The Toxicologist - Society of Toxicology

1075 CARBON MONOXIDE TOXICITY AND THE
MATERNAL-FETAL ENVIRONMENT.
T. Dodd-Butera 1 and M. Broderick 2 . 1 Nursing, California State University San
Bernardino, College of Natural Sciences, San Bernardino, CA and 2 California Poison
Control System, San Diego, CA.
Carbon monoxide (CO) exposure to the maternal-fetal environment has been
linked to preterm delivery, malformation, and fetal demise. National Poison Data
System (NPDS) Information reports approximately 35,000 pregancy-related cases
in the United States, with California cases accounting for approximately 10% during
years 2004-2007. This was an IRB-approved retrospective review of 3805 pregnancy-related
cases, with 77 cases of CO exposure; recorded from the California
Poison Control System (CPCS), years 2004-2007. In cases of exposure where maternal
age was known, all but 3 cases were 20 years and older. Carboxyhemoglobin
(COHb) levels were done on 22 of the CO-exposed cases, with oxygen therapy administered
in 13 cases, and Hyperbaric oxygen (HbO) performed in 3 cases.
COHb levels in two of the three cases administered HbO were recorded at 21%
and 25% and both were in the 2nd trimester. The third case was in the first
trimester, with a COHb level of 13%. Initial short-term follow-up indicated maternal
and fetal well-being, but follow-up to birth was not noted in any of the cases.
Previous toxicology studies in animal models have indicated adverse cardiac and
neurologic potential post-exposure to CO during gestation. A recommendation for
a revised follow-up clinical toxicology protocol unique to pregnancy could be considered
by poison centers, in order to improve outcome measurements and add to
the body of scientific knowledge regarding in utero exposures in humans; particulary
those substances with teratogenic potential. This would improve the quality of
toxicology data for human exposures to CO during pregnancy.
1076 CHARACTERIZATION OF A NOVEL SERIES OF
ENDOTHELIN-A RECEPTOR ANTAGONISTS IN THE
SETTING OF INFECTION ASSOCIATED PRETERM
BIRTH.
N. S. Olgun, H. J. Patel, R. A. Stephani and S. E. Reznik. Pharmaceutical
Science, St. John’s University, Jamaica, NY.
Clinically defined as any birth occurring prior to 37 weeks’ of gestation, preterm
birth (PTB) accounts for approximately 13% of all live births in the United States
each year and is a leading cause of infant mortality. Endothelin-1 (ET-1) is a potent
vasoconstrictor peptide which is upregulated by inflammatory cytokines and is capable
of causing an increase in myometrial tone. In the setting of infection in pregnancy,
ET-1 has been shown to be up-regulated, ultimately leading to PTB. In our
previous work, we have shown that our novel series of 1-3-6-trisubstituted-2-carboxy-quinol-4-ones
act as selective Endothelin-A receptor antagonists (ET A-RAs).
In particular, HJP-272, the prototype compound, binds to the ET A receptor with
an IC 50 value of 70.1nM in a non-competitive manner. We have also shown that
in the animal model, HJP-286, the n-propyl analogue, and HJP-272 successfully
shut down PTB. Concern for the clinical utility of these compounds as tocolytic
agents is based on their potential teratogenic effects. Therefore, in the current work,
we investigate whether or not there are any chronic histological changes taking
place in the animal model following exposure to these agents. C57Bl/6 mice are injected
with either phosphate buffered saline, vehicle(dH20 with KOH and
K2CO3), or HJP-272, HJP-286 or HJP-278 (n-butyl analogue). Animals are observed
for ten days and then sacrificed. All vital organs are harvested, processed, and
observed using light microscopy to assess specific organ toxicity. Previous acute toxicity
studies in which the animals were sacrificed after 24 hours showed no difference
between control and treated animals. From these studies, we can conclude that
not only do our compounds have a high affinity for the ET A receptor, but they
also prevent PTB at doses in which we see no toxicity in the mother. It is our hope
that these compounds may one day affect the way pregnant women presenting with
PTB are treated, as there is currently no FDA approved therapy for this very important
clinical disorder.
1077 AFFECTS OF ALCOHOL CIRRHOSIS AND DIABETES ON
DRUG TRANSPORTER EXPRESSION IN HUMAN LIVER.
V. R. More 1 , Z. Lu 2 , N. Cherrington 3 and A. Slitt 1 . 1 Biomedical and
Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 2 Statistical
Consulting Laboratory, University of Arizona, Tucson, AZ and 3 Department of
Pharmacology and Toxicology, University of Arizona, Tucson, AZ.
Transporters are important for the uptake and excretion of many drugs and environmental
chemicals in the liver. While alterations in the expression of these transporters
would have profound effect on the fate of numerous compounds within the
body, limited data exists regarding the effect of important types of liver injury on
230 SOT 2011 ANNUAL MEETING
transporter expression in human liver. Diabetes and alcohol-induced liver cirrhosis
are two major liver injuries that are present in the American population. Insulin levels
are often elevated in alcoholism, with chronic alcoholism resulting in diabetes.
Because there is a sizable population that presents with these diseases alone or in
combination, it is important to determine the effect of diabetes, cirrhosis, or diabetes
and cirrhosis on transporter expression in human liver. Therefore, drug transporter
and nuclear hormone receptor mRNA expression in normal, diabetic, cirrhotic
and diabetic-cirrhotic human livers was quantified. Target gene fluorescence
intensity was normalized to hypoxanthine phosphoribosyl transferase-1 fluorescence
intensity, and data was log transformed followed by MANCOVA. Cirrhosis
significantly increased ABCC4, 5, ABCG2 and SLCO2B1 mRNA expression, and
decreased SLCO1B3 mRNA expression in liver. Interestingly, in the livers of subjects
with both diabetes and cirrhosis, transporter expression did not differ from
controls, except for ABCC4. Cirrhosis and diabetes-cirrhosis increased NRF2
mRNA expression, and decreased PXR and FXR mRNA expression in liver compared
to livers of normal subjects. Hierarchical cluster analysis indicated that expressions
of ABCC2, 3 and 6; SLCO1B1 and 1B3; and ABCC4 and 5 are more
closely related. Overall, significant cirrhosis, and cirrhosis-diabetes effects on transporter
mRNA expression in human liver were revealed (The Rhode Island foundation,
NIH 5K22ES013782).
1078 PERINATAL BISPHENOL A (BPA) EXPOSURE ALTERS
LIVER ATP-BINDING CASSETTE (ABC) TRANSPORTER
EXPRESSION IN MICE.
A. C. Donepudi 1 , M. Meloon 1 , P. T. Sieli 3 , C. S. Rosenfeld 2 and A. L. Slitt 1 .
1 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island,
Kingston, RI, 2 Department of Biomedical Sciences, University of Missouri, Columbia,
MO and 3 Bond Life Sciences Center, University of Missouri, Columbia, MO.
BPA is a chemical produced in voluminous amounts in manufacturing of plastic
and paper products. BPA exposure is pervasive. Perinatal BPA exposure alters gene
expression in liver, but it is not clear whether these alterations are epigenetic or estrogenic
in origin. ATP-binding cassette (Abc) transporters are efflux transporters,
which efflux endogenous chemicals (e.g. conjugated hormones, leukotrienes) and
xenobiotics. The purpose of this study was to investigate whether in utero (prenatal)
BPA exposure affects liver Abc transporter expression. Female a/a (C57BL/6)
mice were exposed to BPA through the diet (50 μg/kg or 50 mg/kg) or AIN93
Control diet with 7% corn oil from 2 weeks pre-mating with male Avy/a mice. BPA
exposure was maintained through the breeding and lactation period. Pups were
weaned on postnatal day (PND) 21 and maintained on the AIN93 control diet.
Livers were collected from offspring after PND 135, total RNA was isolated, and
Abcc 1-6, Abcg2, and Abcb1a was analyzed by qPCR. BPA perinatal exposure decreased
hepatic Abcc2, Abcg2, and Abcb1a mRNA transporter expression in both
male and female offspring at both concentrations. In contrast, BPA exposure increased
Abcc4 expression in daughters exposed in utero to the 50μg/kg maternal
diet BPA concentration, whereas BPA decreased Abcc4 expression in livers of sons
at both concentrations. BPA exposure decreased Abcc6 expression in livers of sons,
but not daughters. BPA perinatal exposure altered Abc transporter mRNA expression
in liver. These data suggest that in utero BPA exposure might exert detrimental
effects on offspring health by altering the expression of genes that are known to mediate
the transport conjugated hormones and inflammatory mediators.
(5R01ES016042, 3R01ES016042-02S1)
1079 OPPOSING EFFECTS OF DIABETES AND PREGNANCY
ON HEPATOBILIARY EFFLUX TRANSPORTER
EXPRESSION.
A. L. Slitt 1 , J. Xu 1 and L. M. Aleksunes 2 . 1 Biomedical and Pharmaceutical Sciences,
University of Rhode Island, Kingston, RI and 2 Pharmacology and Toxicology, Rutgers
University, Piscataway, NJ.
Efflux transporters are plasma membrane proteins responsible for excreting chemicals
and toxicants from the cell. In the liver, efflux transporters including the multidrug
resistance-associated proteins (Mrps) are markedly induced in mice with diabetes.
In contrast, other conditions such as pregnancy have been shown to decrease
hepatic Mrp levels. Altered expression of efflux transporters influences not only the
hepatic clearance of chemicals, but also susceptibility for hepatotoxicity. The purpose
of the present study was to quantify the mRNA expression of hepatobiliary efflux
transporters in pregnant, diabetic mice. Female C57BL/6 mice were treated
with vehicle or streptozotocin (STZ, 50mg/kg/d for 4 days). Once STZ-treated
mice exhibited elevated glucose levels (>250 mg/dl) for 2 weeks, they were mated
with normoglycemic male C57BL/6 mice until plugged (designated as gestation
day 0). Total RNA was isolated from livers of nonpregnant and pregnant female
mice (gestation day 14) with normal or elevated glucose levels. Messenger RNA expression
was quantified by qPCR. Blood glucose levels were similarly elevated in