Elsevier

Aquatic Toxicology

Volume 90, Issue 1, 20 October 2008, Pages 58-64
Aquatic Toxicology

Acute trimethyltin exposure induces oxidative stress response and neuronal apoptosis in Sebastiscus marmoratus

https://doi.org/10.1016/j.aquatox.2008.07.017Get rights and content

Abstract

Trimethyltin (TMT) is a well-documented neurotoxicant that affects the function of central nervous system (CNS). In this study, we studied the neurotoxicity of TMT on the brain of marine fish Sebastiscus marmoratus. Our results showed that TMT acute exposure induced brain cell apoptosis in the telencephalon, optic tectum and cerebellum. In addition, we observed increased production of reactive oxygen species (ROS), nitric oxide (NO) and one asparate-specific cysteinyl protease named caspase-3 which are often associated with the processes of cell apoptosis, in the brain of S. marmoratus after acute treatment of TMT. Our results indicated that TMT induces neurotoxicity and oxidative stress in marine fish S. marmoratus. Our results suggested that TMT exposure in the environment may affect fish behaviors including schooling, sensory and motorial learnings, based on the observation of cell apoptosis in the cerebral regions.

Introduction

The organotin compound trimethyltin (TMT) is a short-chain trialkytin widely used in industry and agriculture (Feldman et al., 1993). Some polyvinyl chloride products contain high levels of TMT (8.5–24.9 μg/g) (Gomez et al., 2007). Polyvinyl chloride pipes have been widely used in domestic water system, which lead to the presence of TMT in drinking water supplies and in the environment. TMT was also found in marine environment and aquatic specimens (Shawky and Emons, 1998). In some countries, TMT has not been implemented in commercial applications due to its high level of cellular toxicity. However, tracing amounts of TMT have been found in the urine of humans not exposed directly to TMT, which reinforces the concern of environmental contamination (Jenkins and Barone, 2004).

TMT is known as a potent neurotoxicant that mainly affects the function of central nervous system (CNS). It has been shown that TMT exposure in adult mammals causes neuronal degeneration of the hippocampus, amygdala, pyriform cortex, and neocortex (Brown et al., 1979). TMT also affects the synaptic transmission in the cornu ammonis region (CA1) of hippocampus (Kruger et al., 2005). TMT exposure in adult rats causes neurobehavioral alterations, impairs learning and performance which are attributed to neuronal cell death (Moser, 1996, Reiter and Ruppert, 1984, Stanton et al., 1991). Symptoms including decreased hearing, restlessness, psychomotor agitation, ataxia, confusion, disorientation, disturbances of short-term memory, amnesia, as well as partial or generalized seizures have been reported due to TMT caused accidental intoxications (Besser et al., 1987, Saary and House, 2002). In vitro, TMT appears to have a direct effect on neurons and is often used as a model neurotoxicant for studying neuronal degeneration (Aschner and Aschner, 1992, Philbert et al., 2000). It has been shown that TMT reduces ATP level in astrocytoma cells (Eyer et al., 2000), inhibits the uptake and increases the release of excitatory amino acid glutamate in rat primary astrocyte cultures (Aschner and Aschner, 1992, Dawson et al., 1995). TMT exposure in rat cell line (pheochromocytoma cell line, PC12) and in primary cultures of hippocampal neurons caused cell death and nuclear changes including apoptotic chromatin condensation and DNA fragmentation (Figiel and Fiedorowicz, 2002, Viviani et al., 1998).

Despite these findings, the mechanisms underlying TMT-mediated neurotoxicity have not been fully clarified. Protein kinase C (PKC) activation and oxidative stress are required for TMT-induced apoptosis in vitro (Gunasekar et al., 2001a, Gunasekar et al., 2001b, Milaeva et al., 2006, Zhang et al., 2006), and activation of the caspase family of cysteine proteases might mediate TMT-induced apoptosis in vivo (Geloso et al., 2002, Lefebvre d’Hellencourt and Harry, 2005). In a number of different cell lines and primary cells, TMT treatments lead to excess generation of cellular oxidative species associated with apoptotic death (Gunasekar et al., 2001a, Gunasekar et al., 2001b, Jenkins and Barone, 2004, Mundy and Freudenrich, 2006). TMT caused cell death could be reduced by antioxidants or increasing intracellular glutathione level (Cookson et al., 1998, Shin et al., 2005). It is widely accepted that oxidative stress initializes TMT-induced apoptotic cell death.

Although many studies, especially in vitro, have been carried out on the neurotoxicity of TMT, it remains limited in marine animals. The neurotoxicity of TMT at different levels on acute exposure to fish has not been previously investigated. Taking into account the present concern regarding the environmental impact of neurotoxic metals on marine organism, we undertook this study to detect the effects of TMT on the marine fish Sebastiscus marmoratus. The present data showed that TMT-induced neuronal apoptosis in S. marmoratus, accompanied by an increase of reactive oxygen species (ROS) and nitric oxide (NO) in brain.

Section snippets

Chemicals

Trimethyltin chloride was purchased from Fluka AG, Switzerland, with a purity of greater than 97%. Diagnostic Reagent Kits for NO, NO synthase (NOS) and caspase-3 were purchased from Nanjing Jiancheng Bioengineering Institute, China. All other chemicals were of analytical grade and were purchased from commercial sources.

Experimental species

S. marmoratus weighing 25–35 g were captured from an uncontaminated coast area in Xiamen City, Fujian Province, China. Before the experiment, the fish were acclimated in tanks

Total tin in brain

The content of total tin in brain increased after treatment with TMT. A significant increase was observed after treatment with either 50 or 500 μg/kg TMT, respectively, compared with the control (Fig. 2).

Liver biotransformation responses

EROD activity was inhibited in a dose-dependent manner after treatment with TMT. Treatments with TMT in the dose of either 50 μg/kg or 500 μg/kg resulted in a significant decrease of the EROD activity. However, GST activity did not exhibit any statistically significant alteration (Fig. 3).

Apoptosis in brain

TMT

Discussion

In the present study, we observed that TMT exposure induced cell apoptosis in fish brain. In addition, TMT exposure elevated the contents of ROS and NO, and the total activities of NOS and iNOS. These findings strongly suggested that TMT exposure induced neurotoxicity and oxidative stress responses in the brain of fish living under the contaminated environment.

The previous study showed that TMT could be accumulated in the CNS and distributed across the cerebellum, medulla-pons, hypothalamus,

Acknowledgements

This work was supported by the National Natural Science Foundation (40606027) of China and by Fund (MEL0606) of State Key Laboratory of Marine Environmental Science (Xiamen University), China. The authors greatly appreciate Dr. Bin Li at University of Pennsylvania for his assistance with English.

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