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Trail:
Ecosystems
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 Scientific
papers - Ecosystems - page 8
Sources
of Mn in the human food chain
Chronic cumulative Mn intoxication of the general population may
result from habitual ingestion of certain foodstuffs or mineral
supplements (6) naturally high in the element: e.g. tea leaves
(610 p.p.m.), coffee (20 p.p.m.) (especially beans sourced from
the Congo), cloves (263 p.p.m., thyme (82 p.p.m.), brazil nuts
(28 p.p.m.), pecans (36 p.p.m.), soya beans (35 p.p.m.), red
wine (14 p.p.m.), etc. (3,4).
Bioavailability of Mn
is higher in somefoods such as soya (70%) than in others like
oilseeds (50%) (4). Exposures to Mn via its industrial
applications poses a much greater toxicologically threat to
human health; e.g. intranasal exposure to atmospheric fall out
of Mn resulting from its use in steel, explosives, glass and dry
battery manufacture (3,4,94,108), as a contaminant of cement
kiln fuels, and its use as a tricarbonyl Mn additive in unleaded
petrol (3). Mn may also contaminate water supplies as a result
of its industrial or natural applications (3,4).
Mn also pollutes the
atmospheres and food chain due to its use as a fertilizer spray
and as an active ingredient in two widely used dithiocarbamate
fungicides called maneb (28) and mancozeb/manzidan (98). A few
countries apply these fungicides onto growing farm and garden
crops such as blackcurrents, potatoes, tomatoes, apples/pears,
hops, wheat, roses/tulips, whilst a very few countries apply
them as post harvest fungicidal dip treatments, for protecting
strawberries, bananas, tobacco, etc (17,28,130) after harvest to
prolong shelf life.
UK usage of Maneb in
tonnes per annum increased from 142 tonnes in the late 1970s, to
233 tonnes in the early 1980s to 679 tonnes in 1984 (132,133),
then dropped to 297 tonnes in 1994 (133). The temporal dynamics
of maneb usage in the UK correlates to the temporal dynamics of
BSE incidence in the UK (Fig. 8). With Maneb ranking at No 13
and mancozeb at No 4 on the top fifty list of overall tonnage of
pesticide used in the UK in 1994 (133), fears have
understandably been raised concerning the residues of these
compounds arising from their widespread use as post harvest
fungicide treatments.
Whilst the tonnage of
maneb used in 1994 had dropped by 56% since 1984, the tonnage of
mancozeb had increased by 235% in this period (133). Many other
countries have banned or restricted use of these compounds on
the basis of their ability to invoke teratogenic effects such as
hydrocephalus in the fetus (134), and a delayed Parkinsonian-like
neuropsychiatric degenerative disease in workers chronically
exposed to these chemicals (28).
BSE/nv
CJD: a synthetic, synergistic means of invoking the same CNS
mineral disturbance underlying the aetiology of sporadic TSEs?
(Fig. 9)
Fig. 9
The multifactorial aetiological template underpinning the
pathogenesis of the
novel, early onset strain of TSE; bovine spongiform encephalopathy
Mn
permeated the UK's bovine food chain in the 1970s/1980s largely
as a result of the widespread incorporation of chicken manure
into the concentrated feedrations of cattle (119), where it was
used to bind as well as increase the protein content of the
feed. When MBM was banned in 1988, chicken manure was one of the
cheaper sources of protein used to replace it. Its use
subsequently increased for a short while until it was banned in
1991 (119) - at the peak of the UK's BSE incidence rate (Fig.
8). Poultry were fortified with various Mn complexes (Mn
sulphate, Mn oxide, etc.) for promoting egg and broiler
production as well as rearing. Mn was generally fed at high
rates between 100 and 120mg/kg of dry matter composition of diet
(135) because of the inefficient 2-5% rate of dietary absorption
of Mn by monogastric poultry (135). Consequently, 95-98% of the
Mn content of poultry feed is excreted in the manure.
Cows were also increasingly
exposed to foods high in Mn via various cost-cutting byproduct
ingredients that were added into cattle concentrate feed during
the 1970s/1980s (135); palm kemal meal (164p.p.m. Mn), wheat
bran (122 p.p.m.), rice bran (260 p.p.m.), soya bean meal (35
p.p.m.) tea waste (275 p.p.m.) coffee waste (20.6 p.p.m.) red
clover (158 p.p.m.), dried alfalfa (37 p.p.m.) (3,4,69). Nickel
was used to extract certain types of oil (4) that are added to
concentrated feeds could have entered the bovine food chain.
Concentrated Dairy Cow feed was
also supplemented with high rates of Mn at 120 mg/kg (calves at
80 mg/kg) whilst beef cattle that received considerably smaller
quantities of concentrated feeds than dairy cattle were only fed
70 mg/kg (135). (NB. Beef cattle experienced 80% lower rates of
BSE relative to dairy cattle) Ruminants absorb Mn more
efficiently than monogastrics, with 10-18% Mn traversing the gut
wall (135).
Exposure to Mn
residues resulting from the use of Mn fertilizers and 'maneb'/'mancozeb'
fungicides on fodder and forage crops for cattle also occurred -
particularly during the period of peak usage of these compounds
in the late 1980s/early 1990s (131-133). Any Mn originating from
these various sources would also survive the rendering process
of meat and bone meal (MBM) manufacture, and subsequently
bioaccumulate its way up the farm animal foodchain as a result
of the practice of feeding farm animal back to farm animal via
the MBM ingredient.
Alternatively, there
are two other candidate cations which were used significantly in
UK agriculture and along UK waterways. Diquat and Chloramquat
cations (related to the auto oxidising paraquat molecule (17))
were used more intensively in the UK by weight per acre during
the 1980s-1990s than in other countries. Diquat is applied as a
crop desiccator in the UK (17,130) where it is used on peas,
grass crops for seed, laid cereals, oilseeds, hops, lucerne,
potatoes, beans, etc, immediately prior to harvest (and as a
herbicide along waterways), and chloramquat is applied as a
plant regulator on cereals shortly before harvest. Diquat use
(Graph 3) increased by 800% from 20 tonnes of a. i. used per
annum in the later half of the 1970s (131) to 163 tonnes used
per annum in the early 1980s (132). Usage subsequently dropped
and stabilised thereafter, running at 87 tonnes applied in 1984
and 104 tonnes in 1994 (133). Chloramquat use in the UK has
increased more dramatically, starting at 239 tonnes per annum in
the late 1970s (131), 231 tonnes per annum in the early 1980s
(132), then 1112 tonnes per annum in 1984 rising by 110% to 2335
tonnes in 1994 (133) - the highest ranking pesticide in UK usage
terms when related to total area treated.
The 'paraquat' class
of cations are absorbed into plants (17) after application. They
remain persistent in specific environments such as clay soils
(134). Paraquat forms stable free radicals (17), crosses the
blood/brain/barrier in mammals and has been associated with the
aetiology of Parkinsons disease and the induction of
auto-oxidation of, dopaminergic/serotonergic neurones
(10,13,14). The possible binding of diquat to the copper domain
of PrP during CNS Cu deficiency should also be considered
alongside the possible involvement of other candidate cations,
such as Mn or nickel (as a more reactive oxidative species; eg
Mn 4+ or radioactive Mn) in the aetiology of the 'modem' strains
of TSE.
Exposures
to synthetic estrogen/steroid compounds accelerate the
absorption and accumulation of Mn in the CNS: a putative
prerequisite in the aetiology of BSE/nv CJD
Individuals who are low in copper or iron demonstrate a markedly
increased absorption of Mn (3,4). Any increases in
exogenous/endogenous sources of estrogen (54) or glucocorticoid
(137,138,139) also mediates a dramatic increase in absorption,
concentration and distribution of Mn within the organism. When
Panic et al (54) administered estrogen to laying hens, Mn levels
were elevated 15-70 times higher than those found in the
untreated controls.
Elevated levels of
steroids/estrogens are known to increase the permeability of the
blood/brain barrier's microvasculature to macromolecules
(141,142), and this may partly explain the increased uptake of
Mn into the CNS following increased corticosteroid turnover.
The following groups
are therefore placed at a higher risk of increased Mn uptake as
a result of their exposures to above average levels of
estrogens/steroids; Adolescent (143) and pregnant (144) females,
those prescribed the contraceptive pill, hormone replacement
therapy, body building steroids/growth hormone, etc, or those
directly exposed to high levels of synthetic estrogenic
pollutants derived from detergents, pesticides, cosmetics,
phallates, etc, or indirectly exposed via residues in recycled
water supplies/foodstuffs, or via habitual ingestion of
estrogenic foods such as soya which contains the naturally
occurring estrogen, genistein (69). Naturally occurring
estrogens are also at high concentrations in some leguminous
crops such as lucerne and clovers (69), and it is interesting
that lucerne comprised the staple diet of a greater majority of
the captive and wild deer and elk in Colorado (57) and the
ostrichs and other zoo animals that have succumbed to TSEs.
The practise of using
oestrogenic/progesterone hormones for syncronising the heat
period and conception in UK dairy herds during the 1980s/! 990s
could have accelerated the absorption of Mn in the herds which
adopted this therapy.
Whilst estrogenic
growth promoters have been used in many countries worldwide to
boost the final fattening stages of beef cattle (banned since
the mid 1980s in the UK), all of those animals treated are
invariably slaughtered as three year olds before they have had
sufficient time to incubate and manifest the clinical stages of
TSE.
However, countries
that administered these lipophilic hormones intensively to
several species of farm livestock (as well as recycling these
hormones back into cattle via feeding of the tallow fraction of
MBM feed derived from the slaughtered carcases of hormone
treated animals) could have contributed to the potential risk of
chronic Mn overloading in their herds.
The tallow fraction
of MBM carries the lipophilic contaminants present in the feed.
Tallow remained in UK MBM feed once the practise of solvent
extraction was stopped by the rendering industry in the early
1980s (145). Further estrogenic substances - albeit naturally
occurring (69) - permeated the bovine food chain due to the
increased feeding of cheaper protein sources such as soya and
alfalfa during the 1980s (119).
Cattle and humans
drinking in areas where water is drawn from sources polluted by
synthetic estrogenic pollutants could potentially absorb Mn at
an increased rate.
Overloading with
estrogens/steroids can also depress Cu absorption (36) which, in
turn, activates the mobilisation of any remaining Cu stores in
the liver; thus increasing the turnover of ceruloplasmin (84) in
the hepatocytes which could favour an increased oxidation of
Mn2+ into its lethal Mn3+ species (7) - particularly at a time
when supplies of ceruloplasmin's normal oxidative target, Fe2+,
are depleted.
The common thread
centres on the role of these hormones in activating the
pituitary-adrenal axis, whereby mediating an increased turnover
of the adrenocorticotrophic hormone (ACTH) stress response,
which increases absorption and hepatic release of Mn as well as
increasing permeability of the blood brain barrier (137-139).
This permits an increased entry of Mn into the CNS, explaining
why higher levels of Mn are found in the serum/whole blood and
CNS during times of ‘stress’; eg, during infections,
myocardial infarction, rheumatoid arthritis, psychosis, etc. (3)
(4), and following surgery.
Other cations, such as nickel, are also found at high serum
concentrations in these contexts (140).
Interestingly, a
number of TSE epidemiological studies have described these same
conditions as common predisposing factors of CJD (41, 146-147,
175) whilst stress events are well recognised to predispose the
onset of the clinical phase of BSE. However, authors have
invariably attributed any aetiological association between
surgery and CJD to horizontal transmission of an 'infectious
agent' (41).
The extensive
literature citing nickel mediated allergic reactions invoked as
a direct result of using orthopedic prostheses, depth
electrodes, cardiac valves, surgical instruments, steel sutures
or intravenous cannulae composed of nickel alloys (3, p.
220-221) may offer an alternative explanation for the wide
variety of surgical procedures which predispose to CJD (175,
41). Following exposure of any PrP expressing tissues to these
nickel based devices, nickel could theoretically conjugate onto
PrP in susceptible genotypes and initiate TSE.
The association
between growth hormone therapy with extracts of pituitary and 'iatrogenic'
CJD has also been ascribed to horizontal transmission of the CJD
agent (41). Interestingly, Mn is well recognized to concentrate
in the mitochondria-rich pituitary gland (149), and it should
also be noted that long-term therapy with extracts of pituitary
growth hormone is invariably administered in conjunction with
steroids, where both treatments would simultaneously activate
the pituitary-adrenal axis and upregulate ACTH mediated Mn
absorption/release (137-139).
Interestingly,
anecdotal indications of associations between CJD and
steroid/hormone replacement therapy (HRT) medication have been
demonstrated in a few contexts, although these incidences would
be expected; given the significant proportion of
middle-aged/elderly people who are prescribed steroids and HRT,
etc. Long term therapy with steroids was reported in two cases
of CJD in Chile (147). A proportionately large number of 'body
builders'/gymnasts have contracted Nv CJD.
Chelation
of copper in the CNS by organo dithiophosphate insecticides as a
prerequisite of BSE?
It is proposed that the UK's unique mandatory high dose usage of
a systemically formulated 20% concentrated organo phthalimido-phosphorus
insecticide (phosmet) for the control of warble fly on cattle
during the 1980s (2, 150) depleted the supply of available
copper within the bovine's CNS; thus depriving the Cu domain on
PrP (15, 34) and other cuproproteins (such as the amyloid
precursor protein) of a supply of available Cu, causing PrP to
loose its correct conformation. The vacated Cu domain becomes
vulnerable to invasion by other foreign cations present in the
farm animal food chain (e.g. Mn3+, Ni3+ or diquat) that can
compete for binding to histidine imidazoles, and theoretically
transform PrP into its 'infectious' TSE-isoform; the misfolded
PrP-cation complex.
BSE runs at its
highest incidence rate per total head of cattle in counties
(151) such as Hampshire, West Sussex, Norfolk and Wiltshire
where the Cretaceous terrains and sandy soils are renowned for
their low copper status (31); suggesting that an underlying
environmental deficiency of Cu may exacerbate this putative
prerequisite of susceptibility to TSE; as recorded in the
environments supporting sporadic TSE clusters.
Cu deficiency is also
prevalent in the soils of Guernsey Island (31); an area which
hosts the highest incidence rate of BSE in the world (151).
Britanny is one of the most noted 'hotspots' of Cu deficiency in
France, and has suffered 20 of the total of 28 French BSE
casualties recorded to date.
The underlying
problem of Cu deficiencies indigenous to certain UK regions was
exacerbated post 1982 when it first became mandatory to treat
cattle with the Cu-chelating phosmet based insecticides during
the late March period (152) - at a time when copper levels are
already at their lowest level in the seasonal cycle (8).
Interestingly the few
other countries outside of the UK (namely France and Ireland)
who have employed the high dose 'systemic' warblecide brands
containing 20% phosmet - albeit voluntarily and less intensively
- suffer from a relatively less intense incidence of BSE (150).
A
phthalimido-N-methylmercaptan (PNMM) group is yielded during
phosmet metabolism following hydrolytic loss of the alkyi
phosphate moiety (153). It is proposed that PNMM chelates
available copper ions in the CNS - much like mercaptoethanol/dimercaprol
(154) - employing its two sulfurs or nitrogen to form a tight
stable complex with copper which participates in the formation
of a mercaptide ring. PNMM subsequently protects itself against
further enzymic mediated degradation due to the occupation of
its Sulphur catalytic centre with Cu ions. Some of the 'stable'
lipophilic Copper-PNMM complex is traffiked like a 'trojan
horse' into CNS lipid membranes (perhaps initiating lipid
peroxidation and radical reactions), whilst the remainder is
excreted.
A tenfold
upregulation of the surface expression of PrP was invoked after
Whatley et al introduced 12 ppm doses of phosmet into
neuroblastoma cell cultures expressing PrP (155). Such a tenfold
upregulation of the cuproprotein PrP 'in vivo' would place
further demands upon already depleted supplies of free copper in
the neurone, leading to the eventual failure of PrP to maintain
its tertiary conformation, plus a failure of PrP to perform its
putative role in delivering Cu to the superoxide scavenger, SOD
1 (40).
Incidents of
poisoning with some types of OP compound have produced the
occasional case of spongiform encephalopathy with gliosis in
exposed individuals (156, 157). Hydrocephalus (158) and cerebral
edema (153)/spongiosis of the neurophil have been reported as
pathological features following intoxications by phosmet. The
class of spongiform encephalopathy induced by some OPs is
considered to be 'non transmissible' and is similar to the SE
pathology and hydrocephalus induced by other Cu-chelating
chemicals such as Cuprizone (20, 159).
Chronic intoxications
with systemic OPs (160, 161) and estrogenic/steroid pollutants
(84) have been recognized to increase the permeability of the
capillary epithelium of the blood brain barrier, which could
permit an increased uptake of macromolecules such as the
Mntransferrin complex into the brain.
Raised serum levels
of ceruloplasmin have been recorded following contamination by
both 'neuropathic' : OPs (85) and estrogenic/steroid compounds
(84). Once Cu/Fe are deficient in the external environment, any
pollutant-induced upregulation of the liolo' form of
ceruloplasmin expression would suggest that the remaining
reservoirs of Cu stored in the liver are being mobilised. Such
an upregulation of ceruloplasmin would lead to the oxidisation
of larger quantities of Mn2+ into its highly reactive Mn3+
species in hepatocytes (7), particularly when the levels of its
normal oxidative target, Fe 2+, are depleted.
Furthermore, any
pollutant induced upregulation of the membrane bound form of
ceruloplasmin found in the CNS astrocytes (162) could reap
disastrous consequences, creating an in situ conversion of Mn2+
into its trivalerut species at a time when Mn2+/Mn3+ had already
accumulated to toxic proportions in the astrocytes. The degree
of neurotoxic potential of trivalent Mn has always been linked
to the levels of 'available' Mn 3+ in the system (7), which is
reciprocally related to the levels of Mn SOD expression in the
intoxicated individual. The unique high dose
usage of systemic OPs on cattle in the UK (2) (150) would have
potentiated many of the toxicological effects resulting from the
concurrent over-exposure of cattle to Mn. Malik et al (163) have
shown that OPs and Mn interact in biological systems to produce
a powerful synergistic effect where each potentiates the
toxicity of the other; for OPs and Mn interact with many of the
same enzymic pathways, such as cytochrome P450 (160, 164-166).
Lipophilic OPs also
cross the blood brain barrier (160, 161) and initiate CNS lipid
peroxidation potentially resulting in a range of radical
reactions (167-172) which can proliferate in environments
deficient in Se, Fe, Cu, Zn and compound the impact of any
coexisting cation-initiated radical reactions.
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