Re: Detection of satratoxin g and h in indoor air from a water-da...

July 22, 2008

Quack:

1. Your Statement:

" The " lowest level of observed effects " when applied to animals, who

are voiceless, describes levels at which immediate biophysical effects

can be ascertained.

However, for a human, " lowest level of observed effect " might more

appropriately be looked at as the level at which some activity of life

was seriously impacted, like the ability to work or the ability to

enjoy ones life and thrive.. or recover from an illlness instead of

merely survive.. "

RESPONSE:

Perhaps you missed my post on the LOAEL and the specific endpoints (072008)

Decreased food consumption

Decreased thyroid wt and alpha-globulin

Increased T4, serum-albumin, and A/G Ratio

These are objective measures, and measures of activity of life - unlike

" perceptions " .

[Note: I use perceptions on a case-by-case basis not on a population basis]

And as I posted awhile back there are standard neurotox-behavioral tests

that are used these days to estimate the more subtle responses.

2. Your Statement:

The " like the ability to work or the ability to enjoy ones life and thrive " .

RESPONSE

They are quality measures comparable with " Nuisance " effects not toxicity

effects.

3. Your Statement:

" like the ability to work or the ability to enjoy ones life and thrive "

RESPONSE:

Perhaps you haven't worked in a typical US company, but stress and enjoying

ones-self are a part of the job and of life. Think about this question -

Perhaps you are inhibiting my ability to enjoy life and I should remove you?

4. Your Statement:

" Mold exposure may be far higher

during say, a windstorm, than on a calm morning.. Thousands of times

higher.. "

RESPONSE:

Inside or outside?

If inside, could you substantiate your claim?

If outside, do you wish to regulate nature too? My, my.

Tony

.......................................................................

" Tony " Havics, CHMM, CIH, PE

pH2, LLC

5250 E US 36, Suite 830

Avon, IN 46123

www.ph2llc.com

off

fax

cell

90% of Risk Management is knowing where to place the decimal point...any

consultant can give you the other 10%(SM)

This message is from pH2. This message and any attachments may contain

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distributed without this statement.

July 23, 2008

Steve. thank you.

I'm just trying to claw my way back to health.. basically..

I saw another interesting paper yesterday.. this one is on ochratoxin A.

There are a huge number of papers on ochratoxin A, and a leading

researcher on OTA (he works for a major agricultural testing firm)

told me that he has found high levels of OTA in homes - very high

levels..

This was in Toxicological Sciences.. The PDF is a free download..

Reduction in Antioxidant Defenses may Contribute to Ochratoxin A

Toxicity and Carcinogenicity

http://toxsci.oxfordjournals.org/cgi/reprint/96/1/30

July 23, 2008

LiveSimply wrote:

> I'm just trying to claw my way back to health.. basically..

Sickbuildings Group

Mon Oct 2, 2006 43722

Re: Fired Due to Environmental Illnesses!! WHen is Enough, Enough!

> ,

> What do you recommend for people who can't practice extreme

avoidance, for example, people whose work ends up exposing them to low

levels of mold.

> For example, before I got sick, I could go into any building without

> any problems, but now, its not infrequent that when I go into

> businesses that I get sick. I dread the idea of having to work in

> those places but when I get better enough to start really looking

for work I very well might end up having to.

>

> What do people in that situation do?

>

------------------------------------------------------

That's when you absolutely MUST practice a strategy of extreme

avoidance and make a concerted effort at monitoring and controlling

your exposure at ALL times so that you can build up enough reserve to

tolerate some limited exposure at OTHER times, just as I'm doing now.

At this moment I am in a building that used to knock me flat in

minutes, and now I can work all day here.

But to do that, I " balance the books " by constantly looking at

indicators of exposure that are usually more subtle that ones people

are usually referring to.

Responding to minor perceptive " Hits " instead of just major " Slams " .

People tend to quickly jump to the conclusion that they already know

what I am describing when I say " extreme avoidance " , often thinking

that this just means a " tent out in the desert " , even though this is

not what I actually said:

http://health.groups.yahoo.com/group/sickbuildings/message/32214

-MW

July 24, 2008

>Science is a wonderful tool, and I couldn't possibly respect Tony's grasp of>scientific principals more than I do, however, just as anecdotal evidence>alone cannot explain all events I don't think that science can either.

It can explain a hell of a lot though, I believe we could at least understand mold related illness as well as we understand Parkinson's or alzheimer's, or MS, which is a lot better than we understand it now. Nothing is going to happen if we don't break though this ignorance barrier, physicians have to understand this illness is real and profound and every day they ignore it is another day thousands if not maybe millions suffer to a large degree needlessly.

Christ

,

In my opinion, therein lies the great mystery. I believe that not only are

there synergistic effects of combinations of exposures, but that the

chronology of exposures of various substances for some people may also play

a role.

Science is a wonderful tool, and I couldn't possibly respect Tony's grasp of

scientific principals more than I do, however, just as anecdotal evidence

alone cannot explain all events I don't think that science can either.

There are just too many possible variables, not the least of which is

individual biological make-up.

To re-state an analogy previously made by someone else that is perhaps

overly simplistic, most of us can eat peanuts or shrimp and not be affected.

Many people have eaten either or both and not been affected, yet find

themselves suddenly in a crisis because of an allergy that has developed for

no explainable reason.

Yes, we humans know a lot, and can explain and understand a plethora of

things about our world by applying sound scientific principals. But not

everything.

Cheers,

Chuck Reaney

Re: Detection of satratoxin g and h in indoor air

from a water-da...

Tony,

Seems you left a few key elements out of your equation:

What is the minimum dose of exposure to these airborne toxins before human

illness occurs when:

a. there are other microbial contaminants that could cause a synergistic

effect with these airborne toxins that are found in water damaged buildings.

b. each individual's immune system is different, causing different doses

to elicit symptoms.

c. people are exposed via all routes of exposure simultaneously, so to

only calculate out the numbers for the two airborne toxins and conclude

anything one way or the other, does not tell the true story.

d. people are exposed for varying amounts of time to these toxins in water

damaged buildings

e. one cannot determine the absence or existence of the dose of airborne

mycotoxins in a water damaged building to cause human illness - based on

toxicological extrapolations alone. It ain't science.

Add the above variables into the equation, come up with a legt dose before

human illness occurs from the scenario and maybe you have got something.

But otherwise - in the words of a friend - it is a " red herring " to use the

calculations you just did to conclude implausibility of resultant human

illness from exposure of the airborne toxins in the study as they relate to

HUMAN exposure in water damaged buildings.

But... that is some pretty math. Too bad it doesn't mean anything of

relevance in the big picture.

Sharon

In a message dated 7/16/2008 7:31:50 A.M. Pacific Daylight Time,

aahavics@... writes:

Quack:

Regarding:

Mycopathologia. 2008 Aug;166(2):103-7. Epub 2008 Apr 29.

Detection of satratoxin g and h in indoor air from a water-damaged

building.

1. Let's see:

0.25 ng/m3

+

0.43 ng/m3

= 0.68 ng/m3

2. Then let's assume 20m3/day for a 55 kg woman (more conservative than

a man).

ng/m3 m3 ng kg mg/kg

0.68 20 13.6 55 0.0000010

So dose is 0.000001 mg/kg.

3. The smallest LOAEL I could find for a mycotoxin is:

LOAEL is DON = 0.03 mg/kg (28-day study)

4. So the safety factor is:

30,000

5. Try again.

.......................................................................

" Tony " Havics, CHMM, CIH, PE

pH2, LLC

5250 E US 36, Suite 830

Avon, IN 46123

www.ph2llc.com

off

fax

cell

90% of Risk Management is knowing where to place the decimal point...any

consultant can give you the other 10%(SM)

This message is from pH2. This message and any attachments may contain

legally privileged or confidential information, and are intended only

for

the individual or entity identified above as the addressee. If you are

not

the addressee, or if this message has been addressed to you in error,

you

are not authorized to read, copy, or distribute this message and any

attachments, and we ask that you please delete this message and

attachments

(including all copies) and notify the sender by return e-mail or by

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confidentiality or a privilege. All personal messages express views only

of

the sender, which are not to be attributed to pH2 and may not be copied

or

distributed without this statement.

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July 24, 2008

Tony,

I don't know if you can see it, but to my eyes, you are taking what I

say and trying to trivialize it.

I'm just trying to point out some of the (to me, obvious) shortcomings

with your kind of thinking.

Its not scientific in that it ignores known experience and obviously

attempts to

obscure with logical fallacies some very important issues.

I'm not an expert and I don't pretend to be.

I don't have infinite resources, I am just giving my

observations as to the kinds of biases that pseudo 'scientific' " risk

managers " are bringing to the table,

with terrible impact on public health. You are approaching this with a

huge ingrained bias, you see that, don't you?

Ultimately, its going to reflect very badly on your profession.

Because these issues real and they are effecting a LOT of people,

nationally and globally.

People's lives are being destroyed needlessly.

> Quack:

>

> 1. Your Statement:

>

> " The " lowest level of observed effects " when applied to animals, who

> are voiceless, describes levels at which immediate biophysical effects

> can be ascertained.

>

> However, for a human, " lowest level of observed effect " might more

> appropriately be looked at as the level at which some activity of life

> was seriously impacted, like the ability to work or the ability to

> enjoy ones life and thrive.. or recover from an illlness instead of

> merely survive.. "

>

> RESPONSE:

>

> Perhaps you missed my post on the LOAEL and the specific endpoints (072008)

>

> Decreased food consumption

> Decreased thyroid wt and alpha-globulin

> Increased T4, serum-albumin, and A/G Ratio

>

> These are objective measures, and measures of activity of life - unlike

> " perceptions " .

>

> [Note: I use perceptions on a case-by-case basis not on a population basis]

>

> And as I posted awhile back there are standard neurotox-behavioral tests

> that are used these days to estimate the more subtle responses.

>

> 2. Your Statement:

>

> The " like the ability to work or the ability to enjoy ones life and thrive " .

>

> RESPONSE

>

> They are quality measures comparable with " Nuisance " effects not toxicity

> effects.

>

> 3. Your Statement:

>

> " like the ability to work or the ability to enjoy ones life and thrive "

>

> RESPONSE:

>

> Perhaps you haven't worked in a typical US company, but stress and enjoying

> ones-self are a part of the job and of life. Think about this question -

> Perhaps you are inhibiting my ability to enjoy life and I should remove you?

>

> 4. Your Statement:

>

> " Mold exposure may be far higher

> during say, a windstorm, than on a calm morning.. Thousands of times

> higher.. "

>

> RESPONSE:

>

> Inside or outside?

> If inside, could you substantiate your claim?

> If outside, do you wish to regulate nature too? My, my.

>

> Tony

>

July 25, 2008

There is a large body of research that shows that trichothecenes are strongly potentiated by bacterial endotoxins like LPS. That reaction, in and of itself, would explain many of the effects caused by water damaged buildings.

But, somehow, the powers that be (the same powers that be that are admittedly, deliberately, ignoring many other health problems which impact the industrial sphere) have managed to overlook these synergisms when setting policy, with the assistance of many.

Toxicol Sci. 2007 Aug;98(2):526-41. Epub 2007 May 4. Links

Neurotoxicity

and inflammation in the nasal airways of mice exposed to the

macrocyclic trichothecene mycotoxin roridin a: kinetics and

potentiation by bacterial lipopolysaccharide coexposure.

Islam Z, Amuzie CJ, Harkema JR, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824, USA.

Macrocyclic

trichothecene mycotoxins produced by indoor air molds potentially

contribute to symptoms associated with damp building illnesses. The

purpose of this investigation was to determine (1) the kinetics of

nasal inflammation and neurotoxicity after a single intranasal

instillation of roridin A (RA), a representative macrocyclic

trichothecene; and (2) the capacity of lipopolysaccharide (LPS) to

modulate RA's effects. C57Bl/6 female mice were intranasally instilled

once with 50 mul of RA (500 mug/kg body weight [bw]) in saline or

saline only and then nose and brain tissues were collected over 72 h

and processed for histopathologic and messenger RNA (mRNA) analysis.

RA-induced apoptosis specifically in olfactory sensory neurons (OSNs)

after 24 h postinstillation (PI) causing marked atrophy of olfactory

epithelium (OE) that was maximal at 72 h PI. Concurrently, there was

marked bilateral atrophy of olfactory nerve layer of the olfactory

bulbs (OBs) of the brain. In the ethmoid turbinates, upregulated

messenger RNA (mRNA) expression of the proapoptotic gene FAS and the

proinflammatory cytokines tumor necrosis factor-alpha, interleukin

(IL)-6, IL-1, and macrophage inhibitory protein-2 was observed from 6

to 24 h PI, whereas expression of several other proapoptotic genes

(PKR, p53, Bax, and caspase-activated DNAse) was detectable only at 24

h PI. Simultaneous exposure to LPS (500 ng/kg bw) and a lower dose of

RA (250 mug/kg bw) magnified RA-induced proinflammatory gene

expression, apoptosis, and inflammation in the nasal tract. Taken

together, the results suggest that RA markedly induced FAS and

proinflammatory cytokine expression prior to evoking OSN apoptosis and

OE atrophy and that RA's effects were augmented by LPS.

PMID: 17483119 [PubMed - indexed for MEDLINEJ Food Prot. 2006 Jun;69(6):1334-9.Links

Deoxynivalenol

and satratoxin G potentiate proinflammatory cytokine and macrophage

inhibitory protein 2 induction by Listeria and Salmonella in the

macrophage.

Mbandi E, Pestka JJ.

Department

of Food Science and Human Nutrition and Center for Integrative

Toxicology, Michigan State University, East Lansing, Michigan 48824,

USA.

Health risks from microbial pathogens

and toxins encountered in food and the environment continue to be of

worldwide concern. The purpose of this research was to test the

hypothesis that trichothecene mycotoxins amplify inflammatory responses

to foodborne bacterial pathogens. We assessed the capacity of

deoxynivalenol (DON) and satratoxin G (SG) to potentiate chemokine and

proinflammatory cytokine production in RAW 264.7 murine macrophages

induced by Listeria monocytogenes and Salmonella Typhimurium. When

macrophage cultures were incubated with killed irradiated suspensions

of the pathogens for 24 h, the minimum Listeria concentrations for

induction of macrophage inhibitory protein 2 (MIP-2), interleukin-1beta

(IL-beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) were 0.01,

0.01, 1.0, and 1.0 microg/ml (P < 0.05) and the minimum Salmonella

concentrations were 0.01, 0.01, 0.1, and 0.1 microg/ml, respectively (P

< 0.05). Induction of all four mediators by both pathogens was

potentiated by DON (at 100 and 250 ng/ml); observed responses were

significantly higher than predicted additive responses (P < 0.05).

SG (at 2 and 5 ng/ml) also significantly amplified induction of

IL-1beta and TNF-alpha (P < 0.05) by both Listeria and Salmonella.

These results indicate that DON encountered in Fusarium-contaminated

food and SG from Stachybotrys-contaminated indoor environments could

magnify innate inflammatory responses to foodborne bacterial pathogens.

PMID: 16786854 [PubMed - indexed for MEDLINE](this following one is free)http://toxsci.oxfordjournals.org/cgi/pmidlookup?view=long & pmid=16687389

Toxicol Sci. 2006 Aug;92(2):445-55. Epub 2006 May 9. Links

Toll-like

receptor priming sensitizes macrophages to proinflammatory cytokine

gene induction by deoxynivalenol and other toxicants.

Pestka J, Zhou HR.

Department

of Food Science and Human Nutrition, and Center for Integrative

Toxicology, Michigan State University, East Lansing, 48824, USA.

pestka@...

Activation of the innate

immune system might predispose a host to toxicant-induced inflammation.

In vitro macrophage models were employed to investigate the effects of

preexposure to Toll-like receptor (TLR) agonists on induction of

proinflammatory cytokine gene expression by the trichothecene mycotoxin

deoxynivalenol (DON) and other toxicants. Priming of the murine RAW

264.7 macrophage line or peritoneal murine macrophages with the TLR4

agonist lipopolysaccharide (LPS) at 100 ng/ml for 4, 8, and 16 h

significantly increased DON-induced IL-1beta, IL-6, and TNF-alpha mRNA

expression as compared to LPS or DON alone. The minimum LPS

concentration for sensitization of both cell types was 1 ng/ml. LPS

priming also potentiated IL-1beta mRNA induction by DON in human

whole-blood cultures, suggesting the relevance of the murine findings.

As observed for LPS, preexposure to TLR agonists including zymosan

(TLR2), poly (I:C) (TLR3), flagellin (TLR5), R848 (TLR7/8), and ODN1826

(TLR9) sensitized RAW 267.4 cells to DON-induced proinflammatory gene

expression. Amplified proinflammatory mRNA expression was similarly

demonstrated in LPS-sensitized RAW 264.7 cells exposed to the microbial

toxins satratoxin G, Shiga toxin, and zearalenone as well as the

anthropogenic toxicants nickel chloride, triphenyltin,

2,4-dinitrochlorobenzene, and 2,3,7,8-tetrachlorodibenzodioxin. The

results suggest that prior TLR activation might render macrophages

highly sensitive to subsequent induction of proinflammatory gene

expression by xenobiotics with diverse mechanisms of action.

PMID: 16687389 [PubMed - indexed for MEDLINE] Toxicol In Vitro. 2006 Sep;20(6):899-909. Epub 2006 Mar 6. Links

In vitro effects of trichothecenes on human dendritic cells.

Hymery N, Sibiril Y, Parent-Massin D.

Laboratoire

de Toxicologie Alimentaire, EA 3880 UniversitÃ© de Bretagne Occidentale,

TechnopÃ´le Brest-Iroise 29280 PlouzanÃ©, France.

The

aim of this work was to study the in vitro effects of trichothecenes on

human dendritic cells. Trichothecenes are mycotoxins produced by fungi

such as Fusarium, Myrothecium, and Stachybotrys. Two aspects have been

explored in this work: the cytotoxicity of trichothecenes on immature

dendritic cells to determine IC 50 (inhibition concentration), and the

effects of trichothecenes on dendritic cell maturation process. Two

mycotoxins (T-2 and DON) known to be immunotoxic have been tested on a

model of monocyte-derived dendritic cells culture. Cytotoxic effects of

T-2 toxin and DON on immature dendritic cells showed that DON is less

potent than T-2 toxin. The exposure to trichothecenes during dendritic

cell maturation upon addition of LPS or TNF-alpha markedly inhibited

the up-regulation of maturation markers such as CD-86, HLA-DR and CCR7.

Features of LPS or TNF-alpha -mediated maturation of dendritic cells,

such as IL-10 and IL-12 secretions and endocytosis, were also impaired

in response to trichothecenes treatment. These results suggest

trichothecenes have adverse effects on dendritic cells and dendritic

cell maturation process.

PMID: 16517116 [PubMed - indexed for MEDLINE]Toxicol Appl Pharmacol. 2006 Feb 15;211(1):53-63. Epub 2005 Jul 11. Links

LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse.

Islam Z, Pestka JJ.

Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.

Simultaneous

exposure to lipopolysaccharide (LPS) markedly amplifies induction of

proinflammatory cytokine expression as well as IL-1-driven lymphocyte

apoptosis by trichothecene deoxynivalenol (DON) in the mouse. The

purpose of this research was to test the hypothesis that LPS priming

will sensitize a host to DON-induced proinflammatory cytokine induction

and apoptosis. In mice primed with LPS (1 mg/kg bw) ip. and treated 8 h

later with DON po., the minimum DON doses for inducing IL-1alpha,

IL-1beta, IL-6 and TNF-alpha serum proteins and splenic mRNAs were

significantly lower than the DON doses required for vehicle-primed

mice. LPS priming also decreased onset time and dramatically increased

magnitude and duration of cytokine responses. LPS-primed mice

maintained heightened sensitivity to DON for up to 24 h. LPS priming

doses as low as 50 microg/kg bw evoked sensitization. DNA fragmentation

analysis and flow cytometry also revealed that mice primed with LPS (1

mg/kg) for 8 h and exposed to DON (12.5 mg/kg) exhibited massive

thymocyte loss by apoptosis 12 h later compared to mice exposed to DON

or LPS alone. LPS priming decreased DON-induced p38 and ERK 1/2

phosphorylation suggesting that enhanced mitogen-activated protein

kinase activation was not involved in increased cytokine responses.

Taken together, exposure to LPS rendered mice highly susceptible to DON

induction of cytokine expression and this correlated with increased

apoptosis in the thymus.

PMID: 16009389 [PubMed - indexed for MEDLINE]Chem Biol Interact. 2003 Oct 25;146(2):105-19. Links

Potentiation of trichothecene-induced leukocyte cytotoxicity and apoptosis by TNF-alpha and Fas activation.

Uzarski RL, Islam Z, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.

Trichothecene

mycotoxins cause immunosuppression by inducing apoptosis in lymphoid

tissue. Trichothecene-induced leukocyte apoptosis can be augmented by

bacterial lipopolysaccharide (LPS) but the mechanisms involved in this

potentiating effect are not completely understood. The objective of

this study was to test the hypothesis that the trichothecene

deoxynivalenol (DON, vomitoxin) can interact with LPS directly and

other mediators or agonists associated with immune/inflammatory

responses to induce apoptosis in primary murine leukocyte cultures.

Primary leukocyte suspensions were prepared from murine thymus (TH),

spleen (SP), bone marrow (BM) and Peyer's patches (PP) and then

cultured with DON in the absence or presence of LPS, prostaglandin E2

(PGE2), anti-immunoglobulin (as antigen mimic), dexamethasone, Fas

ligand, or TNF-alpha. Cytotoxicity and apoptosis were evaluated by MTT

assay and morphologic assays, respectively. DON was found to inhibit

LPS-induced proliferation and dexamethasone-induced apoptosis in SP

cultures. In contrast, potentiation of DON-induced apoptosis and

cytotoxicity was observed in BM cultures treated with anti-Fas and in

TH cultures treated with TNF-alpha. When potentiation of DON-induced

apoptosis by TNF-alpha was assessed using pharmacological inhibitors,

generation of ROS, intracellular Ca2+, p38/SAPK, and caspase-3

activation were found to play roles. Taken together, these data

demonstrate that LPS and its downstream mediators can interact with

trichothecenes to modulate proliferative, cytotoxic and apoptotic

outcomes in leukocytes in a tissue-specific manner.

PMID: 14597125 [PubMed - indexed for MEDLINE]Toxicol Sci. 2003 Jul;74(1):93-102. Epub 2003 May 28. Links

Role of IL-1(beta) in endotoxin potentiation of deoxynivalenol-induced corticosterone response and leukocyte apoptosis in mice.

Islam Z, Pestka JJ.

Department

of Food Science and Human Nutrition, Institute of Environmental

Toxicology, Michigan State University, East Lansing, Michigan, 48824,

USA.

Endotoxin (lipopolysaccharide, LPS) and

the trichothecenes are microbial toxins that are frequently encountered

in food and the environment. Coexposure to LPS and the trichothecene

deoxynivalenol (DON, vomitoxin) induces corticosterone-dependent

apoptosis in thymus, Peyer's patches, and bone marrow in mice. The

purpose of this study was to test the hypothesis that interleukin-1beta

(IL-1beta) plays a central role in corticosterone induction and

subsequent leukocyte apoptosis in this model. Coexposure to LPS (0.1

mg/kg, ip) plus DON (12.5 mg/kg, po) was found to significantly

upregulate splenic IL-1beta mRNA and IL-1beta protein expression in

B6C3F1 mice, as compared to treatments with vehicle or either of the

toxins alone. B6.129S7-IL1r1tm1Imx mice, which are functionally

deficient for the IL-1 receptor 1, produced significantly less

corticosterone upon coexposure to LPS plus DON than did corresponding

wild-type (WT) C57BL/6J mice. Consistent with these findings, IL-1

receptor 1-deficient mice were recalcitrant to apoptosis induction in

leukocytes as determined by assessment of DNA fragmentation assay and

flow cytometry. Furthermore, intraperitoneal injection of IL-1 receptor

antagonist (100 microgram/mouse, twice at 3 h intervals) in B6C3F1 mice

significantly inhibited LPS plus DON-induced increases in plasma

corticosterone, as well as apoptosis in thymus, Peyer's patches, and

bone marrow. To confirm IL-1beta's capacity to induce apoptosis, B6C3F1

mice were injected with the cytokine (500 ng/mouse, ip) three times at

2 h intervals, and then corticosterone and apoptosis were monitored.

Plasma corticosterone levels and thymus and Peyer's patch apoptosis in

IL-1beta-injected mice were significantly higher at 12 h than in

control mice. Plasma adrenocorticotropic hormone (ACTH) levels in LPS

plus DON-treated B6C3F1 mice did not correlate with the induction of

plasma corticosterone or leukocyte apoptosis. Taken together, the

results indicate that IL-1beta is an important mediator of LPS plus

DON-induced corticosterone and subsequent leukocyte apoptosis and,

furthermore, this cytokine possibly acts through an ACTH-independent

mechanism.

PMID: 12773775 [PubMed - indexed for MEDLINE]Toxicol Appl Pharmacol. 2003 Mar 1;187(2):69-79. Links

Differential

induction of glucocorticoid-dependent apoptosis in murine lymphoid

subpopulations in vivo following coexposure to lipopolysaccharide and

vomitoxin (deoxynivalenol).

Islam Z, King LE, Fraker PJ, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.

Lipopolysaccharide

(LPS) and vomitoxin (VT) synergistically induce glucocorticoid-

mediated apoptotic cell death in lymphoid tissues of the mouse. Based

on the known effects of glucocorticoids, it was hypothesized that the

combined exposure to LPS and VT targets immature lymphocyte

populations. To test this hypothesis, we quantified the effects of VT

and LPS on apoptosis induction in T lymphocyte subsets in thymus and B

lymphocyte subsets in Peyer's patches and bone marrow. Flow cytometry

revealed that a single dose of LPS (0.1 mg/kg body wt ip) together with

VT (12.5 mg/kg body wt po) promoted apoptosis of immature

(CD4(-)CD8(-), CD4(+)CD8(+)) and mature (CD4(-)CD8(+)) thymocytes at 12

h with a subsequent reduction of these populations being detectable at

24 h. RU 486, a glucocorticoid receptor antagonist, significantly

abrogated apoptosis in CD4(-)CD8(-), CD4(+)CD8(+), and CD4(-)CD8(+)

subsets and also prevented loss in cell numbers. In Peyer's patches,

mature-B lymphocytes (B220(+)IgM(-)IgD(+)) underwent apoptosis and, in

bone marrow, pro/pre-B lymphocytes (B220(+)IgM(-)IgD(-)) and mature-B

lymphocytes (B220(+)IgM(-)IgD(+)) underwent apoptosis at 12 h after

toxin co- exposure. RU 486 blocked LPS + VT-induced apoptosis of the

aforementioned subsets in Peyer patches and bone marrow at 12 h. Taken

together, these data suggest that LPS can interact with VT in mice to

induce the glucocorticoid-driven apoptotic loss of immature thymocytes

and cytotoxic T lymphocytes in thymus, mature-B lymphocytes in Peyer's

patch, and pro/pre-B lymphocytes and mature-B lymphocytes in bone

marrow in mice.

PMID: 12649039 [PubMed - indexed for MEDLINE] J Toxicol Environ Health A. 2003 Feb 28;66(4):379-91.Links

Modulation

of lipopolysaccharide-induced proinflammatory cytokine production by

satratoxins and other macrocyclic trichothecenes in the murine

macrophage.

Chung YJ, Jarvis B, Pestka J.

Department

of Food Science and Human Nutrition, Institute for Environmental

Toxicology, Michigan State University, East Lansing, Michigan

48824-224, USA.

The satratoxins and other

macrocyclic trichothecene mycotoxins are produced by Stachybotrys, a

mold that is often found in water-damaged dwellings and office

buildings. To test the potential immunomodulatory effects of these

mycotoxins, RAW 264.7 murine macrophage cells were treated with various

concentrations of satratoxin G (SG), isosatratoxin F (iSF), satratoxin

H (SH), roridin A (RA), and verrucarin A (VA) for 48 h in the presence

or absence of suboptimal concentra-tion of lipopolysaccharide (LPS, 50

ng/ml), and tumor necrosis factor-alpha (TNF-alpha ) and interleukin-6

(IL-6) production were assayed by enzyme-linked immunosorbent assay

(ELISA). In LPS-stimulated cultures, TNF-alpha supernatant

concentrations were significantly increased in the presence of 2.5,

2.5, and 1 ng/ml of SG, SH, and RA, respectively, whereas IL-6

concentrations were not affected by the same concentrations these

macrocyclic trichothecenes. When cells that were treated with LPS and

SG (2.5 ng/ml) were evaluated by real-time polymerase chain reaction

(PCR),TNF-alpha mRNA was found to increase at 24, 36, and 48 h compared

to control cells. At higher concentrations, cytokine production and

cell viability were markedly impaired in LPS-stimulated cells. Without

LPS stimulation, neither TNF-alpha, nor IL-6 was induced. These results

indicate that low concentrations of macrocyclic trichothecenes

superinduce expression of TNF-alpha, whereas higher concentrations of

these toxins are cytotoxic and concurrently reduce cytokine production.

The capacity of satratoxins and other macrocyclic trichothecenes to

alter cytokine production may play an etiologic role in outbreaks of

Stachybotrys-associated human illnesses.

PMID: 12554543 [PubMed - indexed for MEDLINE]Toxicol Appl Pharmacol. 2002 Apr 1;180(1):43-55. Links

Endotoxin potentiation of trichothecene-induced lymphocyte apoptosis is mediated by up-regulation of glucocorticoids.

Islam Z, Moon YS, Zhou HR, King LE, Fraker PJ, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224, USA.

Exposure

to bacterial endotoxin (lipopolysaccharide, LPS) is quite common and

may increase human susceptibility to chemical-induced tissue injury.

The purpose of this study was to identify mechanisms by which LPS

potentiates lymphoid tissue depletion in B6C3F1 mice exposed to the

common food-borne trichothecene mycotoxin, vomitoxin (VT). As

demonstrated by DNA fragmentation and flow cytometric analysis,

apoptosis in thymus, Peyer's patches, and bone marrow was marked in

mice 12 h after administering Escherichia coli LPS (0.1 mg/kg body wt

ip) concurrently with VT (12.5 mg/kg body wt po), whereas apoptosis in

control mice or mice treated with either toxin alone was minimal. Based

on observed increases in tumor necrosis factor-alpha (TNF-alpha) and

interleukin (IL)-6 serum concentrations following LPS and VT

cotreatment, the roles of these cytokines in apoptosis potentiation

were assessed. Injection with rolipram, an inhibitor of TNF-alpha

expression, or use of IL-6 knockout mice was ineffective at impairing

thymic apoptosis induction by the toxin cotreatment, suggesting that

these cytokines did not mediate LPS potentiation. Toxin cotreatment

increased splenic cyclooxygenase-2 mRNA expression, suggesting possible

involvement of prostaglandins in apoptosis. However, indomethacin, a

broad spectrum inhibitor of cyclooxygenases, failed to block thymus

apoptosis. Toxin cotreatment increased serum corticosterone and,

furthermore, RU 486, a glucocorticoid receptor antagonist,

significantly abrogated apoptosis in thymus, Peyer's patches, and bone

marrow following LPS + VT exposure. The results presented herein and

the known capacity of glucocorticoids to cause apoptosis indicate that

hypothalamic-pituitary-adrenal axis plays a key role in LPS

Elsevier Science (USA).

PMID: 11922776 [PubMed - indexed for MEDLINE]Toxicol Sci. 2000 Feb;53(2):253-63. Links

Lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol) synergistically induce apoptosis in murine lymphoid organs.

Zhou HR, Harkema JR, Hotchkiss JA, Yan D, Roth RA, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824-1224, USA.

Human

exposure to Gram-negative bacterial lipopolysaccharide (LPS) is common

and may have an important influence on chemical toxicity. LPS has been

shown previously to enhance synergistically the toxicity of

trichothecene mycotoxins. Because either of these toxin groups alone

characteristically target lymphoid organs at high doses, we evaluated

the effects of coexposure to subthreshold doses of Salmonella

typhimurium LPS and vomitoxin (VT) administered by intraperitoneal

injection and oral gavage of B6C3F1 mice, respectively, on apoptosis in

lymphoid tissues after 12-h exposure. The capacity of LPS (0.5 mg/kg

body weight) and VT (25 mg/kg body weight) to act synergistically in

causing apoptosis in thymus, spleen, and Peyer's patches was suggested

by increased internucleosomal DNA fragmentation in whole cell lysates

as determined by gel electrophoresis. Following terminal

deoxynucleotidyl transferase (TdT)-mediated fluorescein-dUTP nick

end-labeling (TUNEL) of tissue sections, a dramatic enhancement of

fluorescence intensity indicative of apoptosis was observed in thymus,

spleen, Peyer's patches, and bone marrow from coexposed animals as

compared to those given the agents alone. Evaluation of hematoxylin and

eosin-stained tissue sections of treatment mice revealed the

characteristic features of lymphocyte apoptosis, including marked

condensation of nuclear chromatin, fragmentation of nuclei, and

formation of apoptotic bodies in tissues from mice. Combined treatment

with VT (25 mg/kg body weight) and LPS (0.5 mg/kg body weight)

significantly increased (p<0.05) the amount of apoptotic thymic and

splenic tissue as compared to the expected additive responses of mice

receiving either toxin alone. When apoptosis was examined in cell

suspensions of thymus, spleen, Peyer's patches, and bone marrow by flow

cytometry in conjunction with propidium iodide staining, the percentage

of apoptotic cells was significantly increased (p<0.05) in

cotreatment groups as compared to the additive responses to LPS and VT

given alone. The results provide qualitative and quantitative evidence

for the hypothesis that LPS exposure markedly amplifies the toxicity of

trichothecenes and that the immune system is a primary target for these

interactive effects.

PMID: 10696773 [PubMed - indexed for MEDLINE] Avian Dis. 1999 Oct-Dec;43(4):649-55.Links

Short-term exposure to subacute doses of aflatoxin-induced depressed mitogen responses in young mallard ducks.

Hurley DJ, Neiger RD, Higgins KF, Rottinghaus GE, Stahr H.

Department of Biology and Microbiology, South Dakota State University, Brookings 57007, USA.

Mallard

ducklings were fed diets containing corn naturally contaminated with

mixed aflatoxins, purified T-2 toxin, or no detectable mycotoxin in two

trials. The aflatoxin level used was 12 ppb in the first trial and 33

ppb in the second. T-2 was added at 2 ppm in both trials. No pathology

was associated with the aflatoxin used in this study, and T-2--induced

lesions were described in a previous publication. The weights of

primary (thymus and bursa of Fabricius) and secondary (spleen) lymphoid

organs were significantly reduced in the T-2--treated birds. The total

number of viable cells recovered from the thymus was significantly

reduced in aflatoxin-treated birds. The numbers of viable cells

recovered from thymus, bursa of Fabricius, and spleen were all

significantly reduced after treatment with T-2. In each trial,

significantly lower mitogenic responses were seen to pokeweed mitogen

and concanavalin A in birds fed aflatoxin or T-2, representing

reduction in both B-cell and T-cell mitogenesis. Birds fed aflatoxin

also had significantly reduced Escherichia coli O55

lipopolysaccharide-induced mitogenic responses. These studies indicate

that subacute oral exposure to aflatoxin caused a loss of normal

lymphocyte reactivity in mallard ducklings. This finding supports the

hypothesis that waterfowl that ingest even small quantities of

mycotoxin-contaminated waste grain are likely to be more susceptible to

bacterial or viral infections.

PMID: 10611980 [PubMed - indexed for MEDLINE] J Toxicol Environ Health A. 1999 May 28;57(2):115-36.Links

Amplified

proinflammatory cytokine expression and toxicity in mice coexposed to

lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol).

Zhou HR, Harkema JR, Yan D, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824, USA.

A

single oral exposure to the trichothecene vomitoxin (VT) has been

previously shown in the mouse to increase splenic mRNA levels for

several cytokines in as little as 2 h. Since one underlying mechanism

for these effects likely involves superinduction of transiently

expressed cytokine genes, VT may also potentially amplify cytokine

responses to inflammatory stimuli. To test this possibility, the

effects of oral VT exposure on tumor necrosis factor-alpha (TNF-alpha),

interleukin-6 (IL-6), and IL-1beta expression were measured in mice

that were intraperitoneally injected with lipopolysaccharide (LPS), a

prototypic inflammatory agent. As anticipated, VT alone at 1, 5, and 25

mg/kg body weight increased splenic mRNA expression of all three

cytokines after 3 h in a dose-response fashion. LPS injection at 1 and

5 mg/kg body weight also induced proinflammatory cytokine mRNA

expression. There was a synergistic increase in TNF-alpha splenic mRNA

levels in mice treated with both VT and LPS as compared to mice treated

with either toxin alone, whereas the effects were additive for IL-6 and

IL-1beta mRNA expression. When relative mRNA levels were examined over

a 12-h period in mice given LPS (1 mg/kg) and/or VT (5 mg/kg),

significant enhancement was observed up to 6, 12, and 3 h for

TNF-alpha, IL-6, and IL-1beta, respectively. When plasma cytokine

concentrations were measured, TNF-alpha was found to peak at 1 h and

was significantly increased at 1, 3, and 6 h if mice were given LPS and

VT, whereas LPS or VT alone caused much smaller increases in plasma

TNF-alpha Plasma IL-6 peaked at 3 h in LPS, VT, and LPS/VT groups, with

the combined toxin group exhibiting additive effects. Plasma IL-1beta

was not detectable. The potential for VT and LPS to enhance toxicity

was examined in a subsequent study. Mortality was not observed up to 72

h in mice exposed to a single oral dose of VT at 25 mg/kg body weight

or to an intraperitoneal dose of LPS at 1 or 5 mg/kg body weight;

however, all mice receiving VT and either LPS dose became moribund in

less than 40 h. The principal histologic lesions in the moribund mice

treated with VT and LPS were marked cell death and loss in thymus,

Peyer's patches, spleen, and bone marrow. In all of these lymphoid

tissues, treatment-induced cell death had characteristic histologic

features of apoptosis causing lymphoid atrophy. These results suggest

that LPS exposure may markedly increase the toxicity of trichothecenes

and that the immune system was a primary target of these interactive

effects.

PMID: 10344227 [PubMed - indexed for MEDLINE] Toxicology. 1998 Feb 6;125(2-3):203-14.Links

Modulation

of nitric oxide, hydrogen peroxide and cytokine production in a clonal

macrophage model by the trichothecene vomitoxin (deoxynivalenol).

Ji GE, Park SY, Wong SS, Pestka JJ.

Department of Food Science and Human Nutrition, Michigan State University, East Lansing 48824-1224, USA.

Characterization

of how vomitoxin (VT) and other trichothecenes affect macrophage

regulatory and effector function may contribute to improved

understanding of mechanisms by which these mycotoxins impact the immune

system. The RAW 264.7 murine cell line was used as a macrophage model

to assess effects of the VT on proliferation and the production of

nitric oxide (NO), hydrogen peroxide (H2O2) and cytokines. Using the

MTT cleavage assay, VT at concentrations of 50 ng/ml or higher was

found to significantly decrease proliferation and viability of RAW

264.7 cells without stimulation or with stimulation by

lipopolysaccharide (LPS) or interferon (IFN)-gamma. In the absence of

an activation agent, VT (25-250 ng/ml) had negligible effects on the

production of NO, H2O2, and cytokines. Upon activation with LPS at

concentrations of 10 to 100 ng/ml, VT at 25-100 ng/ml markedly enhanced

production of H2O2 but was inhibitory at 250 ng/ml. VT enhancement of

H2O2 production was observed as early as 12 h after LPS stimulation.

When IFN-gamma was used as the stimulant, VT (25-250 ng/ml) delayed

peak H2O2 production. VT (25-250 ng/ml) also markedly decreased NO

production in cells activated with LPS or IFN-gamma. Interestingly, VT

superinduced TNF-alpha and IL-6 production in LPS-stimulated cells and

also elevated TNF-alpha in IFN-gamma stimulated cells. These results

suggest that VT can selectively and concurrently upregulate or

downregulate critical functions associated with activated macrophages.

PMID: 9570333 [PubMed - indexed for MEDLINE]J Toxicol Environ Health. 1996 May;48(1):1-34.Links

Toxicology of deoxynivalenol (vomitoxin).

Rotter BA, Prelusky DB, Pestka JJ.

Centre for Food and Animal Research, Agriculture and Agri-Food Canada, Ottawa, Ontario, Canada.

Trichothecene

mycotoxins are a group of structurally similar fungal metabolites that

are capable of producing a wide range of toxic effects. Deoxynivalenol

(DON, vomitoxin), a trichothecene, is prevalent worldwide in crops used

for food and feed production, including in Canada and the United

States. Although DON is one of the least acutely toxic trichothecenes,

it should be treated as an important food safety issue because it is a

very common contaminant of grain. This review focuses on the ability of

DON to induce toxicologic and immunotoxic effects in a variety of cell

systems and animal species. At the cellular level, the main toxic

effect is inhibition of protein synthesis via binding to the ribosome.

In animals, moderate to low ingestion of toxin can cause a number of as

yet poorly defined effects associated with reduced performance and

immune function. The main overt effect at low dietary concentrations

appears to be a reduction in food consumption (anorexia), while higher

doses induce vomiting (emesis). DON is known to alter brain

neurochemicals. The serotoninergic system appears to play a role in

mediation of the feeding behavior and emetic response. Animals fed low

to moderate doses are able to recover from initial weight losses, while

higher doses induce more long-term changes in feeding behavior. At low

dosages of DON, hematological, clinical, and immunological changes are

also transitory and decrease as compensatory/adaptation mechanisms are

established. Swine are more sensitive to DON than mice, poultry, and

ruminants, in part because of differences in metabolism of DON, with

males being more sensitive than females. The capacity of DON to alter

normal immune function has been of particular interest. There is

extensive evidence that DON can be immunosuppressive or

immunostimulatory, depending upon the dose and duration of exposure.

While immunosuppression can be explained by the inhibition of

translation, immunostimulation can be related to interference with

normal regulatory mechanisms. In vivo, DON suppresses normal immune

response to pathogens and simultaneously induces autoimmune-like

effects which are similar to human immunoglobulin A (IgA) nephropathy.

Other effects include superinduction of cytokine production by T helper

cells (in vitro) and activation of macrophages and T cells to produce a

proinflammatory cytokine wave that is analogous to that found in

lipopolysaccharide-induced shock (in vivo). To what extent the

elevation of cytokines contributes to metabolic effects such as

decreased feed intake remains to be established. Although these effects

have been largely characterized in the mouse, several investigations

with DON suggest that immunotoxic effects are also likely in domestic

animals. Further toxicology studies and an assessment of the potential

of DON to be an etiologic agent in human disease are warranted.

PMID: 8637056 [PubMed - indexed for MEDLINE] Fundam Appl Toxicol. 1993 Nov;21(4):535-45. Links

Comparative effects of immunotoxic chemicals on in vitro proliferative responses of human and rodent lymphocytes.

Lang DS, Meier KL, Luster MI.

Environmental

Immunity Section, National Institute of Environmental Health Sciences,

Research Triangle Park, North Carolina 27709.

In

order to determine the comparability of human and rodent in vitro

systems, the direct effects of various therapeutic or environmental

chemicals on proliferative responses of lymphocytes of mouse, rat, and

human origins were examined and analyzed by a detailed statistical

approach. Four compounds of diverse structure and mechanism of action

which are known to impair lymphocyte transformation, such as

hydroquinone, T-2 toxin, lead nitrate, as well as the widely used

immunosuppressive drug cyclosporin A, were chosen as model test

substances. T cells were stimulated by phytohaemagglutinin as well as

monoclonal antibodies directed at the T cell receptor/CD3 complex,

while B cells were activated by the T-independent mitogens, including

Staphylococcus aureus cells, Escherichia coli lipopolysaccharide, and

Salmonella typhimurium mitogen with specificity for human, mouse, and

rat lymphocytes, respectively. In almost all cases the chemicals

altered lymphoproliferative responses in a concentration-related manner

in all three species. In general, overall similarities in the relative

sensitivity of lymphoblastogenesis were obtained when the human

dose-response curves were compared to the rodent response curves.

Frequent, statistically significant species-dependent discrepancies of

the overall response curves between mice and rats were observed. Large,

statistically significant differences were observed for inorganic lead,

revealing obvious divergences of the effect patterns in all cases,

across all species. In this case, rodent species, especially the rat,

were very sensitive to immunomodulation by lead, whereas human cells

were relatively resistant. It is suggested that direct interspecies

comparisons of immunological effects due to chemical treatment in vitro

can provide a greater understanding of the relationship between animal

and human data, which will improve the confidence of extrapolation from

findings in laboratory animals to human health risk.

PMID: 8253306 [PubMed - indexed for MEDLINEToxicol Appl Pharmacol. 1991 Jun 1;109(1):51-9.Links

Increased endotoxin sensitivity following T-2 toxin treatment is associated with increased absorption of endotoxin.

MJ, Lafarge-Frayssinet C, Luster MI, Frayssinet C.

National Institute of Environmental Health Sciences, Immunotoxicology Group, Research Triangle Park, North Carolina 27709.

Oral

exposure to T-2 Toxin (T-2) in experimental animals results in a

syndrome similar to that observed in endotoxemia. Endotoxins are

lipopolysaccharide, outer-membrane components of gram-negative bacteria

which induce acute, inflammatory responses. In the present study,

several aspects of endotoxin pathophysiology were investigated in mice

following simultaneous exposure to T-2 and endotoxin, including

mortality, hypothermia, tumor necrosis factor-alpha (TNF-alpha) and

corticosterone production, and thymic weight. The disposition of

endotoxin was also assessed, Acute, simultaneous exposure to T-2 (4

mg/kg, po) and endotoxin (3 micrograms/mouse, ip) resulted in increased

mortality, hypothermia, TNF-alpha production, and thymic atrophy

compared to treatment with either T-2 of endotoxin alone. Pretreatment

of mice with endotoxin, a regime that renders the animals resistant to

the effects of endotoxin, reduced many endotoxin effects in animals

treated simultaneously with T-2 and endotoxin. Upon further

investigation, it was observed that T-2 increased the absorption rate

of endotoxin: as the peak height of serum endotoxin increased, the

time-to-peak decreased, and the area under the curve was unchanged in

animals treated simultaneously with T-2 and endotoxin. It was concluded

that increased endotoxin absorption accounted for the increases in

mortality, hypothermia, and TNF-alpha associated with T-2 exposure.

PMID: 2038749 [PubMed - indexed for MEDLINE] Am J Vet Res. 1990 Nov;51(11):1869-72.Links

Effect of T-2 toxin on resistance to systemic Salmonella typhimurium infection of newly hatched chickens.

Ziprin RL, Elissalde MH.

USDA, Agricultural Research Service, College Station, TX 77840.

Newly

hatched chickens were treated with the trichothecene mycotoxin, T-2

toxin, during the first day of life. Control chickens were treated with

other agents known to cause immunosuppression--cyclosporine,

cyclophosphamide, and aflatoxin. Chickens were infected on day 6 (5

days after treatment with T-2 toxin) by intraperitoneal inoculation

with Salmonella typhimurium. Blood samples were collected from treated

chickens (noninfected) and used to assess the responsiveness of blood

lymphocytes to T-cell or B-cell mitogens, phytohemagglutinin, or

lipopolysaccharide, respectively. The T-2 toxin had a profound negative

effect on the ability of the chickens to resist salmonellosis, as

measured by survival. However, the toxin effect in reducing

phytohemagglutinin- and lipopolysaccharide-stimulated mitogenesis,

though significant (P greater than 0.05), was not severe. Our data

indicate a direct effect of T-2 toxin on native resistance to systemic

salmonellosis, which was not accompanied by marked alteration in T- or

B-cell responses to mitogenic stimulation.

PMID: 2240815 [PubMed - indexed for MEDLINE Arch Environ Contam Toxicol. 1989 May-Jun;18(3):388-95.Links

Effects of macrocyclic trichothecene mycotoxins on the murine immune system.

BJ, Hsieh GC, Jarvis BB, Sharma RP.

Macrocyclic

trichothecenes are a class of mycotoxins, some of which exhibit

substantial antileukemic properties. These compounds vary in their

toxicity by approximately 100 fold and are suspected immunotoxins. We

studied 11 of these mycotoxins: roritoxin B, myrotoxin B, roridin A,

verrucarin A, 16-hydroxyverrucarin A, verrucarin J, baccharinoid B12,

roridin D, roridin E, baccharinoid B4 and baccharinoid B5 for their

immunotoxicity in CD-1 mice. An equitoxic dose was prepared in 1% DMSO

in saline and administered i.p. at half the LD50. Organ weights, WBC,

RBC, differentials of blood cell counts, blastogenesis of splenic

lymphocytes in response to concanavalin A (Con A), lipopolysaccharide

(LPS), phytohemagglutinin (PHA) and pokeweed mitogen (PWM), and mixed

lymphocyte reaction (MLR) were studied on day 4 after administration of

each mycotoxin. Organ weights showed significant differences between

the controls and the baccharinoids with a decrease in spleen weight in

baccharinoid B12 and an increased liver weight in B4 and B5 treated

animals. Administration of myrotoxin B, roridin A, verrucarin J and

roridin E had total WBC counts statistically different from controls,

while mice administered myrotoxin B shoed a decrease in numbers of RBC.

Differentials of WBC were unremarkable regardless of the mycotoxin.

Roritoxin B and baccharinoid B5 increased Con A stimulation of splenic

lymphocytes. Roridin A and baccharinoid B12 increased LPS stimulation

of splenic lymphocytes while baccharinoid B5 decreased the LPS

response. Stimulation of splenic lymphocytes with PHA was significantly

increased by roridin A and baccharinoid B5. Stimulation of splenic

lymphocytes with PWM was not altered significantly by any

mycotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2786385 [PubMed - indexed for MEDLINEhttp://www.medscape.com/viewarticle/577678_print

July 25, 2008

There is a large body of research that shows that trichothecenes are strongly potentiated by bacterial endotoxins like LPS. That reaction, in and of itself, would explain many of the effects caused by water damaged buildings.

I agree, and would apply that model (LPS or otherwise potentiated immune system) to the development of acquired hypersensitivities to other xenobiotics as well.

Really good research work, Quack. Nice job!

Steve Temes

July 26, 2008

There are so many relationships like that, I am sure. What we REALLY

need are good MODELS to understand and describe what is happening.

I would posit that *there are multiple, common pathways that are

commonly impacted by multiple toxicants and that those areas are the

areas where the synergism between toxicants becomes extremely

important*.

The same things happen again and again, for different reasons, but they add up..

This is TERRIFYING to me because I think that increasingly, " we " are

apparently " deciding " , it seems, as a society, to expose EVERYONE to

increasing amounts of toxicants like mercury.. " to lower costs "

I notice that you live in the Northeast. Did you realize that changes

in the kinds of coal that are being burned is increasing exposure to

mercury dramatically in that area?

- That said, please read this article.. (below)

Does this seem as important to you as it does to me?

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371/journ\

al.pbio.0050035

Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt

Precursor Cell Function

Zaibo Li, Tiefei Dong, PrÃ¶schel, Mark Noble*

1 Department of Biomedical Genetics, University of Rochester Medical

Center, Rochester, New York, United States of America

Identification of common mechanistic principles that shed light on the

action of the many chemically diverse toxicants to which we are

exposed is of central importance in understanding how toxicants

disrupt normal cellular function and in developing more effective

means of protecting against such effects. Of particular importance is

identifying mechanisms operative at environmentally relevant toxicant

exposure levels. Chemically diverse toxicants exhibit striking

convergence, at environmentally relevant exposure levels, on

pathway-specific disruption of receptor tyrosine kinase (RTK)

signaling required for cell division in central nervous system (CNS)

progenitor cells. Relatively small toxicant-induced increases in

oxidative status are associated with Fyn kinase activation, leading to

secondary activation of the c-Cbl ubiquitin ligase. Fyn/c-Cbl pathway

activation by these pro-oxidative changes causes specific reductions,

in vitro and in vivo, in levels of the c-Cbl target platelet-derived

growth factor receptor-Î± and other c-Cbl targets, but not of the TrkC

RTK (which is not a c-Cbl target). Sequential Fyn and c-Cbl

activation, with consequent pathway-specific suppression of RTK

signaling, is induced by levels of methylmercury and lead that affect

large segments of the population, as well as by paraquat, an organic

herbicide. Our results identify a novel regulatory pathway of

oxidant-mediated Fyn/c-Cbl activation as a shared mechanism of action

of chemically diverse toxicants at environmentally relevant levels,

and as a means by which increased oxidative status may disrupt

mitogenic signaling. These results provide one of a small number of

general mechanistic principles in toxicology, and the only such

principle integrating toxicology, precursor cell biology, redox

biology, and signaling pathway analysis in a predictive framework of

broad potential relevance to the understanding of pro-oxidantâ€“mediated

disruption of normal development.

> In a message dated 7/25/2008 4:15:46 PM Eastern Daylight Time,

> quackadillian@... writes:

>

> There is a large body of research that shows that trichothecenes are

> strongly potentiated by bacterial endotoxins like LPS. That reaction, in and

> of itself, would explain many of the effects caused by water damaged

> buildings.

>

> I agree, and would apply that model (LPS or otherwise potentiated immune

> system) to the development of acquired hypersensitivities to other

> xenobiotics as well.

>

> Really good research work, Quack. Nice job!

>

> Steve Temes

>

July 28, 2008

"I would posit that *there are multiple, common pathways that are

commonly impacted by multiple toxicants and that those areas are the

areas where the synergism between toxicants becomes extremely

important*."

Quack,

I don't know that much about how mercury acts as a "potentiator", but it certainly can cause damage to the neurological system.

The way I view the potentiated immune system being linked to acquired hypersensitivities is analogous to how the immune system "learns" to recognize foreign invaders. There is innate immunity and acquired immunity. When certain biological or chemical substances are present during a period when immune inflammatory agents are produced within the individual, the immune system wants to "recognize and remember" these invaders next time so it can mount an early defense against them. Think about cold viruses or other disease causing organisms that you only get sick from one time and then you develop an immunity to them.

I think something similar is happening when the immune system becomes sensitized to environmental contaminants that result in hypersensitivity reactions like reactive airways dysfunction syndrome (RADS) or MCS. In many ways it is similar to "becoming allergic", but the mechanism is other than IgE. It seems to often involve chemoreceptors that trigger nerve signals -- and often the vanilloid receptor of the trigeminal nerve, which is the innate chemical sensor. I have read several good literature articles about neurogenic sensitization, such as those written by Pall, Barbara Sorg and Meggs.

When these acquired hypersensitivity mechanisms are better understood, I think it will explain most of what "mold illness" is all about.

Steve Temes

There are so many relationships like that, I am sure. What we REALLY

need are good MODELS to understand and describe what is happening.

I would posit that *there are multiple, common pathways that are

commonly impacted by multiple toxicants and that those areas are the

areas where the synergism between toxicants becomes extremely

important*.

The same things happen again and again, for different reasons, but they add up..

This is TERRIFYING to me because I think that increasingly, "we" are

apparently "deciding", it seems, as a society, to expose EVERYONE to

increasing amounts of toxicants like mercury.. "to lower costs"

I notice that you live in the Northeast. Did you realize that changes

in the kinds of coal that are being burned is increasing exposure to

mercury dramatically in that area?

- That said, please read this article.. (below)

Does this seem as important to you as it does to me?

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371/journal.pbio.0050035