The Toxicologist - Society of Toxicology

2605 CO-EXPOSURE TO RADIATION AND
ENVIRONMENTAL TOXICANTS (PBDE 99 AND MEHG)
DURING A DEFINED CRITICAL PHASE OF NEONATAL
BRAIN DEVELOPMENT ENHANCES COGNITIVE
DEFECTS IN ADULT MICE.
P. Eriksson1 , B. Stenerlöw2 , A. Fredriksson1 and S. Sundell-Bergman3 .
1Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden,
2Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University,
Uppsala, Sweden and 3Department of Soil and Environment, Swedish University of
Agricultural Sciences, Uppsala, Sweden.
Organisms, including man, are continuously exposed to low doses of ionizing radiation
(IR) as well as to environmental toxicants. Hence, in the process of developing
numerical limits for environmental protection, there is a strong need to consider
interactive effects between radiation and other environmental stressors. It is
known that exposure to IR during gestation can cause developmental neurotoxic effects
in mammals. Animal studies have shown that flame retardants, polybrominated
diphenyl ethers (e.g. PBDE 99), and methyl mercury (MeHg) can cause developmental
neurotoxic effects. Today there is a lack of knowledge concerning
effects and consequences from low-dose exposure to IR during neonatal brain development
and its interaction with environmental chemicals. Epidemiological studies
have indicated that IR exposure to the brain during infancy might deteriorate
cognitive ability in adulthood. Ten-day old neonatal NMRI male mice were exposed
to a single oral dose of PBDE 99 (2,2’,4,4’,5-pentabromodiphenyl ether)
(0.8 mg/kg bw) or MeHg (0.40 or 4.0 mg/kg bw). Four hours after this exposure
the mice were irradiated with 60Co gamma radiation at doses of 0,2 and 0,5 Gy.
The animals were observed for spontaneous behaviour at the ages of 2- and 4months,
and swim maze performance at the age of 5 months. Neither the single
dose of PBDE 99 (0.8 mg/kg bw), MeHg (0.4 mg/kg bw) nor the radiation dose of
0.2 Gy affected the spontaneous behaviour, but co-exposure to IR and PBDE 99 or
MeHg caused developmental neurobehavioural defects. The study shows that coexposure
to IR and environmental toxicants like PBDE 99 and MeHg, during a
critical period of neonatal brain development, significantly enhance developmental
neurobehavioural defects and with consequence for adult cognitive functions.
2606 PERINATAL EXPOSURE OF MICE TO DIOXIN
INDUCES DEPRESSION-LIKE BEHAVIOR IN A LOW-
DOSE SPECIFIC MANNER.
A. Haijima, Y. Zhang, T. Endo, M. Kakeyama and C. Tohyama. Laboratory of
Environmental Health Sciences, Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
The goal of our study is to characterize and clarify the mechanism of developmental
neurotoxicity of dioxins. In our recent studies, deficits in fear memory were observed
in mice exposed to dioxins in a dose-dependent manner (e.g., Haijima et al.,
2010), and that the impaired learning and enhanced perseverative behavior were induced
in a low-dose-specific manner (Endo et al., 2010). Here, we studied the effects
of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on depression-like behaviors
as well as its dose-response relationship in mice. Pregnant C57BL/6 mice were administered
TCDD by gavage at a dose of 0, 0.6 or 3.0 μg/kg b.w. on gestational day
12.5. The TCDD dose is approximately 1/300 or 1/60 of the LD50 value. After the
mice reached adulthood, they were subjected to a forced swim test (FST) to examine
emotional stress responses. The plasma corticosterone level was measured by
ELISA at 0, 30 and 120 min after the FST. In the FST, mice perinatally exposed to
0.6 μg TCDD/kg b.w. showed a significantly shorter latency to become immobile
and a significantly longer duration of immobility than the control mice, particularly
in the first 2 min of the FST, while mice exposed to 3.0 μg TCDD/kg b.w.
showed profiles almost indistinguishable from those of the control mice. In addition,
mice exposed to 0.6 but not 3.0 μg TCDD/kg b.w. showed high plasma corticosterone
level just after the FST. These results suggest that perinatal exposure of
mice to TCDD induces depression-like behavior in mice in a low-dose-specific
manner.
2607 ASSESSING LATER-LIFE BEHAVIORAL PHENOTYPES
IN RESPONSE TO PRENATAL EXPOSURE TO
BENZOPYRENE.
M. M. McCallister1 , M. Maguire2 , A. Ramesh3 and D. B. Hood4 . 1Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 2Neuroscience and
Pharmacology, Meharry Medical College, Nashville, TN, 3Biochemistry and Cancer
Biology, Meharry Medical College, Nashville, TN and 4Neuroscience and
Pharmacology, Meharry Medical College, Nashville, TN.
Benzo(a)pyrene is an environmental contaminant that is a member of the polycyclic
aromatic hydrocarbon (PAH) family. It was reported that environmental levels
encountered in the air of New York City can affect child IQ scores adversely.
558 SOT 2011 ANNUAL MEETING
These results are comparable to that reported for low-level lead exposure. The hallmark
of lead exposure in studies involving children and animals is behavioral
deficits. Since in animal studies the most common way to study adverse effects of
lead on behavior is operant conditioning, we have used this same behavioral technique
in the present study. Animal model studies have shown that prenatal exposure
to PAH’s causes behavioral deficits accompanied by a downregulation of glutamate
receptor subunits. This reduction is postulated to be correlated with
impairments in neuronal activity in later life. In this study, we hypothesize that prenatal
exposure to benzo(a)pyrene results in deficits in behavioral learning. Timedpregnant
Long Evans Hooded rats were orally exposed to 0, 150, 300, 600 or
1200μg/kg of B(a)P by oral gavage. The disposition of B(a)P to fetal brain was
quantified as a function of exposure (E14-E17) during peak periods of neurogenesis
for cerebral cortex and hippocampus. Beginning on P90, offspring pups were
habituated and tested in a discrimination reversal-operant behavioral paradigm.
The results demonstrate a dose-dependent decrease in the ability to learn the reversal
task with associated decreases in correct responses and an enhancement in incorrect
responses in the exposure cohort. Taken together, these studies provide mechanistic
insights into how in utero polycyclic aromatic hydrocarbon exposure
contributes to adverse neurobiological outcomes.
Supported in part by U54NS041071, S11ES014156, T32MH065782, and
RRO3032.
2608 DEVELOPMENTAL IODIDE DEFICIENCY:
REDUCTIONS IN THYROID HORMONES AND
IMPAIRED HIPPOCAMPAL TRANSMISSION.
M. Gilbert 1 , J. Hedge 1 , R. Zoeller 2 , K. Kannan 3 , K. Crofton 1 , L. Valentin-
Blasini 4 , B. Blount 4 and J. Fisher 5 . 1 U.S. EPA, Research Triangle Park, NC,
2 University of Massachusetts, Amherst, MA, 3 New York Department of Health,
Albany, NY, 4 CDC, Atlanta, GA and 5 U.S. FDA, Little Rock, AR.
Iodine (I) is essential for thyroid hormone (TH) synthesis, and severe iodine deficiency
(ID) during development produces neurological impairments. ID may exacerbate
the effects of environmental chemicals on the thyroid axis. This study examined
graded levels of ID during pregnancy on the thyroid axis, neurobehavior, and
hippocampal electrophysiology in exposed offspring. Female LE rats were placed on
diets with varying degrees of ID for 6 wks prior to breeding. I was added to a casein-based
diet to produce 5 levels from adequate (>200 ng/gm) to deficient (