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agents appear to contribute to diseases that occur later Polymerase chain reaction analysis was utilized to
in life. [15-18] Osmond and Barker have suggested (and determine the genotype of the animals as previously
this has been supported by others) that there are critical described. [27] All experimental mice were male. Mice
periods during fetal development where programming were given free access to food and water before and
by a stimulus or insult has a lasting or lifelong effect. [19] during the experiment.
We know that various tissues, including the brain, go
through developmental programming to determine Treatment of mice
the number of cells (programmed cell death), types Amyloid precursor protein transgenic mice were
of cells, that participate to the final development treated with CPO administered orally, dissolved in
of the brain. [20] It has been suggested that exposure corn oil. During a preexperimental phase, all females
of tissues to insults at critical times could result in were trained to drink corn oil from a syringe, to ensure
reprogramming to give rise to diseases later in life. [18] It proper administration of the vehicle and also to reduce
has been suggested that exposure of the brain to toxic stress associated with handling and exposure to a new
agents triggers a process that will elicit the onset of stimulus. Following this training period, the females
AD, reprogram the brain to have AD start at an earlier were paired with APP males in segregated cages, for up
age, or to exacerbate the process of AD. [21] This can be to a week, in order for mating to occur. The appearance
achieved by a number of ways. Metabolic, blood flow, of vaginal plugs was taken as evidence of successful
endocrine, nutritional changes can affect blood lipids, insemination, at which time the females were separated
plasma insulin, obesity, atherosclerosis, behavior and from the males and placed in single housing in cages.
learning in small mammals and primates. [21-23] The Each female was randomly assigned to one of six
application of this process to AD has been recently CPO (Chem Service, West Chester, PA; 99.1% pure)
suggested and demonstrated in the latent early-life dose groups: oil vehicle (at each time), 1 mg/kg bw/
associated regulation model. [24,25] day for 3-week during gestation, 1 mg/kg bw/day
for 3-week during lactation, and 1 mg/kg bw/day
This study evaluated the effects of the pesticide starting at 2 months of age. For the gestation and
chlorpyrifos oxon (CPO) on the development of AD lactation groups there were 6 females in each group;
later in life. To test this hypothesis, we determined the this was done to ensure that potential dose effects
influence of CPO on AD by treating APP transgenic could not be confounded with individual variation
mice during gestation, during lactation and after associated with a single dam and to provide sufficient
weaning. Our data showed that CPO exacerbated the numbers of offspring for statistical analysis. There
pathogenesis of AD in the mouse model and that this were no differences in weight or reduced locomotor
process may be partially mediated by inflammation and activity following treatment (data not shown). Animal
by the effects of CPO on acetylcholinesterase (AChE) studies were conducted according to regulations by the
inhibition. These findings validate the influence National Institutes of Health and as approved by the
of environmental toxins on the development and Institutional Animal Care and Use Committee at the
progression of AD. Medical University of South Carolina and Ralph H.
Johnson VA Medical Center.
METHODS
Age of mice for analysis of memory deficits and biomarkers
Transgenic Alzheimer’s disease mice Memory function, amyloid plaque and brain biomarkers
The mice used for these studies expressed the mutant were evaluated after significant memory deficits
form of human presenilin-1 (DeltaE9) and the mutant developed in the AβPP mice.
form of the chimeric mouse/human APP695. [26] The
mouse prion protein promoter directed the expression Spatial memory deficit
of both transgenes. The DeltaE9 mutation of the human The memory deficit in the animals was measured
presenilin-1 gene is a deletion of exon nine and by the Morris water maze test as we have described
corresponds to a form associated with early-onset AD. previously. [27,28] Briefly, the spatial memory capability
The APP695 gene harbors the K595N/M596L (Swedish) of each animal was assessed with the Morris water
AD-causing mutations. The coding sequence of mouse maze test (700-0718-4 W San Diego (SD) instruments)
Aβ peptide domain was humanized by replacing the which evaluates memory in a swimming test. Mice were
three amino acids that differ between the two species individually trained in a 1.2 m open field water maze in a
with the human residues. These APP/ΔPS1-Tg (referred pool filled with water to a depth of 30 cm and maintained
to as APP) mice start developing amyloid plaques at 25 °C. An escape platform (10 cm square) was placed
at about 3-4 months of age. These mice were on a 1 cm below the surface of the water. All animals
C57BL/6J background. underwent nonspatial pretraining for 4 consecutive days,

32 Neuroimmunol Neuroinflammation | Volume 2 | Issue 1 | January 15, 2015