The Toxicologist - Society of Toxicology

2147 CATALASE MANIPULATIONS MODIFY VOLUNTARY
ETHANOL INTAKE IN DEVELOPMENTALLY LOW-
LEVEL LEAD EXPOSED RATS.
M. Virgolini, M. S. Mattalloni and L. M. Cancela. IFEC CONICET Department
. de Farmacologia., Fac. de Ciencias Quimicas. Universidad Nacional de Cordoba,
Cordoba, Argentina.
Lead (Pb) is a developmental neurotoxicant that modify several responses to drugs
of abuse. We have demonstrated that low-level Pb-exposed rats showed increased
ethanol (ET) consumption in a limited free-choice paradigm compared to their
control counterparts. The current study sought to investigate the role of catalase
(CAT) on ET intake, being CAT an enzyme implicated in both, brain ethanol metabolism,
and Pb-induced anti-oxidant defense system. We postulate that concomitant
exposure to Pb and ET would stimulate CAT activity leading to the higher ET
intake observed in developmentally Pb-exposed animals. Thirty-five day old animals
exposed to 220 ppm Pb during gestation and lactation were evaluated in their
voluntary ethanol intake during 2 h for 28 days according to the following scheme:
days 1-4: ET 2%; days 5-8: ET 4%; days 9-12: ET 6%; days 13-16: ET 8%; days
17-20: ET 10%. After stable 10% ET consumption was achieved, all rats were injected
with: 1) vehicle (saline); 2) an inhibitor of CAT activity: AT, 3-amino 1,2,4
triazole (0.25 mg/kg i.p.) 5 h before the onset of the daily ET choice session (days
21-28), or 3) an activator of CAT activity: 3-NPA, 3 nitropropionic acid (10, 20,
and 30 mg/kg s.c.) 90 min before the corresponding ET choice session (days 25-
28). Immediately after the last free-choice session, all rats were sacrificed and several
brain regions harvested to measure brain CAT activity. Blood was also collected to
measure CAT activity, Pb, and ET levels. A 35-day-old and a 70-day-old group that
have not consumed ethanol were included. We demonstrated that pretreatment
with AT blunted, whereas 3NPA (20 mg/kg) further increased the higher voluntary
ET intake previously observed in Pb-exposed rats. Corresponding changes were observed
in blood and brain CAT activity. These results emphasize the importance of
CAT as an antioxidant enzyme and a key component of brain ET metabolism, ascribing
a critical role for acetaldehyde in Pb-induced ET reinforcing effects.
2148 WATERBORNE MANGANESE EXPOSURE ALTERS
STEREOTYPIC BEHAVIORS AND PLASMA
METABOLITES IN DEVELOPING RATS.
S. C. Fordahl 1 , P. Cooney 1 , Y. Qiu 2 , G. Xie 2 , W. Jia 2 and K. Erikson 1 .
1 Nutrition, University of North Carolina at Greensboro, Greensboro, NC and
2 Nutrition, University of North Carolina at Greensboro, North Carolina Research
Campus, Kannapolis, NC.
Symptoms of manganese (Mn) neurotoxicity appear as Mn accumulates in the
basal ganglia (notably the striatum and globus pallidus (GP)), but to date no reliable
biomarkers have been identified to correspond with early Mn neurotoxicity.
The purpose of this study was to identify plasma metabolites that correlate with GP
and striatal Mn accumulation and the onset of stereotypic behavioral changes.
Twenty-one day old rats exposed to 1g Mn/L (as MnCl2) drinking water for six
weeks were monitored for stereotypic behaviors over a 24hr period using video surveillance
in their home-cage environment. This surveillance protocol is advantageous
to accurately capture behavior abnormalities that persist under “normal living”
conditions. At the end of the study, plasma, GP and striatal samples were
analyzed for Mn, iron, and metabolomic data. Pearson’s correlations were made between
these data and total distance traveled (TDT), turn, sniff, rear, and grooming
resulting in several significant relationships linking Mn to these behaviors. Plasma
Mn was significantly correlated with GP Mn (r=0.455, p=0.025), TDT (r=0.459,
p=0.024), and repetitive turning (r=0.589, p=0.002), but not striatal Mn. Striatal
Mn was only linked to the plasma iron:Mn ratio (r=-0.439, p=0.032), which also
was a stronger predictor of TDT and turn behavior. Similarly, TDT was significantly
associated with GP and striatal Mn, but turning was only linked to GP Mn.
Significant associations between, GP Mn, TDT and repetitive turning also emerged
with several plasma metabolites; most notably, homogentisic acid (r=0.603,
r=0.420, and r=0.598, respectively), an indicator of tyrosine metabolism. These
data reveal that relationships between plasma Mn, GP Mn, plasma metabolites and
altered stereotypic behaviors can lead to the identification of reliable biomarkers of
Mn neurotoxicity.
Funded by: NINDS 1R15NS061309-01
2149 PRE-WEANING MN EXPOSURE LEADS TO
PROLONGED ASTROCYTE ACTIVATION AND
LASTING EFFECTS ON THE DOPAMINERGIC SYSTEM
IN ADULT RATS.
C. Kern and D. R. Smith. Environmental Toxicology, University of California, Santa
Cruz, CA.
Little is known about the effects of manganese (Mn) exposure over neurodevelopment
and whether these early insults result in effects lasting into adulthood. To determine
if early Mn exposure produces lasting neurobehavioral and neurochemical
effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND
1–21) and evaluated 1) behavioral performance in the open arena in the absence
(PND 97) and presence (PND 98) of a d-amphetamine challenge, 2) brain
dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal
cortex, striatum, and nucleus accumbens (PND 107), and 3) astrocyte
marker glial fibrillary acidic protein (GFAP) levels in these same brain regions
(PND 24 and 107). We found that pre-weaning Mn exposure did not alter locomotor
activity or behavior disinhibition in adult rats, though Mn-exposed animals
did exhibit an enhanced locomotor response to d-amphetamine challenge. Preweaning
Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens
and prefrontal cortex, respectively, compared to controls. We also found
increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings,
and increased GFAP levels in prefrontal cortex, medial striatum and nucleus
accumbens of adult (PND 107) rats exposed to pre-weaning Mn, indicating an effect
of Mn exposure on astrogliosis that persisted and/or progressed to other brain
regions in adult animals. These data show that pre-weaning Mn exposure leads to
lasting molecular and functional impacts in multiple brain regions of adult animals,
long after brain Mn levels returned to normal.
2150 EFFECTS OF PERINATAL LEAD EXPOSURE ON
LEARNING AND MEMORY ARE MODIFIED BY SEX
AND REARING CONDITION.
K. Pothakos, D. Anderson, R. Schray, L. Walinchus and J. Schneider. Pathology,
Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
Recent clinical data suggest that gender and environment may act as modifiers of
the association between lead (Pb) exposure and neuropsychological outcome.
However, the influences and potential interactions between these factors on behavioral
outcome from developmental Pb exposure has received little attention experimentally.
Thus, the present study was performed to examine the influence of these
factors on behavioral outcome of rats exposed to different levels of Pb during development.
Dams were fed Pb-containing food for 10 days prior to breeding and remained
on the same diet through weaning. Pups were weaned onto control food
without Pb. At weaning, animals were either housed 3 to a cage with no added toys
(social/impoverished) or 6 to a larger cage with added toys that were changed every
3rd day (enriched). At day 55, males and females were assessed for spatial learning
and reference memory in a Morris water maze. There was a significant effect of environment
on learning in both males and females with control enriched animals
performing significantly better than control impoverished animals. In females, enrichment
overcame the detrimental effects of Pb on learning at all but the highest
level of Pb exposure. In males, enrichment had no effect at the lowest level of exposure
but counteracted effects of Pb at higher exposure levels. Enriched females at all
but the highest level of Pb exposure performed better on probe tests (eg. percent of
time in platform/target area) than matched impoverished animals. In males, enrichment
only had an effect on probe performance in the highest Pb exposure group.
These data suggest that there are complex interactions between gender, rearing environment,
and developmental Pb exposure on behavioral outcomes and that these
relationships need to be studied in greater detail spanning different exposure paradigms
and cognitive functions. Supported by ES015295.
2151 A MOUSE MODEL OF Pb-STRESS INTERACTIONS AT
BLOOD Pb < 10 μg/dl.
K. Merchant-Borna, S. Liu, D. Weston and D. A. Cory-Slechta. Department of
Environmental Medicine, University of Rochester School of Medicine, Rochester, NY.
Lead (Pb) exposure and psychological stress are co-occurring risk factors that preferentially
target low SES communities. Both act on the brain mesocorticolimbic
dopamine system and the hypothalamic pituitary-adrenal (HPA) axis. Stress hormones
impact brain dopamine systems and can thereby influence associated behaviors.
Previous studies have demonstrated persistent interactions in rats of both maternal
and continuous Pb exposure with prenatal stress in offspring of both genders.
The current study extended these observations to a mouse (C57BL/6J) model to
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