Page 201 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

168 SECTION | I General

VetBooks.ir proteomic applications have been applied to gain a better could affect the response of fish to pesticides when com-
pared to exposure to pesticides alone.
understanding of target organ toxicities, mechanisms of
toxicity and biomarkers of exposure for a variety of
toxicants.
Hepatotoxicity
Monitoring liver function is crucial in toxicologic evalua-
Aquatic Toxicology and Pesticides
tion. Hence, it is no surprise that toxicoproteomic experi-
In veterinary toxicology, pesticide use and potential nontar- ments have been conducted to gain a better understanding
get toxicity in aquatic organisms is always a concern. In of proteins that change with hepatotoxicity. For example,
order to gain a better understanding of the mechanisms of toxicoproteomics has been used to identify metabolic
toxicity, changes in protein expression have been assessed pathways affected by drug-induced cirrhosis in rat mod-
in fish exposed to single or multiple pesticides. For exam- els. In these studies, thioacetamide and ethanol have both
ple, proteomic analyses of proteins in brain responsive to been shown to down-regulate proteins involved in oxida-
methyl parathion in zebrafish (Danio rerio)have been tive stress and fatty acid β-oxidation pathways during
investigated. In this study, it was found that six proteins, early phases of cirrhosis (Low et al., 2004; Venkatraman
which were predominantly cytoplasmic proteins, signifi- et al., 2004). Ivermectin hepatotoxicity has been investi-
cantly changed with methyl parathion exposure (Huang gated in gilthead sea bream fish (Sparus aurata). Of the
et al., 2011). The proteins most affected by methyl para- proteins that significantly changed, 30 proteins decreased
thion are known to be involved in catalysis, binding, cell and six proteins increased with exposure to ivermectin
structure, and metabolic regulation. In another study in (Varo et al., 2010). The major hepatic proteins that chan-
brains from male, flathead minnows (Pimephales prome- ged were apoA-1 (lipid metabolism), β-globin, and ATP
las), protein expression was compared in fish exposed to synthase subunit beta (oxidative stress response and regu-
permethrin, terbufos, or a binary mixture of both pesticides lation of energy).
(Biales et al., 2011). In this study, 24 proteins changed Plasma protein biomarkers for drug-induced hepato-
with exposure to these pesticides when compared to con- toxicity have also been revealed using proteomics techni-
trols. Some of the proteins identified are known to be asso- ques. In one study conducted to investigate plasma
ciated with the cytoskeleton, glycolysis, hypoxia and the proteins that may correlate with acetaminophen hepato-
ubiquitin proteasome system. The investigators also com- toxicity, rats were given low (100 mg/kg) and high
pared protein expression patterns in treated fish versus con- (1250 mg/kg) doses of acetaminophen and the liver pro-
18
trol fish. Interestingly, the permethrin protein expression teins were analyzed using 2D-LC/MS/MS with 16 O/ O
pattern was distinguishable from that in the controls, isotope labeling (Gao et al., 2017). This study revealed 31
enabling them to discriminate between the two treatment proteins that changed with liver toxicity; however, there
groups with 87.5% accuracy. When comparing the proteins was one protein that increased dramatically with liver
identified in the aforementioned studies, the protein damage, HMOX1 (heme oxygenase 1). The investigators
dihydropyrimidase-like 3 was downregulated in zebrafish were able to show that HMOX1 could be used as a poten-
exposed to methyl parathion; however, this protein was up- tial plasma biomarker of liver damage.
regulated in the flathead minnows exposed to permethrin. Quantitative proteomics approaches have also been
Since aquatic species can be affected by multiple employed to study heavy metal-induced hepatotoxicity.
stressors, a study was conducted in goldfish (Carassius Using 2D-DIGE, the toxic pathways by which chronic
auratus) in which 2-DGE was used to investigate changes mercury hepatotoxicity occurs in aquatic organisms
in hepatic proteins after exposing the goldfish to pesticide highlighted potential biomarkers for monitoring mercury
mixtures and varying water temperatures. When com- in fish. When compared to controls, medaka fish treated
pared to controls, or to goldfish exposed to one variable with mercuric chloride (1 or 10 μg/mL) for 60 days had
(pesticide mixtures or temperature changes), proteins that 45 hepatic proteins that were markedly changed. The
changed with the multiple stressors included those hepatic proteins affected were related to mitochondrial
involved in cellular stress response, carbohydrate and function, cytoskeleton assembly, and oxidative stress
lipid metabolism, and cell structure and cell death (Wang et al., 2013).
(Gandar et al., 2017). Overall, they noted that with
increased temperature and pesticide exposure, there was Toxins
deregulation of the cell cycle via apoptosis inhibition, a
marked increase in proteins associated with oxidative Valuable information regarding toxicological evaluation
stress, and a decrease in glucose formation in the liver. of venom (“venomics”) has also been made possible
Therefore, the exposure to environmental cocktails of pes- through toxicoproteomic investigations. These investiga-
ticides, in combination with increased water temperature, tions have been used to identify protein toxin components