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Trail:
Ecosystems
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 Scientific
papers - Ecosystems - page 6
Deficient
levels of radical scavenger cofactor metals Cu, Zn, Fe, Se in
foodchains supporting all three TSE clusters sampled.
The soils and herbage samples drawn from the
CWD, scrapie and
CJD cluster zones in Colorado, Iceland and Slovakia demonstrated
marked deficiencies of Cu, Zn Se, Fe, Na, Mg and P in common
(Tables 1-3). For instance, the concentration of these elements
in the soils of the Colorado CWD endemic zone were 5, 15, 1.8,
2.8 and 74 fold less respectively than their equivalent levels
in samples taken from CWD-free areas in Utah State.
Interestingly, the
Pronghorn antelope is the only species of free ranging ruminant
in the Colorado TSE zone that has failed to contract CWD,
despite their close cohabitation with CWD affected deer and elk
(57,58). Work by Clemens et al. (72) may offer an explanation
for the pronghorn's CWD-free status. They demonstrated the
pronghorn's unique ability to conserve/regulate Se in Se
deficient environments in relation to the markedly less
efficient ability displayed by deer and bison. As Pronghorn are
unique to the N American prairies - having evolved there over
the last 20 million years (73) - they have obviously adaped to
the challenges posed by their indigenous terrain and are
likewise better equiped at maintaining adequate activities of
the Se-activated glutathione peroxidase enzyme/antioxidant
vitamin E which may play preventative roles in scavenging
radical cascades triggered off in those ruminants who are
resident in 'TSE endemic' ecosystems.
Likewise, the plant
material drawn from the Icelandic scrapie endemic regions also
shared the same deficiencies of Cu, Se, Zn, Fe, Na, P, Mg found
in Colorado/Slovakia. But unlike Colorado/Slovakia, these
elements were also deficient in the scrapie free valleys,
suggesting the potential vulnerability of the entire Icelanic
sheep population to scrapie, should levels of Mn suddenly rise
for any reason - eg via Mn contamination from a fresh outfall of
volcanic ash (74) - whereby engaging the dual 'toxic template'
theoretically required for triggering off TSE.
The results of the
soil samples drawn from the same farms in Iceland during
August/September 1998 demonstrated uniform levels of all
elements on both the scrapie-free and scrapie endemic farms.
Interestingly, the levels of most elements recorded in the soil
were at the opposing end of the scale in relation to their
levels in herbage; For instance, Mn levels were very low, Zn/Fe
were high, Cu/molybdenum were excessive, whilst selenium
maintained the same deficient status found in herbage.
The low levels of Cu
in herbage is perhaps explained by the well recognised chelating
action of Molybdenum on Cu. Thus explaining how the excess of Cu
found in the soil is reduced to a state of 'secondary Cu
deficiency' by the time it reaches the plant horizon, as a
result of the chelating action exerted by the high levels of
molybdenum in the soil.
The significant 21/2+ fold higher
levels of Mn recorded in the herbage of the scrapie farms points
to the presence of some critical environmental factor that
increases uptake of Mn into herbage on the scrapie farms whilst
remaining absent on scrapie-free farms.
CONCLUSIONS DRAWN FROM TEST RESULTS
These results add support to the hypothesis that TSE susceptible
genotypes will succumb to sporadic TSE if they have been
dependent on an ecosystem which demonstrates the following
coexisting abnormalities in its mineral status:
-
Excessive
levels of the divalent cation metal, manganese - which can
act as a pro oxidant in Mn SOD deficient genotypes.
-
Deficient
levels of Cu, Zn, Se and Fe; being critical cofactor
components of the major groups of radical scavengers - the
SODs catalases, glutathionine peroxidases, vitamin E (10).
-
Deficient
levels of Cu, Fe, P and Mg; where low Cu/Fe/P/Mg induces an
excessive absorption of divalent cation Mn (3,4) and its
ultimate accumulation in the CNS, and low Mg levels assist
Mn 2+ to compete and substitute at various 'Mg specific'
catalytic sites normally occupied by Mg2+ (3,4,7), leading
to the failure of activation of enzymes like Mg activated
ATP in CNS synaptosomes (75).
Mn absorption is accelerated during conditions of sub clinical
Fe and Cu deficiency (3, 4), as well as in states of P
deficiency (4,31). Results of this survey suggest that this
precise scenario is actualized 'in vivo' in mammals residing in
these TSE ecosystems. The mineral deficiencies were recorded in
herbage that was harvested during July/August, at the stage of
the seasonal cycle when these elements have reached their peak
concentrations (8). (NB, concentrations of Cu/Fe in herbage can
oscillate by as much as 30 times around one seasonal cycle (8)).
This suggests that mineral levels would have measured lower if
sampling had been carried out at any other time of the year,
rendering susceptible mammals at a peak of vulnerability to TSEs
in the winter/early spring period; especially relevant to those
cervidae/sheep residing in the protracted snowbound districts of
Colorado's Front Range / the High Tatras / the N Icelandic
mountains who have only had access to 'hay' fodder - hay
carrying lower concentrations of copper and higher
concentrations of Mn than other types of winter feed (69, 66).
Whilst low Cu levels in Icelandic herbage is probably linked to
the chelating action of the high molybdenum levels analysed in
the soils, the low levels of Cu in the herbage of the Colorado
and Slovakia TSE clusters is further compounded by the excessive
levels of Ca analysed in the plant material drawn from both the
CWD and CJD regions of Colorado and Slovakia. High levels of Ca
in the diet would further exacerbate the already deficient
levels of Cu in these regions by impairing Cu absorption in the
gut of cervidae/ humans due to Ca-mediated pH alterations (35).
Furthermore, the prominent cultivation of the 'high calcium'
alfalfa crop (69) in both of these cluster regions (Colorado
alfalfa measured 2.05% Ca, Zuberec alfalfa 2.46% Ca) would
further compound the problems of High Ca in the local foodchains.
Interestingly, the captive deer that contracted CWD were fed on
an almost exclusive diet of alfalfa (57) whilst the zoo animals
associated with TSE outbreak had also been fed rations
containing alfalfa.
REVIEW
OF THE MN LITERATURE IN RELATION TO THE HYPOTHETICAL PERSPECTIVE
THAT MN3+ SERVES AS THE 'INFECTIOUS' TRANSMISSIBLE
AUTO-OXIDATIVE AGENT IN TSEs
Interspecies/interdevelopmental variations in the rate of Mn
absorption, and its relationship to susceptibility to Mn
intoxication.
Interestingly, Mn is largely absorbed via the duodenum (3) (4),
explaining the more efficient absorption rate of 10-18% of
available dietary Mn in adult ruminants (such as cattle, sheep,
goats and cervidae) in relation to the less efficient absorption
rate of 2-5% of available Mn in the diet of monogastric species
(such as pigs and poultry) (3,4). The significant difference
between the efficiency of Mn absorption in ruminants and
mongastric species may partly explain why ruminants are prone to
TSEs and monogastrics remain virtually TSE free (76,41).
However, airborne Mn is readily absorbed into the brain via the
intranasalolfactory route which may be relevant to some TSEs
(9).
Mn absorption and
retention is considerably increased in the fetus and infant, due
to the immaturity of the duodenal/intestinal barriers and the
immaturity of Mn's excretory pathways, such as the pancreatic
juices and bile. Adult rats absorb 3-4% of orally adminstered Mn
whilst young rats absorb 20% (4, p. 191). Hatano et al. (77) has
reported erythrocyte Mn levels at 100 mg/l in Japanese infants
under 1 month old, whilst 35 mg/l levels were recorded in
Japanese adults. Miller et al. (78) has shown that manganese
excretion is virtually negligible in the neonatal stages due to
low bile output. Mena et al 1978 (3, p. 262) demonstrated that
premature children have a 25 fold increase in Mn retention in
relation to adults according to the levels monitored fifty days
after Mn ingestion.
Furthermore, trials
(79) have indicated that there is a fourfold increased rate of
entry of Mn into the brain of newborn rats in relation to adult
rats - probably indicating the immaturity of the blood/brain
barrier at these early stages. Another study demonstrated that
the brain (80) of human stillborns contained an average of 46
ppm Mn, whereas brain tissue sampled from all of the post natal
age groups (1day to 80 years) consistently averaged 20 ppm Mn.
It has also been demonstrated that there is a 100% increase in
the rate of Mn's plasma binding and entry into the brain in Fe
deficient rats (79) - demonstrating the possible relevance of
the low Fe readings in the TSE ecosystems (Tables 1 & 2).
Mn will therefore
accumulate more readily in early life due to the immaturity of
the homeostatic mechanisms presiding over absorption and
excretion, placing the embryo and infant in the highest risk
category for susceptibility to Mn intoxication.
Mn absorption
therefore decreases with age, suggesting that exposures to
pathogenic levels of Mn during the vulnerable early life period
could lead to a more virulent, early onset 'strain' of the Mn
delayed neuropsychiatric syndrome. It is proposed that the BSE/nv
CJD 'strain' of TSE, which erupts at a relatively younger age
than conventional sporadic TSEs (81), is the result of a
significant in utero exposure to a more potent oxidative species
of Mn (Mn4+, Mn5+ or a radioactive Mn) in combination with
exposure to Cu chelating insecticides, whereas sporadic TSEs are
the result of post natal exposures to a less reactive oxidative
species of Mn (Mn2+, Mn3+) in combination with a coexisting NCS
Cu deficiency.
The
biochemistry, pathology and symptomology of Mn delayed
psychoneurotoxicity exhibits strong similarities to that
observed in TSEs.
Mn largely concentrates in the pineal, pituitary, median
eminence of the hypothalamus, basal ganglia and olfactory bulb
of the brain, being found specifically in the melanocytes and in
the mitochondria of astrocyte cells belonging to those regions,
where it performs a major role in oxidaion and reduction
reactions (3, 4, 7).
Interestingly, exposures to toxic
levels of divalent Mn manifests its pathogenicity selectively
within the brain. However, when exposure to Mn involves the
inhalation route, the lungs are also affected. CNS mitochondria
do not possess a mechanism for clearance of Mn following
contexts of overloading (7, 82).
Mn has been found in its Mn2+,
Mn3+, Mn4+ valency states in living tissues, the higher
valencies being more highly reactive (7). Mn3+ complexes with
transferrin and readily crosses membranes, and has a slower rate
of elimination from tissues than Mn2+ (7). Mn3+ also possesses
different affinities for endogenous ligands than the Mn2+
species (7), thereby creating a different spectra of
toxicological activity than that encountered during Mn 2+
overload.
There is evidence to
suggest that divalent Mn is oxidized to trivalent Mn by
ceruloplasmin in hepatocytes (83), and it should be noted here
that exposure to estrogenic/steroid pollutants (55) (84),
psychological stress (83) or neuropathic types of organo
phosphates (OPs) (85), considerably upregulates the expression
of caeruloplasmin, thus, presumably, accelerating the oxidative
transformation of Mn 2+ in the liver into its more lethal
pro-oxidative Mn 3+ species - particularly in contexts of Fe
deficiency encountered in TSE ecosystems. (A greater part of
ceruloplasmin's normal activity involves the oxidation of its
Fe2+ target (10)).
'In vitro' studies show that Mn 3+ complexes will readily
auto-oxidise catecholamines, explaining why exposure of humans
or animals to large doses of Mn considerably decreases the
levels of dopamine, serotonin and noradrenaline in the striatum
- particularly in the caudate nucleus and the putamen (10, 11,
86, 87). However, the dopamine-rich substantia nigra usually
remains unaffected (11) in Mn intoxications.
Interestingly, the
brains of scrapie affected sheep (88, 89, 92)/CJD affected
humans (90, 91) have demonstrated the same pattern of dopamine,
serotonin and noradrenaline depletion in the CNS as witnessed in
Mn toxicity - where the putamen and caudate nucleii of the
striatum is most intensively affected, whilst dopamine in the
substantia nigra/mesolimbic system is largely preserved (88).
Various drug
therapies such as bromocriptine, lergotrile, phenothiazine and
chlorpromazine (11,93) considerably raise the levels of Mn in
select areas of the brain producing extrapyramidal symptoms such
as tardive dyskinesia in treated subjects, thus elucidating the
inter-active role which Mn performs with dopamine in these
disorders. Furthermore, treatment of those suffering from the
early stages of Mn neuropsychiatric syndrome with the
dopamine-precursor drug L-DOPA (administered in PD) causes a
dramatic ephemeral remission of major symptoms (3, 11, 94).
Raised levels of GABA
have also been recorded in the caudate nucleus of rats exposed
to toxic levels of Mn (11, 95). A rise in GABA has similarily
been recorded in TSEs, which is presumed to stem from a loss of
synaptic inhibition at the GABA receptors (96).
The
pathological perspective of Mn intoxication
The
pathology of Mn poisoning varies according to the genetic
idiosyncrasies of the victim, the valency of the specific Mn
species involved and the specific Mn-protein conjugate involved
(7), etc. However, all cases generally demonstrate a common
pathological hallmark involving shrinkage and distortion of the
basal ganglia with the destruction of its ganglion cells,
particularly in the caudate nucleii and the putamen (97). These
and other pathological features of Mn intoxication such as
astrogliosis / amyloid plaques composed of bundles of fibrils
/neuronal loss / atrophy in many CNS regions (6) are duplicated
in the victims of CJD, kuru, scrapie and other TSEs (41).
The ventricles are
enlarged in sections of CJD brain (41) - a phenomena that has
not been reported in the limited number of pathological
investigations into Mn intoxications carried out during the
first half of this century. However, the ventricles were
moderately enlarged in a CT and MRI scan of a recent case of
poisoning with the Mn fungicide, Maneb (28). EEGs show a diffuse
slowing following some Mn intoxications (98, 99) - a pattern
usually recorded in sporadic TSEs (41).
Other regions
lesioned in chronic Mn intoxications are the globus pallidus in
the basal ganglia, as well as the pyramidal system, the
cerebellum and its connecting neurones. A similar pattern of
distribution is exhibited in TSEs (97).
In 1927 Ashizawa
found histopathological changes in the pons, the internal
capsule, and cerebral peduncle (100). In 1936 Trendtel reported
degeneration and gliosis in the corpus striatum, in addition to
neuronal loss in the putamen and globus pallidus. He likewise
found similar changes in other areas of the brain (101).
In 1934 Canavan et al., amongst
others, reported atrophy/neuronal loss in the cerebral cortex -
especially in the frontal lobes and in the cerebellum - and
major changes in the basal ganglia which were shrunken and
distorted as normally observed in Mn intoxications (102).
Histopathological studies revealed gliosis and degeneration of
nerve cells, particularly in the optic thalamus, globus pallidus,
lentiform nucleus, caudate nucleus, sub-thalmic nucleus and
putamen.
After improvements in
health and safety in the various occupations involving exposure
to Mn in the later half of this century, studies into the
pathology of Mn intoxication were largely phased out.
Unfortunately, microscopic surveillance technology and knowledge
of membrane proteins was not sufficiently sophisticated at that
time to identify the presence of prion and amyloid plaque
tombstone structures characteristic of prion disease.
Banta et al. (6) carried out a
more recent pathological study in 1977 involving a case of Mn
intoxication associated with dementia and extrapyramidal signs
in a patient from rural Kentucky. Micrography of a biopsy of
cerebral cortex revealed amyloid plaques composed of bundles of
fibrils, lipofuscin granules and argyrophilic neurofibrillary
tangles - tombstone features that are characteristic of both
TSEs and Alzheimers (129).
Apart from Banta's pathological study (6) making reference to
.34 ppm levels of Mn (0.17-0.29 normal) in a frontal lobe biopsy
of a single CJD sufferer as part of their control, no work has
intentionally set out to investigate for any association between
Mn or other cations and TSE aetiology.
Furthermore,
transmission studies utilising CNS homogenate from fatalities of
chronic Mn poisoning have apparently never been attempted. Such
a trial would represent an ideal first step towards eliminating
or demonstrating the possible role of Mn or other cations as the
transmissible entity in prion diseases.
As this theory
suggests that trivalent Mn serves as the transmissible agent in
sporadic TSEs, then any Mn3+ induced neurodegenerative disorder
should be tranmissible via inoculation of diseased CNS
homogenate whether PrP is involved as an Mn3+ conjugate or not.
In contexts of Mn
overloading, Mn3+ may be capable of competing and conjugating
onto a range of other compatable metallo/cuproprotein ligands,
particularly when that protein's normal metal co-partner is in
short supply.
Interestingly,
possible evidence for the lack of necessity of a 'prion' based
infectivity in TSEs was demonstrated in TSE transmission studies
where brain homogenate sourced from TSE diseased mice
successfully transmitted TSE into recipients. However, various
CNS sections taken from these recipients failed to exhibit the
presence of 'prions' (95).
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