The Toxicologist - Society of Toxicology

flammation and xenobiotic metabolism highlighting a range of responses expected
from individuals. The Comparative Toxicogenomics Database was used to identify
gene-chemical interactions for those genes altered by aging. A number of chemical
categories were identified that would be predicted to induce different levels of effects
in young and old individuals. Overall, these studies indicate that there are
major species differences in the profiles of XMEs affected by aging that could impact
chemical toxicity. (This abstract does not necessarily reflect U.S. EPA policy).
2013 AGING RATS ARE PROTECTED FROM
CHLORDECONE AMPLIFIED PROGRESSION OF
CARBON TETRACHLORIDE HEPATOTOXICITY.
H. M. Mehendale. Toxicology, University of Louisiana at Monroe, Monroe, LA.
The prevailing general perception is that aging increases drug- and chemical-induced
hepatotoxicity. The mechanism of many age-dependent adverse drug reactions
and hepatotoxicity are not known. Among the different models used to study
hepatotoxicity, chlordecone (CD) + CCl4 interaction model is the most potent:
toxicity occurs at individually nontoxic levels, extensive liver damage leads to hepatic
failure and death, and the mechanisms have been studied at length. In 3
months old adult rats, this interactive toxicity results in 67-fold amplification of hepatotoxicity
and lethality. However, 14 months old F344 and 24 months old SD
rats are completely resistant to the interactive hepatotoxicity and lethality of
CD+CCl4. The toxic effects of this biological interaction in 3 months old adult rats
include extensive hepatotoxicity characterized by elevated ALT, AST, OCD, ICDH
serum enzyme levels, hepatic necrosis, bankrupt cellular energy and failed tissue repair
leading to progression of injury, hepatic failure, and death. In contrast, in aged
rats, only transient hepatic damage was observed even though the initiation of
bioactivation-mediated liver injury of CCl4 in CD pre-exposed rats is the same as
in the adults. Proteases such as calpain and phospholipases such as secretory phospholipase
A2, (death proteins), known to spread liver injury may be silenced in advanced
age, explaining why the initiated liver injury does not progress. The mechanisms
underlying this remarkable resiliency in advanced age against the highly
amplified toxicity of CCl4 in CD treated rats are of significant interest. These findings
suggest that progression of liver injury is prevented as a consequence of overexpressed
endogenous inhibitors (calpastatin and annexins) of death proteins by stimulated
liver regeneration and tissue repair in advanced age.
2014 COMPARATIVE EFFECTS OF THE
ORGANOPHOSPHORUS INSECTICIDES
CHLORPYRIFOS AND PARATHION IN ADULT AND
AGING RATS.
C. N. Pope 1 , J. Liu 1 and N. Mirajkar 1, 2 . 1 Physiological Sciences, Oklahoma State
University, Stillwater, OK and 2 Pharmaceutical Sciences, Texas Tech University,
Amarillo, TX.
We compared dose-related effects of two organophosphorus insecticides (OPs),
parathion (PS) and chlorpyrifos (CPF), in adult (3 mo) and aging (18 mo) rats.
Radiotransmitters were surgically implanted for radiotelemetry of physiological
endpoints (heart rate, body temperature, motor activity). Following baseline measurements,
rats were treated with either PS (adult: 0, 9, 13.5 or 18 mg/kg, sc; aging:
0, 3, 4.5 or 6 mg/kg, sc) or CPF (both age groups: 0, 28, 140 or 280 mg/kg, sc).
Biochemical (acetylcholinesterase and butyrylcholinesterase), functional (involuntary
movements and SLUD signs) and physiological data were then collected for 96
h. There was greater atrial cholinesterase inhibition in aging compared to adult rats
treated with the lowest dosage of either OP, but relatively similar inhibition between
age groups with higher dosages. PS elicited tremors in aging (at 6, but not 3
or 4.5 mg/kg) and adult (at 18, but not 9 or 13.5 mg/kg) rats. Few signs of cholinergic
toxicity were noted in either aging or adult rats following CPF, however.
Relatively similar changes in heart rate (prolonged reduction with little recovery)
were noted in both age groups with high dosages of either OP. Temperature was reduced
in both age groups, but aging rats showed lesser recovery. Motor activity was
initially reduced in both age groups by the highest dosage of either OP but aging
rats showed hyperactivity 96 h after exposure. We conclude that aging rats are more
sensitive than adults to PS toxicity based on biochemical, functional and physiological
endpoints. While both age groups showed relatively similar physiological
changes early after exposure, age-related differences in temperature and motor activity
were noted later. Finally, although both adult and aging rats show marked
OP-related differences in cholinergic signs, they exhibit relatively similar OP-related
changes in physiological endpoints recorded by telemetry (Supported by
Oklahoma State Board of Regents and grant ES009119 from NIEHS.)
2015 PULMONARY EFFECTS OF INHALED AIR
POLLUTANTS IN ELDERLY MICE: ROLE OF
OXIDATIVE STRESS AND INFLAMMATORY
CYTOKINES.
D. Laskin. Rutgers University, Piscataway, NJ.
One of the most sensitive populations to the adverse health effects of inhaled air
pollutants is the elderly. Mechanisms underlying this increased susceptibility are
unknown. Aging is associated with deterioration of both innate and adaptive immunity.
Most notable changes include age-related deficits in macrophage and neutrophil
activity, which are thought to contribute to increased susceptibility of the
elderly to respiratory infections. Aging is also associated with reduced activity of antioxidants
resulting in oxidative stress. Studies in our laboratory have focused on
analyzing inflammatory and antioxidant responses to air pollutants as potential
mechanisms underlying increases in the sensitivity of the elderly to inhaled air pollutants
including ozone and particulate matter. Following acute exposure of older,
but not younger rodents to these pulmonary irritants, we noted significant structural
alterations in the lungs, including patchy thickening of the alveolar septa and
inflammatory cell localization in alveolar spaces. Significant increases in NOx in
bronchoalveolar lavage fluid were also noted in older mice, as well as lung expression
of lipocalin 24p3, an oxidative stress marker, with no effects in younger mice.
Exposure to air pollutants resulted in a marked upregulation of TNF-alpha in lungs
of both younger and older mice; however this was attenuated in older animals.
Whereas increases in lung IL-6 were noted in both older and younger mice, IL-8
only increased in older animals. In younger mice, constitutive expression of manganese
superoxide dismutase (SOD) decreased after exposure, while in older mice,
constitutive SOD was not detectable and pollutant exposure had no effect on expression
of this antioxidant. Taken together, these data suggest that age related alterations
in antioxidant defense and production of inflammatory mediators may
contribute to enhanced susceptibility of the elderly to pulmonary toxicants.
Supported by NIH grants ES004738, ES005022, GM034310, CA132624 and
AR055073.
2016 TRPING THE SENSOR: THE ROLE OF TRP CHANNEL
SIGNALING IN CARDIOPULMONARY TOXICITY.
S. Jordt 2 , D. J. Conklin 1 , J. Morris 3 , A. Caceres 2 , L. Lee 4 and R. Willette 5 .
1
Medicine, Univesrity of Louisville, Louisville, KY, 2 Pharmacology, Yale University,
New Haven, CT, 3 Pharmacy, University of Connecticut, Storrs, CT, 4 Physiology,
University of Kentucky, Lexington, KY and 5 Heart Failure DPU, GlaxoSmithKline
Pharmaceuticals, King of Prussia, PA.
Transient receptor potential (TRP) ion channels comprise a large family of cationic
(calcium) conducting channels (TRP A, C, M, V) responsive to environmental and
endogenous stimuli. TRP channels are activated by noxious airborne compounds
such as tear gas and reactive aldehydes, as well as endogenously generated unsaturated
aldehydes associated with tissue injury and inflammation, including α, β-unsaturated
aldehydes like acrolein and 4-hydroxynonenal. The TRP receptor channels
transduce a variety of chemical signals via neural afferents (C-fibers) into
sensory signals, including pain (nociceptive) responses. Increasingly, these channels
are being found in other cell types, including airway epithelial and cardiovascular
endothelium. The TRPA1 and TRPV1 (vanilloid- or capsaicin-sensitive) channels
are implicated in pulmonary inflammation and asthma associated with exposure to
noxious stimuli including chlorine, tear gases, isocyanates, tobacco smoke, and
aldehydes. TRP channel activation triggers the release of neuropeptides such as substance
P and CGRP, which stimulate local inflammatory responses, vasodilation,
and edema. Recent work extends these findings to include complex cardiovascular
responses, such as circulatory collapse and hypotension. These responses are triggered
by specific TRP agonists, as well as by unsaturated aldehydes, which implicate
a role of TRP channels located in cardiovascular cells or sensory afferents in these
tissues in these effects. This session will explore several pathophysiological models
that implicate various TRP channels in deleterious effects of noxious stimuli in cardiopulmonary
toxicity and probe the mechanisms that connect channel activation/inhibition
in these responses to exogenous and endogenous stimuli. The relevance
of TRP signaling to human health and the potential for therapeutic targeting
will be addressed.
2017 TRPA1 MEDIATES THE NOXIOUS EFFECTS OF TEAR
GASES AND INDUSTRIAL ISOCYANATES.
S. Jordt. Pharmacy, Yale University, New Haven, CT.
TRPA1, a transient receptor ion channel expressed in chemosensory neurons, was
initially characterized as the receptor for the pungent natural product, mustard oil
(allyl isothiocyanate). Using Ca2+ imaging and electrophysiological techniques, we
SOT 2010 ANNUAL MEETING 429