The Toxicologist - Society of Toxicology

nificantly reduce circulating thyroid hormones. Imaging studies implicate the corpus
callosum and the cerebellum in the pathophysiology of ADHD with the later
structure contributing to the control of cognitive function. We asked whether gender
and PCB exposure interact to alter the developmental trajectory of oligodendrocyte
precursor cells (OPCs) in the cerebellum into either oligodendrocytes, by
measuring myelin basic protein (MBP), or astrocytes, by measuring glial fibrillary
acidic protein (GFAP). We exposed timed pregnant Long Evans dams to PCBs
from gestational day 6 until weaning and obtained (i) sera for measurement of circulating
thyroxine (T4) and IL-6 levels, the latter implicated in white matter development,
and (ii) cerebellar tissue from both male and female offspring at 7, 14, 21
and 42 days of age. Although PCBs significantly reduced T4 levels, they did so
equally in male and female offspring. Both IL-6 and cerebellar MBP levels were significantly
elevated only in males. While cerebellar GFAP levels were lower in PCB
exposed males and higher in females. These data demonstrate that PCBs alter IL-6
and differentiation of OPCs in a sex specific manner leading to greater expression
of cerebellar MBP in males and GFAP in females. These findings may aid in understanding
the role of environmental contaminants in the etiology of ADHD and
elucidate potential mechanisms responsible for the greater incidence of ADHD in
boys. Future studies will examine interactions between thyroidal and gonadal hormones
and cytokines in the etiology of ADHD and related disorders. Supported in
part by NIEHS grant ES015688-01 to RFS.
2601 PRE-PULSE INHIBITION AND THE STARTLE
RESPONSE IN GENETICALLY DIFFERENT PCB-
TREATED MICE.
C. P. Curran, B. Hays, E. Altenhofen, R. Floyd and A. Mynhier. Biological
Sciences, Northern Kentucky University, Highland Heights, KY.
Polychlorinated biphenyls (PCBs) are ubiquitous industrial chemicals banned in
the 1970s due to their wide-ranging toxicity. Children exposed in utero and lactationally
have a higher risk of learning, memory, behavioral and auditory deficits.
The goal of our research is to identify genes which affect susceptibility to these pervasive
pollutants. The liver enzyme CYP1A2 can sequester toxicants such as dioxins
and coplanar PCBs. The aryl hydrocarbon receptor (AHR) binds dioxins and coplanar
PCBs, initiating transcription of several genes including CYP1A2. Rodent studies
have demonstrated that Cyp1a2(+/+) and poor-affinity Ahr d mothers can protect
their offspring from developmental dioxin and PCB exposure compared with
Cyp1a2(-/-) knockout and high-affinity Ahr b1 mice. Our previous research found
genetic differences in the Acoustic Startle Response in PCB-treated mice when
comparing three mouse lines varying at the Ahr and Cyp1a2(-/-) loci. Our current
work extends those findings by using a newly developed mouse line, Ahr d Cyp1a2 (-
/-), and the background strain Ahr b1 Cyp1a2(+/+) as a comparison group. Pregnant
dams were treated at gestational day 10.5 (GD10.5) and postnatal day 5 (PND 5)
with an environmentally relevant mixture of PCBs or the corn oil vehicle. Offspring
were tested at 60 days of age. We measured the baseline startle response to a 110db
stimulus and examined pre-pulse inhibition (PPI) using pre-pulse tones of 74 and
76db. There was a trend toward significance for a genotype x treatment interaction
(P=0.073) with PCB-treated Ahr d Cyp1a2 (-/-)mice showing an enhanced baseline
startle response. All groups showed normal sensorimotor gating; however, PCBtreated
Ahr d Cyp1a2 (-/-)mice had significantly reduced pre-pulse inhibition at the
74dB level compared with corn oil treated controls. The knockout mice also had
significantly reduced pre-pulse inhibition compared with wild type mice under
both the 74db (P