Re: Fw : Study: A Moldy Home May Make You Sad (Refs for Neurogenic theory of depression)

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http://molinterv.aspetjournals.org/cgi/reprint/3/8/441

Molecular Interventions 3:441-444 (2003)

© 2003 American Society of Pharmacology and Experimental Therapeutics

A Neurogenic Theory of Depression Gains Momentum

nne M. and A.

Department of Neuroscience, The Chicago Medical School North Chicago, IL USA

SUMMARY

The rate of adult neurogenesis fluctuates in response to several

environmental factors. Chronic stress, which can lead to neuronal

apoptosis and dendritic atrophy, certainly affects the overall rate of

neurogenesis in the adult brain. Depression, which arises from several

causes, including chronically stressful situations, is known to

correlate with altered hippocampal morphology. But is the link between

depression and neuronal regeneration merely coincidental? Recent

studies indicate that ingestion of antidepressants leads to increased

neurogenesis in the hippocampus. However, the hippocampus is generally

thought important for learning and memory—not for " mood " state—thus,

there is much more to the story that requires clarification. Also,

caveats abound in the interpretation of neurogenesis in the

amelioration of depression; nonetheless, these results are quite

intriguing and might point to better design and prediction of

new-generation antidepressants.

-------next paper----------

PLoS Biol. 2007 February; 5(2): e35.

Published online 2007 February 6. doi: 10.1371/journal.pbio.0050035.

PMCID: PMC1790953

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1790953

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

Precursor Cell Function

Zaibo Li, Tiefei Dong, Pröschel, and Mark Noble*

Department of Biomedical Genetics, University of Rochester Medical

Center, Rochester, New York, United States of America

Sally Temple, Academic Editor

Albany Medical College, United States of America

* To whom correspondence should be addressed. E-mail:

mark_noble@...

Received March 13, 2006; Accepted December 4, 2006.

See " Diverse Toxic Chemicals Disrupt Cell Function through a Common

Path " on page e41.

Abstract

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-α 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-oxidant–mediated

disruption of normal development.

Also see..

http://etd.lib.ttu.edu/theses/available/etd-05252005-163223/unrestricted/Karunas\

ena_Enusha_Diss.pdf

The mechanisms of neurotoxicity induced by a Stachybotrys chartarum

Trichothecene Mycotoxin in an in vitro model

Author: Karunasena, Enusha

Abstract: Sick -building syndrome (SBS ) is a phenomenon in which

individuals in buildings with poor indoor air quality (IAQ )

experience health problems associated with the environment of the

building . Fungal contamination in buildings due to species such as

Stachybotrys chartarum and Penicillium chrysogenum has been correlated

to poor IAQ . Symptoms experienced by individuals exposed to

mycotoxins produced by Stachybotrys species include , headaches ,

fatigue , nausea , vomiting , bleeding from mucosal membranes ,

depression , sleep disturbances , anxiety , vertigo , memory -loss and

seizures . Although these symptoms have been observed in individuals

exposed to Stachybotrys sp . mycotoxins , the mechanisms by which

these compounds may contribute to neurotoxicity are unknown . In this

study , a series of experiments were conducted on human brain

-capillary endothelial cells (HBCEC ) , astrocytes , and progenitor

neuronal cells . The purpose of this study was to evaluate the effects

induced by satratoxin H on neural tissues ; this includes the HBCEC

which forms the blood -brain barrier , followed by the astrocytes

which act as immune cells , and the neurons . These cell lines were

exposed to satratoxin H at concentrations ranging from 1ng /ml to

5000ng /ml . These data were compared to controls ; cells exposed to

known inflammatory compounds such as lipopolysaccharide (LPS ) , cells

exposed to oxidative stress induced by hydrogen peroxide (H202 ) , and

to both LPS and H202 with satratoxin H . Immunofluorescent examination

was used to evaluate apoptosis events , and the expression of cellular

receptors including . Supernatants and cellular extracts were examined

for inflammatory agents as well as compounds associated with apoptosis

.. The results of these studies demonstrated that at satratoxin H

concentrations (1ng /ml - 10ng /ml ) , results were similar to control

cells , while cells exposed to moderate concentrations of 100ng /ml

-1000ng /ml of satratoxin H alone or with LPS or H202 , demonstrated

high expression of inflammatory and apoptotic events . These

experiments demonstrate that the macrocyclic trichothecenes produced

by Stachybotrys chartarum are able to induce apoptotic and

inflammatory cascades in endothelial cells , astrocytes , and neurons

.. These studies suggest that exposure to low to moderate doses of

satratoxin could activate cellular pathways that induce a series of

events leading to neurological tissue damage , which may induce the

symptoms observed in individuals exposed to Stachybotrys chartarum .

.......

Can low level exposure to ochratoxin-A cause parkinsonism?

Journal of the Neurological Sciences, Volume 249, Issue 1, 1 November

2006, Pages 68-75

V. Sava, O. Reunova, A. Velasquez, J. -Ramos

Abstract

Mycotoxins are fungal metabolites with pharmacological activities that

have been utilized in the production of antibiotics, growth promoters,

and other classes of drugs. Some mycotoxins have been developed as

biological and chemical warfare agents. Bombs and ballistic missiles

loaded with aflatoxin were stockpiled and may have been deployed by

Iraq during the first Gulf War. In light of the excess incidence of

amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert

Storm, the potential for delayed neurotoxic effects of low doses of

mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common

mycotoxin with complex mechanisms of action, similar to that of the

aflatoxins. Acute administration of OTA at non-lethal doses (10% of

the LD50) have been shown to increase oxidative DNA damage in brain up

to 72 h, with peak effects noted at 24 h in midbrain (MB),

caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and

its metabolites in the striatum (e.g., CP) were shown to be decreased

in a dose-dependent manner. The present study focused on the effects

of chronic low dose OTA exposure on regional brain oxidative stress

and striatal DA metabolism. Continuous administration of low doses of

OTA with implanted subcutaneous Alzet minipumps caused a small but

significant decrease in striatal DA levels and an upregulation of

anti-oxidative systems and DNA repair. It is possible that low dose

exposure to OTA will result in an earlier onset of parkinsonism when

normal age-dependent decline in striatal DA levels are superimposed on

the mycotoxin-induced lesion.

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

Mitochondrial DNA, base excision repair and neurodegeneration

DNA Repair, Volume 7, Issue 7, 1 July 2008, Pages 1098-1109

Nadja C. de Souza-Pinto, M. III, Tinna V. Stevnsner,

Vilhelm A. Bohr

Abstract

Neurodegeneration is a growing public health concern because of the

rapid increase in median and maximum life expectancy in the developed

world. Mitochondrial dysfunction seems to play a critical role in

neurodegeneration, likely owing to the high energy demand of the

central nervous system and its sole reliance on oxidative metabolism

for energy production. Loss of mitochondrial function has been clearly

demonstrated in several neuropathologies, most notably those

associated with age, like Alzheimer's, Parkinson's and Huntington's

diseases. Among the common features observed in such conditions is the

accumulation of oxidative DNA damage, in particular in the

mitochondrial DNA, suggesting that mitochondrial DNA instability may

play a causative role in the development of these diseases. In this

review we examine the evidence for the accumulation of oxidative DNA

damage in mitochondria, and its relationship with loss of

mitochondrial function and cell death in neural tissues. Oxidative DNA

damage is repaired mainly by the base excision repair pathway. Thus,

we review the molecular events and enzymes involved in base excision

repair in mitochondria, and explore the possible role of alterations

in mitochondrial base excision repair activities in premature aging

and age-associated neurodegenerative diseases.

Mitochondrial and nuclear DNA-repair capacity of various brain regions

in mouse is altered in an age-dependent manner

Neurobiology of Aging, Volume 27, Issue 8, August 2006, Pages 1129-1136

Syed Z. Imam, Bensu Karahalil, Barbara A. Hogue, Nadja C. Souza-Pinto,

Vilhelm A. Bohr

Abstract

Aging is associated with increased susceptibility to neuronal loss and

disruption of cerebral function either as a component of senescence,

or as a consequence of neurodegenerative disease or stroke. Here we

report differential changes in the repair of oxidative DNA damage in

various brain regions during aging. We evaluated mitochondrial and

nuclear incision activities of oxoguanine DNA glycosylase (OGG1),

uracil DNA glycosylase (UDG) and the endonuclease III homologue (NTH1)

in the caudate nucleus (CN), frontal cortex (FC), hippocampus (Hip),

cerebellum (CE) and brain stem (BS) of 6- and 18-month-old male

C57Bl/6 mice. We observed a significant age-dependent decrease in

incision activities of all three glycosylases in the mitochondria of

all brain regions, whereas variable patterns of changes were seen in

nuclei. No age- or region-specific changes were observed in the

mitochondrial repair synthesis incorporation of uracil-initiated

base-excision repair (BER). We did not observe any age or region

dependent differences in levels of BER proteins among the five brain

regions. In summary, our data suggest that a decreased efficiency of

mitochondrial BER-glycosylases and increased oxidative damage to

mitochondrial DNA might contribute to the normal aging process. These

data provide a novel characterization of oxidative DNA damage

processing in different brain regions implicated in various

neurodegenerative disorders, and suggest that this process is

regulated in an age-dependent manner. Manipulation of DNA repair

mechanisms may provide a strategy to prevent neuronal loss during

age-dependent neurodegenerative disorders.

NeuroToxicology

Volume 27, Issue 1, January 2006, Pages 82-92

Acute neurotoxic effects of the fungal metabolite ochratoxin-A

V. Savaa, c, O. Reunovaa, c, A. Velasqueza, c, R. Harbisonb and J.

Sánchez-Ramosa, c, Corresponding Author Contact Information, E-mail

The Corresponding Author

aUniversity of South Florida, Department of Neurology (MDC 55), 12901

Bruce B. Downs Blvd., Tampa, FL 33612, USA

bCollege of Public Health, University of South Florida, Tampa, FL, USA

cResearch Service, Haley VA, Tampa, FL, USA

Received 31 January 2005;

accepted 12 July 2005.

Available online 2 September 2005.

Abstract

Ochratoxin-A (OTA) is a fungal metabolite with potential toxic effects

on the central nervous system that have not yet been fully

characterized. OTA has complex mechanisms of action that include

evocation of oxidative stress, bioenergetic compromise, inhibition of

protein synthesis, production of DNA single-strand breaks and

formation of OTA–DNA adducts. The time course of acute effects of OTA

were investigated in the context of DNA damage, DNA repair and global

oxidative stress across six brain regions. Oxidative DNA damage, as

measured with the " comet assay " , was significantly increased in the

six brain regions at all time points up to 72 h, with peak effects

noted at 24 h in midbrain (MB), CP (caudate/putamen) and HP

(hippocampus). Oxidative DNA repair activity (oxyguanosine glycosylase

or OGG1) was inhibited in all regions at 6 h, but recovered to control

levels in cerebellum (CB) by 72 h, and showed a trend to recovery in

other regions of brain. Other indices of oxidative stress were also

elevated. Lipid peroxidation and superoxide dismutase (SOD) increased

over time throughout the brain. In light of the known vulnerability of

the nigro-striatal dopaminergic neurons to oxidative stress, levels of

striatal dopamine (DA) and its metabolites were also measured.

Administration of OTA (0–6 mg/kg i.p.) to mice resulted in a

dose-dependent decrease in striatal DA content and turnover with an

ED50 of 3.2 mg/kg. A single dose of 3.5 mg/kg decreased the intensity

of tyrosine hydroxylase immunoreactivity (TH+) in fibers of striatum,

TH+ cells in substantia nigra (SN) and TH+ cells of the locus

ceruleus. TUNEL staining did not reveal apoptotic profiles in MB, CP

or in other brain regions and did not alter DARPP32 immunoreactivity

in striatum. In conclusion, OTA caused acute depletion of striatal DA

on a background of globally increased oxidative stress and transient

inhibition of oxidative DNA repair.

Keywords: Ochratoxin-A; Oxyguanosine glycosylase; Superoxide

dismutase; Dopamine; Tyrosine hydroxylase; Apoptosis; Substantia

nigra; Striatum

Article Outline

1. Introduction

2. Materials and methods

2.1. Materials

2.2. Animals and treatment

2.3. Isolation of brain regions

2.4. Evaluation of OTA neurotoxicity

2.5. DNA damage evaluated by the comet assay

2.6. Assessment OGG1 activity

2.7. SOD assay

2.8. Lipid peroxidation assay

2.9. Measurement of dopamine and metabolites

2.10. Tissue preparation

2.11. Immunohistochemistry

2.11.1. Tyrosine hydroxylase (TH) immunoreactivity

2.11.2. TUNEL assay

2.11.3. Rabbit anti-DARPP32

2.12. Statistical analysis

3. Results

4. Discussion

Acknowledgements

References

Thumbnail image

Fig. 1. Each mouse brain was dissected on ice under a

stereo-microscope into six regions: (1) cerebellum (CB); (2)

pons/medulla (PM); (3) midbrain (MB); (4) hippocampus (HP); (5)

caudate/putamen (CP); (6) cerebral cortex (CX).

View Within Article

Thumbnail image

Fig. 2. Representative photomicrographs of " comets " in the substantia

nigra obtained at 6, 24 and 72 h after OTA injection (3.5 mg/kg,

i.p.).

View Within Article

Thumbnail image

Fig. 3. Time course of effects of OTA on DNA damage across six brain

regions mice following administration of OTA (3.5 mg/kg, i.p.). The

extent of DNA damage was calculated from relative changes in length of

comet tails. The mean ± S.E.M. was determined from the average of 50

cells calculated for three animals in each experimental group

(control, 6, 24 and 72 h). Two-way ANOVA revealed that brain region

and time each contributed significantly to the variance (p < 0.0001);

there was no statistically significant interaction between time course

and region. Post-hoc comparison of values at each time point compared

to controls revealed significant increases at each time point for each

region (asterisks indicate p < 0.05; t-test with Bonferroni correction

for multiple comparisons).

View Within Article

Thumbnail image

Fig. 4. Time course of OTA effects on OGG1 activity across specific

brain regions. Results are expressed as mean ± S.E.M. (n = 4–6 samples

per brain region). Two-way ANOVA revealed that brain region and time

each contributed significantly to the variance (p < 0.0001); there was

no statistically significant interaction between time course and

region. Post-hoc comparison of values at each time point compared to

controls revealed significant decreases at 6 h in each region

(asterisks indicate p < 0.05; t-test with Bonferroni correction for

multiple comparisons).

Fig. 5. Relationship between DNA repair (OGG1) and basal levels of

oxidative damage in six brain regions. Each panel plots OGG1 activity

against the baseline oxidative DNA damage (tail/nucleus ratio of the

comet assay) in each brain region at 6, 24 and 72 h after a single

dose of OTA (3.5 mg/kg). Pearson correlation coefficients were

determined for each time point shown in the four panels. There was a

significant inverse correlation between DNA repair activity and

baseline level of DNA damage across regions at all time points except

72 h.

Fig. 6. Dose–response curve obtained following i.p. administration of

OTA. DA concentration was measured in CP of ICR mice 24 h after

administration of OTA. The results are expressed as mean ± S.E.M. Data

averaged for five animals.

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

also see..

The Role of Glia in Neurotoxicity

By Aschner, Lucio G. Costa

http://books.google.com/

On Sun, Jul 6, 2008 at 8:44 PM, LiveSimply <quackadillian@...> wrote:

>

> Its not just depression... The kinds of derangement of brain monoamines that

are caused by mycotoxins causea host of problems.. depression is I am sure just

one of them.. For example, norepinephrine and dopamine are responsible for

executive functioning and attention/arousal..

>

> serotonin is involved with sleep and rest, dreaming, waking, its also one of

the precursors of melatonin which is a miraculous aid to repair in the body..

>

> Serotonin also regulates many aspects of physiology.. the GI system, gastric

emptying and motility, etc.

>

> On Sun, Jul 6, 2008 at 8:32 PM, ginloi <ginloi@...> wrote:

>>

>> Thanks for the thanks!

>>

>> What is more depressing is not having a competent diagnosis more than

anything.

>>

>> I felt vindicated when I was diagnosed.

>>

>> It is depressing for people to call you a fake and malingerer and can affect

you more than

>>

>> the illness...

>>

>> I copied Sharon - hope you don't mind...

>>

>>

>>

>>

>>

>> --- En date de : Dim 6.7.08, LiveSimply <quackadillian@...> a écrit :

>>

>> De: LiveSimply <quackadillian@...>

>> Objet: Re: [] Fw : Study: A Moldy Home May Make You Sad |

Newsweek To Your Health | Newsweek.com

>> À: , " ginloi " <ginloi@...>,

quackadillian@..., " SNK1955@... " <snk1955@...>

>> Date: Dimanche 6 Juillet 2008, 20h26

>>

>> Thank you!

>>

>> Its good that this new paper came out and that Newsweek is covering this..

>>

>> This is NOT the only study that says this. There have been quite a few.

>>

>> Quite a bit of work has been done on ochratoxin in particular but there are

similar studies about trichothecenes.. Those are the two mycotoxins Ive seen the

most stuff on.. This ties in to the " neurogenic model " of depression.

>>

>> If new connections can't grow, neurogenesis stops.. Then the brain cannot

repair itself or integrate learned or emotional information, also people can't

adapt to change..or learn..

>>

>> One of the many things that happens is depression.. Its a significant one but

its one of many things..

>>

>> The body of research on mold effecting neurotransmitters and brain activity

is pretty large.. actually..

>>

>> "

>> http://www.newsweek.com/id/38951

>>

>>

>> Mold and Moods

>>

>> A new study says that mold isn't just a costly and unsightly blight on homes,

it may also be linked to higher rates of depression.

>>

>> Springen

>> Newsweek Web Exclusive

>> Updated: 1:34 PM ET Aug 30, 2007

>>

>> No one likes mold. Yet the unsightly blight is present in an estimated 40

percent of American homes. And those rates may be higher in flood-ravaged areas

like the Gulf Coast. The tiny fungi can irritate the upper-respiratory tract,

causing coughing, wheezing and asthma symptoms in the 5 percent of the

population with allergic antibodies to them.

>>

>> But the effects of mold may be even more diverse than previously thought. A

new study out this week in the American Journal of Public Health suggests that

damp, moldy homes are associated with an increased incidence of depression. Why?

" Some molds are toxins, and exposure to these toxins may hypoactivate parts of

the brain that deal with emotions, " says lead author Edmond Shenassa, assistant

professor of epidemiology at Brown Medical School in Providence, R.I.

>>

>> Shenassa and his colleagues looked at World Health Organization data from

5,882 adults living in eight cities in Europe, including Budapest, Geneva and

Bonn, Germany. WHO interviewers asked residents if they had depressive symptoms

such as decreased appetite, low self-esteem and sleep disturbances. Researchers

found that those that said yes were more likely to live in damp, moldy homes.

" [The study] suggests that healthy homes can lead to healthier lives. The

take-home message is that housing conditions can influence health, " says

Shenassa. While the study did not provide a definitive reason for the link,

study authors said that two factors are likely to be at play. One is the

perceived lack of control over one's environment that mold can create and the

other is mold-related health problems such as wheezing, fatigue and colds. (The

team is conducting follow-up research to see whether mold directly causes

depression.)

>>

>> Not all the experts agree that there is any connection between mold and

depression—despite this new research. Critics wish the study hadn't relied on

self reports. " Having professionals do the inspection and rate homes for

dampness or moldiness is much better than having people self report, " says Pat

Breysse, director of the division of environmental health engineering at the

s Hopkins School of Public Health. Often people " point fingers at mold, " but

" the biological link between mold and a neurotoxic effect that might lead to

depression is very tenuous, in my opinion, " says Breysse.

>>

>> But whether mold is linked to depression or not, many health professionals

agree that homeowners need to fix their houses. The presence of mold doesn't

just mean trouble for allergy sufferers, it also means a home is more likely to

be infested with cockroaches, and it usually brings down property values.

>>

>> So don't wait for an inspector, advises Breysse. " If you've got a leaky pipe

and a big stain in the ceiling, you don't need to hire someone to say there's a

big problem, " he says. " It's an indication that the plumbing is leaking, the

roof is leaking and the upkeep of the house is bad. Bad housing is not healthy

for lots of reasons. That should be the message, not that mold causes

depression. "

>>

>> To prevent the spread of the icky fungi, Shenassa recommends that you keep

the bathroom and the kitchen as dry as possible and have space where one can get

behind appliances to wipe out the water. He also suggests insulating around

pipes, windows and maintaining good ventilation. After all, a dry home is likely

to be a healthier home, even if it's not necessarily happier.

>>

>> URL: http://www.newsweek.com/id/38951

>>

>>

>>

>>

>> ________________________________

>> Envoyé avec .

>> Une boite mail plus intelligente.