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Activity: Former
Insecticide (Organophosphate
Structure:
Adverse
Effects:
Ataxia
Blood
Brain
CNS
Endocrine: Pituitary
Heart
Sciatic Nerve
DFP is a structural analog
of sarin.
Ref: Sarin
(nerve agent GB)-induced differential expression of mRNA
coding for the acetylcholinesterase gene in the rat central
nervous system; by Damodaran TV, Jones KH, Patel AG, Abou-Donia
MB. Biochemical Pharmacology Volume 65, Issue 12 , 15 June
2003, Pages 2041-2047.
|
Diisopropyl
fluorophosphate (DFP) is an organophosphate compound used
as an insecticide, a substrate for
the production of organophosphate military "nerve" gases
and formerly as a topical miotic medication in ophthalmology.
DFP
has been used as an experimental agent in neuroscience because
of its
ability to inhibit cholinesterase and cause delayed peripheral
neuropathy. It has been also used as a miotic agent
in the treatment of glaucoma. Although DFP has caused experimental
distal anoxopathy, no cases of peripheral neuropathy have
been reported in patients treated with this agent for glaucoma.
Major
Uses:
Not
registered for current use in the U.S.
Therap
cat: Cholinergic (ophthalmic)
[Budavari, S. (ed.). The Merck Index - An
Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse
Station, NJ: Merck and Co., Inc., 1996. 883]
Therap
Cat (Vet): Has been used as a miotic
[Budavari, S. (ed.). The Merck Index - An
Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse
Station, NJ: Merck and Co., Inc., 1996. 883]
Insecticide
(former use)
[Hawley, G.G. The Condensed Chemical Dictionary.
10th ed. New York: Van Nostrand Reinhold Co., 1981. 360]
Relatively
mild poison
[Canadian Security Intelligence Service;
Chemical and Biological Terrorism: The Threat According
to the Open Literature. Author: Ron Purver, Strategic Analyst,
CSIS. Chemical Terrorism. Available from http://www.csis-scrs.gc.ca/eng/miscdocs/chemtere.html
as of Sept 19, 2000.]
Ref:
TOXNET Hazardous Substances Data Base for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm
|
Apoptosis
(click
on for all fluorinated pesticides)
Abstract: The
features of organophosphate-induced brain injuries were investigated.
Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD50) of
diisopropylfluorophosphate [synonym
for DFP]
. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate
(20 mg/kg), which are centrally inactive, were pre-treated intramuscularly
to reduce the mortality and eliminate peripheral signs. Diisopropylfluorophosphate
induced severe limbic seizures, and early necrotic and delayed
apoptotic brain injuries. The necrotic
brain injury was observed to be maximal as early as 1 h after
diisopropylfluorophosphate treatment predominently in hippocampus
and piriform/entorhinal cortices, showing a spongiform change
(malacia) of neuropils in severe cases.
In contrast, typical apoptotic (TUNEL-positive) cells started
to appear at 12 h in thalamus, and a mixed type in amygdala. Separately,
nitrite/nitrate content in cerebrospinal fluid was found to significantly
increase after 2 h, reaching a maximal level at 6 h. Pre-treatment
with -NG-nitroarginine, an inhibitor of nitric oxide synthase,
reduced nitrite/nitrate content and, noteworthy, attenuated only
apoptotic brain injury in all four brain regions without affecting
seizure intensity and necrotic injury. Taken together, the
delayed apoptotic injury of brain induced by diisopropylfluorophosphate
poisoning in rats might be mediated in part through nitric
oxide production.
Ref:
Organophosphate-induced brain injuries: delayed apoptosis mediated
by nitric oxide by Yun-Bae Kim et al. Environmental Toxicology
and Pharmacology Vol 7, Issue 2 , April 1999, Pages 147-152
Ataxia
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on for all fluorinated pesticides)
Abstract:
A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP
produces mild ataxia in hens in 7–14 days, which develops
into severe ataxia or paralysis as the disease progresses.
Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase
II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament
(NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF,
CaM kinase II [alpha]-subunit), we determined the effect of a
single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured
by Northern hybridization in cerebrum, cerebellum, brainstem,
midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr,
1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single
1.7 mg/kg, sc. injection of DFP. All the tissues (cerebrum, 52%;
cerebellum, 55%; brainstem, 49%; midbrain, 23%; spinal cord, 80%;
sciatic nerve, 157%;) showed significant increase in c-fos expression
in 30 min and this elevated level persisted at least up to 2 hr.
Expressions of [beta]-actin mRNA and 18S RNA were used as internal
controls. The significant increase in c-fos
expression in DFP-treated hens suggests that c-fos may be one
of the IEGs involved in the development of OPIDN.
Ref:
C-fos
mRNA Induction in the Central and Peripheral Nervous Systems of
Diisopropyl Phosphorofluoridate (DFP)-Treated Hens; by RP
Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.
Blood
(click
on for all fluorinated pesticides)
The study
examined the relationship between inhibition of cholinesterase
activity (CA) and thermoregulatory response in the rat following
exposure to the organophosphate (OP), diisopropyl fluorophosphate
(DFP). Male Long-Evans rats were injected with DFP dissolved in
peanut oil in doses ranging from 0 to 1.5 mg/kg (s.c.). Colonic
T(sub col) and tail skin temperature T(sub tail) were recorded
at 0, 1, 2, and 3 hr post-injection. At 3 hr post-injection the
rat was sacrificed and a blood sample was taken by cardiac puncture
and analyzed for CA. There was a biphasic dose effect of DFP on
T(sub col) with slight but significant elevation in T(sub col)
in the dose range of 0.01 to 0.5 mg/kg and a significant depression
in T(sub col) at doses of 1.0 and 1.5 mg/kg. There
was a dose-dependent fall in CA with DFP administration in the
erythrocyte, plasma, and whole blood fractions. Hypothermia
was associated with 80 to 87% inhibition in CA, whereas the elevation
in T(sub col) was associated with 20 to 70% [abstract truncated]
Ref:
1991 - Relationship between Cholinesterase Inhibition and Thermoregulation
Following Exposure to Diisopropyl Fluorophosphate in the Rat;
by Gordon CJ, Fogelson L, Richards J, Highfill J. Report No. NTIS/PB92-158658
from The National Technical Information Service.
Brain
(click
on for all fluorinated pesticides)
Note:
More
abstracts are available on DFP
Abstract: The
features of organophosphate-induced brain injuries were investigated.
Rats were poisoned intraperitoneally with 9 mg/kg (1.8 LD50) of
diisopropylfluorophosphate [synonym
for DFP]
. Pyridostigmine bromide (0.1 mg/kg) and atropine methylnitrate
(20 mg/kg), which are centrally inactive, were pre-treated intramuscularly
to reduce the mortality and eliminate peripheral signs. Diisopropylfluorophosphate
induced severe limbic seizures, and early necrotic and delayed
apoptotic brain injuries. The necrotic
brain injury was observed to be maximal as early as 1 h after
diisopropylfluorophosphate treatment predominently in hippocampus
and piriform/entorhinal cortices, showing a spongiform
change (malacia) of neuropils in severe cases.
In contrast, typical apoptotic (TUNEL-positive) cells started
to appear at 12 h in thalamus, and a mixed type in amygdala. Separately,
nitrite/nitrate content in cerebrospinal fluid was found to significantly
increase after 2 h, reaching a maximal level at 6 h. Pre-treatment
with -NG-nitroarginine, an inhibitor of nitric oxide synthase,
reduced nitrite/nitrate content and, noteworthy, attenuated only
apoptotic brain injury in all four brain regions without affecting
seizure intensity and necrotic injury. Taken together, the delayed
apoptotic injury of brain induced by diisopropylfluorophosphate
poisoning in rats might be mediated in part through nitric oxide
production.
Ref:
Organophosphate-induced brain injuries: delayed apoptosis mediated
by nitric oxide by Yun-Bae Kim et al. Environmental Toxicology
and Pharmacology Vol 7, Issue 2 , April 1999, Pages 147-152
Abstract:
... We studied the effect of DFP admimistration (1.7 mg/kg/s.c.)
on the expression of Intermediate Filament
(IF) proteins: Glial Fibrillary Acidic Protein (GFAP) and vimentin
which are known indicators of neurotoxicity and astroglial•
pathology. The hens were sacrificed at different time points
i.e. 1,2,5,10 and 20 days. Total RNA was extracted from the following
brain regions: cerebrum, cerebellum, and brainstem as well as
spinal cord. Northern blots prepared using standard protocols
were hybridized with GFAP and vimentin as well as [beta]-actin
and 18S RNA cDNA (controls) probes. The results indicate a differential/spatial/temporal
regulation of GFAP and vimentin levels which may
be due to the result of disruption of glial-neuronal network.
The GFAP transcript levels reached near control levels (88% and
95%) at 20 days post DFP treatment after an initial down-regulation
(60% and 73%) in highly susceptible tissues like spinal cord and
brainstem respectively. However vimentin transcript levels remained
down-regulated (61% and 53%) at 20 days after an early reduced
levels(47% and 55%) for spinal cord and brainstem respectively.
This may be due to the astroglial•
pathology resulting in neuronal alterations or vice-versa. In
cerebellum (less susceptile tissue) GFAP levels were moderately
down-regulated at 1,2 and 5 days and reached near control values
at 10 and 20 days. Vimentin was rapidly reinduced (128%) in cerebellum
at 5 days and remained at the same level at 10 days and then returned
to control values at 20 days after an initial down-regulation
at 1 and 2 days. Thus these alterations were less drastic in cerebellum
as indicated by initial susceptibility followed by rapid recovery.
On the other hand both GFAP and vimentin levels were upregulated
from 2 days onwards in the non-susceptible tissue cerebrum, implying
protective mechanisms from the beginning. Hence the
DFP induced astroglial•
pathology as indicated by the complex expression profile of GFAP
and vimentin mRNA levels may be playing an important role in the
delayed degeneration of axons or is the result of progressive
degeneration of axons in OPIDN.
Ref: Alterations in Levels of mRNAs Coding for Glial Fibrillary
Acidic Protein (GFAP) and Vimentin Genes in the Central Nervous
System of Hens Treated with Diisopropyl Phosphorofluoridate (DFP);
by TiV
Damodaran et al. Neurochemical Research
25 (6): 809-816, June 2000.
•
Astroglial: "The
astroglial cell mass constitutes a prominent part
of the total brain cell number
and volume..." See
full paper:
Astroglial Pharmacology by Elisabeth Hansson et al.
Paper available online at http://www.acnp.org/g4/GN401000079/Ch079.html
|
Abstract:Daily
subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate
caused prolonged inhibition of cholinesterase (ChE) activity in
whole blood and brain and downregulation of muscarinic receptors
in the central nervous system; these changes were accompanied
by progressive, persistent deterioration of working memory and
motor function.
Ref: 1994
- Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats:
Behavioral, Neurochemical and Pharmacological Indices of Tolerance;
by Bushnell PJ, Kelly KL, Ward TR. NTIS report no.NTIS/PB95-148979
[The National Technical Information Service).
Abstract:
A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP
produces mild ataxia in hens in 7–14 days, which develops
into severe ataxia or paralysis as the disease progresses.
Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase
II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament
(NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF,
CaM kinase II [alpha]-subunit), we determined the effect of a
single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured
by Northern hybridization in cerebrum, cerebellum, brainstem,
midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr,
1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single
1.7 mg/kg, sc. injection of DFP. All the
tissues (cerebrum, 52%; cerebellum, 55%; brainstem, 49%; midbrain,
23%; spinal cord, 80%; sciatic nerve, 157%;)
showed significant increase in c-fos expression in 30 min
and this elevated level persisted at least up to 2 hr. Expressions
of [beta]-actin mRNA and 18S RNA were used as internal controls.
The significant increase
in c-fos expression in DFP-treated hens suggests that c-fos may
be one of the IEGs involved in the development of OPIDN.
Ref:
C-fos
mRNA Induction in the Central and Peripheral
Nervous Systems of Diisopropyl Phosphorofluoridate (DFP)-Treated
Hens; by RP
Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.
... In a study of alkyl
phosphate poisoning, Pasi and Leuzinger came to the conclusion
that delayed lesions only occur, if at all, after severe cerebral
anoxia [176]. As regards anatomical
changes in the brain (demyelination), these delayed lesions correspond
to those caused by peripheral neuropathy in acute and chronic
ortho-tricresyl phosphate poisoning and are confined to fluorine-
containing alkyl phosphatesÑfor example, mipafox,
DFP, sarin and soman. A synoptic
evaluation of 536 civilian cases of alkyl phosphate poisoning
made by the above-mentioned authors led them to the conclusion
that acute poisoning by civilian alkyl phosphates did not result
in delayed lesions. It should be noted, however, that their period
of observation of two to three years was inadequate for investigations
of delayed lesions beside the scale of Spiegelberg and others
[p 40].
Ref: Delayed Toxic Effects of Chemical Warfare
Agents. A SIPRI (Stockholm international Peace Research Institute)
Monograph. 1975. ISBN 91-85114-29-4.
http://projects.sipri.se/cbw/research/cw-delayed.pdf
Pub
Med Abstract: The organophosphate Diisopropylfluorophosphate (DFP)
is a well-known inhibitor of cholinesterases. We have recently
observed that neonatal exposure to a single subsymptomal dose
of DFP induces permanent alterations in
muscarinic cholinergic receptors (MAChRs) and in spontaneous behaviour,
in the mice as adults. In order to determine if there is
a critical period for these effects, neonatal mice were given
a single oral dose of 1.5 mg/kg DFP b.wt. on postnatal day 3,
10 or 19, causing equal inhibition of AChE. At the adult age of
4 months the mice were tested for spontaneous motor behaviour,
and were subsequently sacrificed for measurement of density of
MAChRs and subpopulations of MAChRs in the cerebral cortex by
using the antagonist quinuclidinyl benzilate ([3H]QNB), and agonist
carbachol, respectively. At adult age, mice
exposed to DFP on postnatal day (PND) 3 or 10 showed significant
(P < or = 0.01) alterations in spontaneous motor behaviour
and a significant (P < or = 0.01) decrease in muscarinic
receptor density. There were no alterations mice exposed
on PND 19. The proportions and affinity-constants of high- and
low-affinity MAChR binding sites were not affected in mice showing
altered MAChR density. The lack of effect on mice exposed on PND
19 was not due to differences in AChE activity.
Ref: Brain
Res 1995 Apr 17;677(1):13-9. Exposure
to an organophosphate (DFP) during a defined period in neonatal
life induces permanent changes in brain muscarinic receptors and
behaviour in adult mice by Ahlbom J, Fredriksson A, Eriksson
P. (Department of Environmental Toxicology, Uppsala University,
Sweden).
PubMed abstract: Diisopropyl
phosphorofluoridate (DFP) produces
organophosphorus-ester-induced delayed neurotoxicity in sensitive
species. We studied the effect of single dose of DFP on the expression
of phosphorylated cAMP-response element
binding protein (p-CREB), which is a well known transcription
factor involved in several pathways mediating different types
of external stimuli. The hens were perfused with neutral buffered
formalin at different time points, i.e., 0.5, 1.0, and 2.0 hrs,
as well as 1, 2, 5, and 20 days after dosing. The central nervous
system regions of the whole brain were dissected and 7-micron
sections were stained for either p-CREB immunopositivity or with
hematoxylin and eosin. Results indicated an early differential
increase of p-CREB immunopositivity in susceptible regions such
as cerebellum, brainstem, and midbrain
within 2 hrs. These induced levels persisted upto 5 days in these
tissues, although the time course of p-CREB immunopositivity was
distinctly different for each region. In the cerebellum
induction of p-CREB was seen in the granular layer where both
the granulocytes and the glial
cells showed induction. Increased immunopositivity for
p-CREB in the Purkinje cells and
in some basket cells of the molecular layer was noticed over time,
but the induction was not as great as in the granular layer.
Of all the tissues cerebellum showed the strongest intensity of
immunopositivity of the cells as well as the highest (absolute)
number of pCREB-positive cells. The
brainstem showed a similar fluctuating pattern
like the cerebellum with the highest percentage
increase of the immunoreactive cells at 5 days preceded by the
lowest dip in immunopositivity at 2 days. In the midbrain, there
was a time-dependent increase in the immunopositivity from 0.5
hr onwards until reaching control levels at 20 days. Immunopositivity
was also noted in portions of the spina
medularis and spina oblongata. The cerebrum (non-susceptible
tissue) of DFP-treated hens did not show much deviation from the
controls. The endothelial cells of
the susceptible regions showed induction at early time points,
in contrast to the absence of induction in cerebrum. Spatial and
temporal differences in the immunopositivity pattern indicate
probable involvement of CREB-independent pathways also. Overall,
the complex induction pattern of p-CREB, along with our earlier
observations of the early induction of c-fos, c-jun and Protein
Kinase A (PKA) as well as the induction of Calcium2+/Calmodulin
dependent Protein Kinase II (CaM kinase II) at later periods,
strongly suggest an activator role of CREB mediated pathways that
may lead to the clinical development of delayed neurotoxicity.
Ref: 2002
Neurochem
Res Mar;27(3):183-93.
Early differential elevation and persistence of phosphorylated
cAMP-response element binding protein (p-CREB) in the central
nervous system of hens treated with diisopropyl phosphorofluoridate,
an OPIDN-causing compound; by TV Damodaran TV et al.
-- This study compared
the neurotoxic effects of triphenyl phosphite (TPP) in the rat
with those seen after exposure to diisopropylphosphorofluoridate
(DFP), a compound known to produce organophosphorus-induced
delayed neurotoxicity (OPIDN). Animals received either three subcutaneous
injections of triphenyl phosphite (1184 mg/kg body wt each dose)
administered at 3-day intervals or a single subcutaneous injection
of diisopropylphosphorofluoridate (4 mg/kg body wt)... rats injected
with diisopropylphosphorofluoridate showed moderate
degeneration in the gracile fasciculus and nucleus but
did not display degeneration in any other brain region. Injections
of diisopropylphosphorofluoridate did not produce delayed onset
clinical signs. The results indicate that in the rat, different
central nervous system cell groups are affected by these two organophosphorus
compounds and that triphenyl phosphite affects nuclei and tracts
at all levels of the neuraxis, including those associated with
higher-order processing and cognitive functions. In addition,
the distinct degeneration patterns produced by these two compounds
support the view that triphenyl phosphite-induced neurotoxicity
should not be considered as a type of organophosphorus-induced
delayed neurotoxicity, but rather as a separate category of organophosphorus-induced
neurotoxicity. [Lehning EJ et al; Fundam Appl Toxicol 29 (1):
110-8 (1996)]
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm
The effects
of organophosphorus anti-cholinesterase (anti-ChE) agents, soman,
tabun, diisopropylfluorophosphate (DFP) and non-organophosphorus
anti-ChE agents, eserine and neostigmine on sympathetic neurons
and on ganglionic transmission were investigated. Intracellular
recordings were obtained from sympathetic neurons of isolated
rabbit and guinea pig superior cervical ganglia by means of glass
microelectrodes. DFP, soman and eserine
increased and blocked nicotinic cholinergic transmission at low
and high concentrations, respectively. These agents at lower concentrations,
i.e. 1 micro M or lower, facilitated nicotinic transmission by
inhibiting ganglionic cholinesterases. Whereas, these agents at
higher concentrations, i.e. 1 or 10 micro M appeared to block
nicotinic transmission by different mechanisms. ...
Ref: 1989 - Cellular Actions and Interactions
of Anticholinesterases and Their Antidotes in Mammalian Autonomic
Neurons; by Dun NJ. Report No. NTIS/AD-A215 077/9 from The National
Technical Information Service.
The Morris
water task was used to measure the effects of chronic diisopropylfluorophosphate
(DFP) treatment on C57BL/6Ibg mice. Control mice showed good task
acquisition and searched accurately for the platform after it
was removed from the pool, suggesting that they had formed a spatial
map of the platform's location relative to distal cues.
In contrast, mice chronically treated with DFP prior to training
showed a marked deficit in spatial learning.
Chronic DFP treatment did not affect ability to locate a visible
platform and did not impair task retention in mice trained to
find the hidden platform prior to DFP treatment. The
chronic DFP treatment decreased muscarinic binding in cortex,
hippocampus, and striatum. These results indicate that
C57BL mice are capable of spatial learning in the water task.
The ability of chronic DFP treatment to
impair place but not cue learning suggests that the cholinergic
dysfunction produced by DFP is similar to those produced by lesions
of central cholinergic s [abstract truncated]
Ref:
1987 - Effects of Chronic Diisopropylfluorophosphate Treatment
on Spatial Learning in Mice; by Upchurch M, Wehner JM. Report
No. NTIS/AD-A188 368/5 from The National Technical Information
Service.
The biodisposition
of diisopropylfluorophosphate (DFP), soman, and sarin was studied
in the major organs of the mouse after i.v. administration of
sublethal but pharmacologically active doses. DFP was also administered
via inhalation, allowing comparison of disposition data between
the two routes of administration. Only trace quantities of parent
compounds were found in tissues. The major portion of the radioactivity
was determined to be vocalently bound or free metabolites of the
parent compounds. All compounds tested induced immediate hypothermia
and hypoactivity lasting at least 7 hr.
However, substantial quantities of radioactivity remained
in the brain following recovery from the pharmacological effects.
Cholinesterase inhibition was also not correlated with
either free agent or bound or free metabolites, suggesting that
non-cholinesterase binding of the parent compounds may play a
role in the depression of CNS activity. The pharmacological effects
of i.v. administered tabun were also evalu [abstract truncated]
Ref:
1986 - Studies on the Biodisposition of Organophosphates in Mice;
by Martin BR. Report No. NTIS/AD-A183 850/7 from The National
Technical Information Service.
The effect
of diisopropylfluorophosphate (DFP) and several other organophosphates
on brain membranes was studied. DFP bound
to a wide range of proteins in synaptic plasma membranes (SPM),
but no effect was detected on cross-linking of these proteins
by several imidate reagents. DFP, soman,
sarin, and tabun administered in vivo significantly altered the
levels of endogenous opioids peptides in several brain regions.
A search for an endogenous enzyme in brain capable of inactivating
DFP was inconclusive, but suggested that one might be present
in the soluble fraction.
Ref:
1986 - Neurochemical Mechanism of Organophosphorus Compounds:
Effect on Neuromembrane; by Lee NM. Report No. NTIS/AD-A217 464/7
from The National Technical Information Service.
Cholinesterase
(ChE) activity in selected brain regions and trunk blood was studied
20 min, 1 hr, and 24 hrs after bilateral injection of various
doses of diisopropylfluorophosphonate (DFP), soman and sarin into
the corpus striatum of male rats. Locomotor activity was measured
after bilateral intrastriatal injection of doses of DFP, soman
and sarin that reduced striatal ChE activity to 40% of control
or less, with a minimum of inhibition of ChE elsewhere in the
brain or blood. DFP appeared to diffuse
throughout the brain parenchyma more than soman and sarin, and
the latter two compounds appeared also to enter the peripheral
circulation. However, no gross signs of toxicity due to
peripheral ChE inhibition were observed. Locomotor
activity was reduced significantly 20 min after bilateral intrastriatal
administration of DFP (81.5 nmol). Keywords: Organophosphates,
Striatum, Cholinesterase. Annual rept. 30 Sep 83-29 Sep 84.
Ref: 1984 - Effect of Intracerebral
Injection of Organophosphates on Brain Neurochemistry and Peripheral
Physiology; by Robinson SE. Report No. NTIS/AD-B120-517/8 from
The National Technical Information Service.
CNS
(click
on for all fluorinated pesticides)
Organophosphate insecticides
such as ... DFP are potent cholinesterase
enzyme inhibitors that act by interfering
with the metabolism of acetylcholine, resulting in the accumulation
of acetylcholine at neuroreceptor transmission sites. [Klaassen,
C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology.
The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill,
1995. 979]
-- MUSCARINIC (PARASYMPATHETIC) EFFECTS may include bradycardia,
bronchospasm, bronchorrhea, salivation, lacrimation, diaphoresis,
vomiting, diarrhea, and miosis. NICOTINIC (SYMPATHETIC AND MOTOR)
EFFECTS may include tachycardia, hypertension, fasciculations,
muscle cramps, weakness, and RESPIRATORY PARALYSIS. CENTRAL EFFECTS
may include CNS depression, agitation,
confusion, delirium, coma, and seizures.
-- Children may have different predominant signs and symptoms
than adults: CNS depression, stupor,
flaccidity, dyspnea, and coma are the most common signs in children.
-- ... Its high lipid solubility, low molecular weight, and volatility
facilitate inhalation and transdermal absorption. DFP
also readily penetrates the central nervous system. [Hardman,
J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.).
Goodman and Gilman's The Pharmacological Basis of Therapeutics.
9th ed. New York, NY: McGraw-Hill, 1996. 167]
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm
Abstract:
Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester
induced delayed neurotoxicity (OPIDN) in the hen, human and other
sensitive species. We studied the effect of a single dose of DFP
(1.7 mg/kg/sc) on the expression of c-jun, which is one of the
heterodimerizing ITFs (Inducible Transcriptional Factors) of the
AP-1 family. The hens were sacrificed at different time points
ie 0.25,.0.50, 1 and 2 hrs. Total RNA was extracted from the following
brain regions: cerebrum, cerebellum, brainstem, midbrain and as
well as spinal cord. Northern blots prepared using standard protocols
were hybridized with c-jun as well as b-actin and 18S RNA cDNA
(control) probes. The results indicate differential regulation
of c-jun levels which may be due to the activation of both cholinergic
and non-cholinergic pathways of CNS,
besides changing roles of c-jun (as mediator of degeneration or
regeneration) depending on heterodimerization with other ITFs.
In the highly susceptible tissues like brainstem and spinal cord
c-jun transcript levels increased at 15 minutes and continued
to increase gradually till it reached the maximum at 2 hrs. Overall
spinal cord showed the maximum levels of c-jun induction (207%)
at 2 hrs time point of all the CNS tissues. The enhancement
of cholinergic transmisson by the inhibition of cholinestrase
may be responsible for the gradual increase mediated by neural
and vascular factors. In contrast, less susceptible tissue, cerebellum
showed almost immediate induction to high level of (179%) at 15
minutes and the levels stayed more or less the same until it peaked
to 185% at 2 hrs. Relatively low abundance of cholinergic neurons
and high number of sensitized specialized cell types like Bergman
glia and Purkinje cells may be responsible for the immediate higher
induction. Non-susceptible tissue cerebrum did not show any changes
in the c-jun levels. In midbrain the induction pattern was very
similar to that of brainstem. This differential
induction pattern of c-jun encomposing the differences in the
quantity and time course was directly proportionate to the degree
of susceptibility and cellular heterogeneity of different regions
of CNS. The significant increase
in c-jun levels along with our earlier observation on the increased
c-fos levels indicate that AP-1 family of genes may be one of
the IEGs involved in the long term changes which eventually lead
to OPIDN.
Ref:
Early Differential Induction of C-jun
in the Central Nervous System of
Hens Treated with Diisopropylphosphorofluoridate (DFP) by TV
Damodaran et al. Neurochemical Research 25 (12): 1579-1586, December
2000.
Abstract:
A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP
produces mild ataxia in hens in 7–14 days, which develops
into severe ataxia or paralysis as the disease progresses.
Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase
II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament
(NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF,
CaM kinase II [alpha]-subunit), we determined the effect of a
single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured
by Northern hybridization in cerebrum, cerebellum, brainstem,
midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr,
1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single
1.7 mg/kg, sc. injection of DFP. All the
tissues (cerebrum, 52%; cerebellum, 55%; brainstem, 49%; midbrain,
23%; spinal cord, 80%; sciatic nerve, 157%;) showed significant
increase in c-fos expression in 30 min and this elevated level
persisted at least up to 2 hr. Expressions of [beta]-actin
mRNA and 18S RNA were used as internal controls.
The significant increase in c-fos expression
in DFP-treated hens suggests that c-fos may be one of the IEGs
involved in the development of OPIDN.
Ref:
C-fos
mRNA Induction in the Central and Peripheral
Nervous Systems of Diisopropyl Phosphorofluoridate (DFP)-Treated
Hens; by RP
Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.
Abstract:
Daily subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate
caused prolonged inhibition of cholinesterase (ChE) activity in
whole blood and brain and downregulation of muscarinic receptors
in the central nervous system; these changes were accompanied
by progressive, persistent deterioration of working memory and
motor function.
Ref: 1994
- Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats:
Behavioral, Neurochemical and Pharmacological Indices of Tolerance;
by Bushnell PJ, Kelly KL, Ward TR. NTIS report no.NTIS/PB95-148979
[The National Technical Information Service).
Abstract:
Behavioral effects of organophosphates (OPs) typically decrease
with repeated exposure, despite persistence of OP-induced inhibition
of acetylcholinesterase (AChE) and downregulation of muscarinic
acetylcholine (ACh) receptors. To characterize this tolerance
phenomenon, rats were trained to perform an appetitive operant
task which allowed daily quantification of working memory (delayed
matching-to-position), reference memory (visual discrimination)
and motor function (choice response latencies and inter-response
times (IRTs) during delay). Findings indicate that animals showing
a definitive sign of tolerance to OP administration (subsensitivity
to a cholinergic agonist) were also functionally
impaired on both the motoric and mnemonic demands of a working
memory task. The nature of this impairment suggests further
that it results from compensatory changes in the CNS, e.g., muscarinic
receptor downregulation, considered to produce 'tolerance' to
OPs in exposed animals.
Ref: 1991 - Behavioral and Neurochemical Changes in Rats Dosed
Repeatedly with Diisopropylfluorophosphate; by Bushnell PJ, Padilla
SS, Ward T, Pope CN, Olszyk VB. Report No. NTIS/PB91-200238 from
The National Technical Information Service.
The Morris
water task was used to measure the effects of chronic diisopropylfluorophosphate
(DFP) treatment on C57BL/6Ibg mice. Control mice showed good task
acquisition and searched accurately for the platform after it
was removed from the pool, suggesting that they had formed a spatial
map of the platform's location relative to distal cues.
In contrast, mice chronically treated with DFP prior to training
showed a marked deficit in spatial learning. Chronic DFP
treatment did not affect ability to locate a visible platform
and did not impair task retention in mice trained to find the
hidden platform prior to DFP treatment. The
chronic DFP treatment decreased muscarinic binding in cortex,
hippocampus, and striatum. These results indicate that
C57BL mice are capable of spatial learning in the water task.
The ability of chronic DFP treatment to
impair place but not cue learning suggests that the cholinergic
dysfunction produced by DFP is similar to those produced by lesions
of central cholinergic s [abstract truncated]
Ref:
1987 - Effects of Chronic Diisopropylfluorophosphate Treatment
on Spatial Learning in Mice; by Upchurch M, Wehner JM. Report
No. NTIS/AD-A188 368/5 from The National Technical Information
Service.
Endocrine:
Pituitary
(click
on for all fluorinated pesticides)
Sixteen of 100 rats
administered DIFP at a dose of 0.5 mg/kg every 72 hours for 730
days developed chromophobe adenomas of the pituitary
gland, a tumor with a rare spontaneous incidence.
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE.
http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm
Heart
(click
on for all fluorinated pesticides)
Organophosphate
esters were studied in terms of their ability to affect neuropeptides
in the rat central nervous system. The in vivo biosynthesis of
enkephalin peptides in the basal ganglia and of vasopressin and
oxytocin in the hypothalamus were studied and the effect of subcutaneous
administration of diisopropylfluorophosphate (DFP) in the biosynthesis
of these neuropeptides was assessed. It
was found that DFP inhibited the biosynthesis of vasopressin and
oxytocin. These results suggest that organophosphates exert their
effects not only on cholinergic systems but also on neuropeptide
systems important in endocrine and cardiovascular function. Annual
rept. 1983-1984, {abstgract truncated]
Ref:
1986 - Effects of Organophosphate Esters on Neuropeptide Systems;
by McKelvy JF. Report No. NTIS/AD-A186 594/8 from The National
Technical Informatin Service.
Sciatic
Nerve (click
on for all fluorinated pesticides)
A number of organophosphates produced delayed neurotoxicity in
man which may be modeled ... in several animal species ... /such
as/ the adult hen Gallus domesticus. The development of delayed
neurotoxicity was studied in adult white Leghorn hens after a
single, oral dose (1.0 mg/kg) of diisopropylfluorophosphate and
after the administration of repeated low-level oral doses (125
mug/kg, 5 days/wk; 1.0-5.0 mg/kg, total dose) of DFP. The relationship
of dosage, time, and frequency of administration of subneurotoxic
doses of DFP under conditions of a multiple-dose procedure was
examined. The comparative activities of hen brain and
sciatic nerve neurotoxic esterase (NTE) were studied. The
percentage inhibition of NTE paralleled the incr in the degree
of severity of the acute pharmacological response. The chronic
dosing regimen resulted in a small, yet definite, inhibitory effect
of DFP on brain NTE and cholinesterase activities. A maximum level
of brain NTE inhibition occurred followed by a decrease and eventual
leveling off of the inhibitory effect. The comparative NTE studies
demonstrate that substrate hydrolysis by hen sciatic nerve preparations
was considerably less when compared with hen brain extracts using
equivalent tissue weights. The percentage of NTE of the total
paraoxon-resistant activity was lower in sciatic
nerve preparations compared with brain preparations. The
effects of DFP on the NTE activities from brain and sciatic nerve
preparations were definitely inhibitory, and quantitative
differences exist between NTE content and activity in peripheral
and central nervous systems.
[Olajos EJ et al; Ecotoxicol and Environ Safety 2 (3-4): 383-399
(1978)]
-- ... The results show that DFP ... initially
increases rat sciatic nerve conduction and reduces refractoriness.
Continued exposure had a diminished effect with nerve excitability
eventually returning to control. During recovery, the nerve membrane
responsiveness to potassium-induced depolarization significantly
changed in a manner which would indicate either decreased Na,
K-ATPase activity, or decreased potassium ion transmembrane flux.
The data suggest that compensatory changes occcur in rat nerve
in response to organophosphorus exposure, and further, that these
compensatory changes involve alteration in membrane ion fluxes.
[Anderson RJ, Dunham CB; Arch Toxicol 58 (2): 97-101 (1985)]
Ref: TOXNET Hazardous Substances Data Base. DIISOPROPYL
FLUOROPHOSPHATE CASRN: 55-91-4
http://www.fluoridealert.org/pesticides/isofluorphate-toxnet.htm
NOTE FROM FAN: While DFP was found not to be a teratogen in rat
studies, we include this abstract for whatever its worth - EC.
Teratogenic (click
on for all fluorinated pesticides)
Abstract:
Many organophosphorus (OP) insecticides are teratogenic to vertebrates,
acting on acetylcholineesterase, kynurenine formamidase, and possibly
other serine esterases. We sought to identify their protein targets
in the yolk sac membrane (YSM) and
to correllate their OP binding with developmental changes. OP
compounds with different teratogenic potentials were administered
to chicken eggs at day 4 and the eggs were incubated to day 10
when the YSMs were removed and homogenized. Cell
free extracts were prepared and incubated with [3H]diisopropyl
fluorophosphate. The reaction mixture was then boiled with
sodium dodecylsulfate (SDS) and beta-mercaptoethanol and the proteins
in it were resolved by SDS PAGE. The gels were fixed, stained
and either autofluorographed or sliced and the amount of radioactivity
in each slice was determined. There were
3 major DFP-binding proteins in the YSM,
#1 94 KD; #2
83 KD; #3 72 KD, accounting for 8,
4 & 88% of the DFP binding, respectively. Pretreatment
of the embryos with 1.6 umole/egg of EPN, a mildly teratogenic
insecticide, completely suppressed DFP
binding to peak 3 but suppressed binding
to peaks 1 & 2
only 50%. An equal amount of diazinon, a highly teratogenic
insecticide, suppressed binding to peak 3 by 50% and to peaks
1 & 2 by 80%. These and other findings suggest that OP binding
to peak 3 does not have teratogenic implication but binding to
peaks 1 & 2
does.
Ref:
Yolk sac membrane targets of the organophosphorus insecticides;
by Suntornwat O, Kitos P. FASEB J 1990;4(7):A2051
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