracellular Ca(2+) chelator, BAPTA-AM, and calpain inhibitors suppressed the Cr(VI)-induced DNA fragmentation. The number of cells showing low mitochondrial membrane potential (MMP), high level of superoxide anion radicals (O(2)(-)), and high activity of caspase-3, which are indicators of mitochondria-caspase-dependent pathway, increased significantly in Cr(VI)-treated cells. An antioxidant, N-acetyl-l-cysteine (NAC), decreased DNA fragmentation and inhibited the changes in MMP, O(2)(-) formation, and activation of caspase-3 induced by Cr(VI). No increase of the expressions of Fas and phosphorylated JNK was observed after Cr(VI) treatment. Cell cycle analysis revealed that the fraction of G2/M phase tended to increase after 24 h of treatment, suggesting that Cr(VI)-induced apoptosis is related to the G2 block. These results indicate that Ca(2+)-calpain- and mitochondria-caspase-dependent pathways play significant roles in the Cr(VI)-induced apoptosis via the G2 block, which are independent of JNK and Fas activation. The inhibition of apoptosis and all its signal transductions by NAC suggests that intracellular reactive oxygen species (ROS) are important for both pathways in Cr(VI)-induced apoptosis of U937 cell.

PMID: 15163545 [PubMed - indexed for MEDLINE]

Very interesting is all I can say. As you know from all my previous posts, I've gabbed a lot about Ca2 (how integral it is in causing permanent disability in MS) and caspases (caspase 3, in particular) and how they are important players in MS.

So,......why was all the study regarding CRVI pollution and its possible connection to clusters or some forms of MS suddenly stopped?

hmmmmmmmmmmmm.......

Deb

[BioDocFL]

OddDuck,
Two incidents that I have stuck in my memory were: 1) British soldiers in World War II were stationed in the Shetland Islands and they built new wells for the locals. Later there were cases of MS where there had never been any before. 2) Ditto in the Florida Keys, a new water supply system was built on one of the key islands for the locals and later there was a noticeable increase in MS cases. Those authors were trying to make the case that it was something conveyed by migratory birds. It was a number of years ago when I saw those articles so I can't remember the journals. Interesting though.
Wesley

[OddDuck]

You know, Wesley, it's so curious that you mention the "military". There were some mentions of the military's involvement (aircraft, etc.) with hexavalent chromium pollution, but I just narrowed it down for the focus of this posting. Hey, I guess you could call military aircraft "migratory birds", couldn't ya? Did somebody try to have a bizarre sense of humor when doing a cover-up back then?

Isn't that odd, though?

Deb

[BioDocFL]

A simple question: how does this explain the female predominance of MS? That is a question that should occur with any theory. I think for a theory to have legs, it's got to address some of the basic facts we know about MS. Why females more than males? Why myelin, oligodendrocytes, blood-brain barrier more than the cardiac, respiratory, digestive, endocrine, etc. systems? Why do so many different factors trigger bouts of MS with regards to a particular theory? Gee, it feels better to dish out questions rather than come up with answers. Of course you've got my curiosity going though with regards to mitochondria and toxins.
Wesley

[OddDuck]

That's assuming that MS itself has only one "causal" agent, trigger, or influence.

This (toxic influence) doesn't explain something like the more female predominance. But the fact that Dr. Claudia Lucchinetti has found more than one pattern of MS (and probable pathogenesis, also) just might. And of course, gender patterns in MS is under scrutiny as we speak.

Who says MS is even really only "one" type of disease? MS appears to be a "catch-all" label.

And endocrine function (adrenal) DOES figure into MS. See my prior posts about the continuing research from the Netherlands regarding norepinephrine and the pathogenesis of MS. China has found the same thing in their research.

Certain "patterns" of MS may indeed be more prevalent for women precisely because of hormonal differences. If immune function is found to be involved in certain specific types of MS, that would make sense, also. Due to child bearing physiological processes in women, our immune makeup and how it functions is vastly different than in men. Why do women with MS appear to get better during the time they are pregnant? Because for one thing, our immune system changes from TH1 predominance to TH2 and basically stays there, so it doesn't identify the fetus as "foreign" and attack and expel it immediately. Also, during pregnancy, IL10 is increased (which protects the blood/brain barrier), and then drops down again after pregnancy, thereby allowing MS relapse quite often. If the BBB gets permeable again from a sudden drop in IL10, well, the trouble starts again. Who says that MS in some women is even the same disease as it is in men?

MS itself has way too many different biological/physiological processes happening on a case-by-case basis. AND....it has been found that there can be cross-over or association between MS and other diseases and syndromes, such as cardiac, respiratory, and digestive problems. Research has shown a very high prevalence of IBS or colitis going right along with MS (or again, should I say some "patterns" of MS - maybe some still unknown). TNFa is inflammatory and needs to be controlled in MS. TNFa is a factor in many of these other diseases, also.

We could go on and on. MS is all over the board. You can't make ANY one "statement" about MS, and find it to be unequivocally true in all cases. That's the problem. Well, maybe you can make one. You can isolate MS to affecting basically the central nervous system. I guess that tells us something..........what, we aren't sure yet, but something.

MS does exhibit effects and damage to more than myelin. It can also deteriorate axons without ever really touching myelin much at all. What about those cases of MS?

You know how I describe it? I say "it's all in the timing". Not necessarily in the cause. It's like the timing chain in a car. If it's off by even a hair, what happens? Everything in the engine is off, and nothing triggers on time or correctly and it spits and sputters, and stalls, etc. etc. I say in any pattern or type of MS, if the body's physiological "timing" is off at all for ANY reason, it just causes a chain reaction. It doesn't matter where in the process the timing is messed up at, either (whether it's with growth factors, apoptosis and NK cells, APCs, MHCII, ion channels, neuronal synapses, mitochondria and ATP, immune system function, etc.). If one little "message" doesn't get to the next place in line at the right time, or with a clear enough message, the rest of the chain goes haywire. So................how to balance the timing, huh?

LOL.......... I know what you mean, Wesley. That's why I don't usually get into causal relationships. It'll drive a person nuts! I think there are way too many causes for MS, because there are way too many syndromes of MS.

I just stumbled on this one causal relationship today, and found it interesting. I threw it out there for thought and discussion. I guess it worked.

Hey, the other day I found a possible genetic causal relationship regarding PTX3 and threw that out for discussion, also. That one shows quite a bit of validity, too.

In any event, I like the drug desipramine precisely because it addresses ALL of the above possible problems in MS, and is likely to provide at least an adjunctive "tool" for balancing the body in MS. So, I mainly stick with pharmacological relationships, but once in while I go off on other spins.

Here's something for ya. In all my research, I see a real cross-over between MS and cancer. Have you noticed that yet? What do they compare MS treatment with the most? Chemotherapy in cancer, don't they? As a matter of fact, some of the stronger medications they are testing and using for MS ARE cancer medications. Physiologically, a lot of the same processes are going on, there's just a difference in disease presentation. Who says MS isn't caused by some form of a cancer? But then, they've found hundreds of things that "cause" cancer, also. Hence, they now mainly concentrate on treatments, not on one single cure for all cancers. I'm of the opinion that eventually, the same thing will happen with MS.

I'm of the belief that MS is too big of a box. Too many symptoms and/or disease presentations are considered "MS" these days. Is that simply for lack of any other name to call a physiological dysfunction that can't be narrowed down? The medical industry can't even stay focused on what criteria is to be used in order to diagnose MS. It changes quite often. How is that determined? And by whom? Based on what determining factors? Majority rule?

I think it's a shame how many people are suffering from MS, and all of the unknowns that goes with it. It breaks my heart.

But remember, all of the above reflects ONLY my opinion, based on nothing more than just a little research, a lot of hunches, and probably a big mouth.

Deb

[MacGyver]

We could go on and on. MS is all over the board. You can't make ANY one "statement" about MS, and find it to be unequivocally true in all cases. That's the problem. Well, maybe you can make one. You can isolate MS to affecting basically the central nervous system. I guess that tells us something..........what, we aren't sure yet, but something.

Well, not even this statement might be valid anylonger, at least according to this new study, showing that more than 50% of the examined patients had peripheral nervous system lesions

PUBMED: Subclinical lesions of peripheral nervous system in multiple sclerosis patients

[OddDuck]

Hi, MacGyver!

LOL........... for heaven's sake! I see you're right! Oh, boy, now THAT'S going to send quite a few researchers off on other directions now, too, won't it?

Ok.....so I guess we're seeing now where MS is not exclusive to just certain parts of the body anymore.

The problem is the ability to "get in there to see" what's going on, ya know? I know it's in the works, but we really need to see new testing methods and devices for getting a better view inside the body to ascertain what's happening. Then the problem is getting the neuros in the field to use them. How many doctors do you know use MRS or even measure your cytokines (via ELISPOT) to see which ones are up and which are down at any given time? They can do all of that, but when I asked them to do those tests, they balked. Are they afraid that the immune testing will show that your immune system might be in balance, and then they'll have to explain some things? Such as why they want you on immunotherapy? (I kept saying, "but my immune system is FINE! I can tell!" Thing is.....it turned out I was right, too.) I mean...come on......how can a doctor just sit there and tell you you need immunotherapy just by looking at you. I don't think he realized I knew he could PROVE to me whether my immunse system was out of balance until I suggested it. I said "Ok....do an ELISPOT and prove it to me". LOL (I don't think that suggestion went over real big.) There are also tests to measure levels of CPLA2, PTX3, and even norepinephrine. But they won't use them.

I still don't understand that. Some neuros have literally hundreds of MS patients, and they won't do these simple tests and do their own database correlations. Which with the age of computers, how hard is that? I did it all the time on the side. (Not for MS analysis, though.)

Odd.............

Deb

[BioDocFL]

OddDuck,
I'll give you a tight connection between 'autoimmune diseases' and some cancers and it relates to polyamines. (Oh no! He's still on that!) Anyway, difluoromethylornithine (DFMO) an analog of ornithine is currently in clinical trials as treatment for fighting cancers. It inhibits ornithine decarboxylase and thereby inhibits polyamine synthesis. There are mouse models of lupus in which the mouse develops a lupus-like disease automatically, some strains earlier than others. If they are given DFMO (1% in drinking water) the lupus does not develop. I believe that work was done by TJ Thomas at Robert Wood Johnson School of Medicine & Dentistry in New Jersey, probably about 15 years ago.
I'll give you another connection but a full explanation will have to wait until I can type in another massive email. In brief, the breast cancer tumor suppressor BRCA1 was recently found to be associated with X chromosome inactivation. In experiments, suppression of BRCA1 by interfering RNA led to reactivation of some genes on the inactive X. BRCA1 mutations account for ~5-7% of breast cancer cases. Male breast cancer is rare but Klinefelter's syndrome males (XXY) have a 50x greater chance of getting breast cancer than XY males. Klinefelter's syndrome males have an inactive X chromosome. You haven't heard much about the inactive X with regards to autoimmune diseases. I'll give you the strongest part of my hypothesis in the long email, but you might start thinking about the female predominance of these diseases, loss of X inactivation, and keep in mind that some of the polyamine genes I have been babbling about are on the X chromosome.
I'm forgeting which topic I'm on now! I'll post the X inactivation babble under the polyamine topic that Aaron created. Thanks Aaron.

Wesley

[OddDuck]

I see what you're saying regarding X chromosomes (I've had a few minor thoughts regarding that myself, but I end up getting myself confused.......).

The thing is, you'd think you'd see more.......oh, what do I want to say..........brain damage (intellectual), such as retardation, Down's syndrome, etc. if the X chromosome was so involved in MS. You do see some correlating intellectual dysfunction with most of the mitochondrial diseases, and even quite a few of the dystrophies. That's what throws me. The lack of, and even more incredibly, the extremely HIGH intellect in folks with the autoimmune, or CNS diseases.

I can't seem to reconcile that with the possibility of the X chromosome being flawed in MS. I know..........DNA fragmentation. But then, for the most part, I haven't studied genetics, so frankly, what the heck do I know anyway?

(Man, I might have been really dangerous had I ever gone to college and ever actually learned something! LOL Talk about the phrase "creating a monster"..... )

Deb