Research progress on central neurotoxicity mechanism and prevention of trimethyltin chloride / 中国药理学通报

Trimethyltin chloride is a highly toxic by-product produced during the process of synthesizing polyvinyl chloride plastics. It has specially central neurotoxicity, which is mainly manifested as inducing the death of neurons in human and animal central nervous system, especially hippocampal neurons. TMT poisoning can cause seizures, diarrhea, learning and memory impairment and other clinical manifestations, and even coma or death in severe cases. In order to better understand the role of TMT neurotoxicity in central nerve system, this paper reviews the research progress on both the molecular mechanism and therapeutic drugs of central neurotoxicity caused by TMT, thereby providing new ideas for the prevention and treatment of TMT-in-duced neurotoxicity.

Effect of trimethyltin chloride on brain metabolism detected by PET-CT / 中国职业医学

{L-End}Objective To explore the feasibility of using positron emission tomography (PET) -computed tomography (CT) to detect brain metabolic abnormalities caused by trimethyltin chloride (TMT) poisoning. {L-End}Methods Specific pathogen free healthy SD rats were randomly divided into model group and control group with six rats in each group. Rats in the model group were intraperitoneally injected with a single dose of 10 mg/kg body mass of TMT solution, and rats in the control group were intraperitoneally injected with a single dose of an equal volume of 0.9% sodium chloride solution. Rats were anaesthetized after three days of modeling and underwent PET-CT brain scanning to detect the standardized uptake value (SUV) of 18F-2-fluro-D-deoxy-glucose (18F-FDG). After scanning, rats were sacrificed and brain tissues were collected for brain organ coefficients calculation and brain histopathological analysis. {L-End}Results The rats in the model group showed symptoms of head tremor, limb twitching, irritability and others after TMT modeling. There was no significant difference in the body mass between the two groups of rats on the third day of modeling (P>0.05). The 18F-FDG uptake in the cerebral cortex, cerebellum and brainstem of the rats in the model group was significantly weakened compared with the control group, with deceased SUV values (all P<0.05). No obvious abnormalities were found in CT images and freshly collected brain tissues of rats of the control and model groups. The brain organ coefficients of rats in the two groups showed no significant difference (P>0.05). The results of hematoxylin-eosin staining of brain tissue showed that the cerebral cortex of rats in the model group had more tiny cavities than that of the control group, and some neuronal cells and a small number of hippocampal vertebral cells were tightly and deeply stained, with the cytoplasm and nucleus poorly demarcated, and pericellular space enlarged. The results of Nissen staining showed that the arrangement of neuronal cells in the model group was slightly disordered, and the interstitial space was slightly enlarged, but no other significant abnormal changes were observed. {L-End}Conclusion PET-CT can be used in detecting the metabolic abnormalities of brain in TMT poisoning rat model, making it a sensitive detection method for TMT poisoning.

Three cases of occupational acute trimethyltin chloride poisoning / 中华劳动卫生职业病杂志

Trimethyltin chloride is a highly toxic substance, which is absorbed through respiratory tract, skin and digestive tract, with central nervous system injury as the main clinical manifestations, and can be accompanied by damage to various organs. In this paper, the treatment process of 3 patients with acute trimethyltin chloride poisoning was reviewed, and their clinical manifestations, auxiliary examination, diagnosis and treatment were analyzed. Three patients were misdiagnosed as mental abnormality, encephalitis, and hepatic encephalopathy in different hospitals in the early stage of medical treatment, suggesting that clinicians should pay attention to the occupational contact history of poisoned patients and conduct toxicant detection in time to avoid misdiagnosis and mistreatment.

Follow up analysis of 6 patients with severe trimethyltin chloride poisoning for 4 years / 中华劳动卫生职业病杂志

Objective: Objective to investigate the health changes of patients with severe trimethyltin chloride (TMT) poisoning in four years. Methods: Six patients with severe TMT poisoning treated in the First Affiliated Hospital of Gannan Medical College in August 2016 were numbered 1, 2, 3, 4, 5 and 6 respectively. The patients were followed up 0.5, 2 and 4 years after poisoning and compared and analyzed. The follow-up contents include: symptom degree, score of simple mental intelligence examination scale (MMSE) and modified Rankin Scale (MRS) , cranial magnetic resonance imaging (MRI) , EEG, etc. Results: The symptoms of dizziness, headache, chest tightness, palpitation, nausea and vomiting decreased gradually in 6 patients. The symptoms of speech disorder and memory decline in No.1, 2 and 3 patients gradually increased, and the scores of MMSE and Mrs gradually decreased; Patients No.4, 5 and 6 had improved speech disorder, but their memory decreased, MMSE and Mrs scores were still flat, and mild cognitive impairment. The brain atrophy of No.1, 2 and 3 patients was aggravated, which showed obvious atrophy of hippocampus, temporal lobe, insular lobe and cerebellum and enlargement of ventricle; There was no significant change in brain atrophy in No.4, 5 and 6 patients. Conclusion: The neurotoxic symptoms in the later stage of severe TMT poisoning are still serious, and the neurotoxic time is long.

Occupational exposure limit of trimethyltin chloride in workplace air / 中国职业医学

OBJECTIVE: To establish the occupational exposure limit for trimethyltin chloride(TMT) in workplace air. METHODS:According to the GBZ/T 210.1-2008 Guide for Establishing Occupational Health Standards--Part 1: Occupational Exposure Limits for Airborne Chemicals in the Workplace, the relevant literatures on toxicology, population epidemiology and foreign occupational exposure limit of TMT were collected and analyzed. A total of 276 workers with TMT occupational exposure were selected as the exposure group and 25 workers without TMT occupational exposure were selected as the control group.Worksite survey of occupational health and occupational medical examination were carried out. Combined with the literature data, the occupational exposure limit of TMT in the workplace air was calculated by using the 90% medical reference level(internal exposure limit) of the urine TMT level of workers who exposed to TMT without moderate hypokalemia. RESULTS: The time-weighted average of TMT in the workplace air is 0.100 mg/m~3 and the short-term exposure limit is 0.200 mg/m~3 in the United States based on total organic tin. The highest concentration of TMT in the workplace air in Germany is 0.005 mg/m~3. The literature data analysis results showed that the incubation period of TMT poisoning is mostly 3-6 days, and the main symptoms of TMT poisoning are hypokalemia in the early stage, followed by neuropsychiatric symptoms such as headache, memory loss and aggressive behavior. The median(M) and the 0-100 th percentile(P_0-P_(100)) of exposure to TMT were 8.35(< 0.20-91.40) μg/m~3 in the exposure group. The individual TMT exposure level of workers in different positions from high to low were crushing, granulation, withdrawal and assembly positions. The M(P_0-P_(100)) of urinary TMT level in the exposure group was 16.94(<0.50-591.14) μg/L. There was a positive correlation between the individual TMT exposure level and urine TMT level in the exposure group(Spearman correlation coefficient=0.62, P<0.01). The detection rate of hypokalemia in the exposure group was higher than that in the control group(26.1% vs 4.0%, P < 0.05). However, there was no significant difference in the detection rate of moderate hypokalemia between the two groups(3.3% vs 0.0%, P>0.05). The 90% medical reference value of urine TMT was 89.90 μg/L in workers exposed to TMT without moderate hypokalemia. CONCLUSION: In order to prevent acute hypokalemia damage caused by TMT, we recommended that the occupational exposure limit of TMT in the workplace air should be set at 0.025 mg/m~3 in China, and this limit should be the maximum allowable concentration.

Characteristics of peripheral nerve damage caused by occupational acute trimethyltin chloride poisoning / 中国职业医学

OBJECTIVE: To explore the characteristics of peripheral nerve injury caused by occupational acute trimethyltin chloride(TMT) poisoning. METHODS: The clinical manifestations and test data of neurotic electrophysiology, pure tone hearing threshold and acoustic immittance in 16 patients with occupational acute TMT poisoning were retrospectively analyzed. The patients were followed up after 6 months of discharge. RESULTS: Among the 16 cases of occupational acute TMT poisoning, 6, 4 and 6 cases were with mild, moderate and severe poisoning, respectively. For the firstly appeared symptoms, 7 cases had abnormal mental behavior and memory loss, 5 cases had tinnitus and hearing loss, 5 cases had decreased visual acuity, 2 cases had diplopia and 2 cases had binocular pain. The main clinical manifestations included 8 cases of disturbance of consciousness, and 6 cases of abnormal orientation and aggressive behavior. After correction of hypokalemia, 7 cases of patients had limb muscle weakness, hypomyotonia and weakened tendinous reflect, 9 cases had decreased tactile sensation below the groin in the lower limbs, and 6 cases had instability of walking. The main manifestations of neuroelectrophysiological detection were: 9 patients(accounting for 56.3%) showed abnormal neuroelectromyography, 4 cases of severe poisoning had damaged motor nerve, sensory nerve axon and myelin sheath, and the proximal nerve was also partially damaged. There were 2 cases of moderate poisoning showing abnormal symptoms, the axon and myelin sheath of sensory nerve were damaged, one common peroneal nerve was demyelinated. Three cases of mild poisoning had one common peroneal nerve axon damaged, one proximal tibial nerve damaged, and the axon and myelin sheath of sensory nerve were damaged. Brainstem auditory evoked potential I wave and visual evoked potential P100 latency prolonged and amplitude decreased in some of the patients with mild, moderate and severe poisoning. The sensorineural hearing loss occurred in 81.3% of patients. CONCLUSION: Occupational acute TMT poisoning can cause damage to motor nerve, sensory nerve axon and myelin sheath of extremities. Both distal and proximal nerves might be involved. It can also damage cochlear hair cells and optic nerve. Attention should be paid to the early treatment of peripheral nerve damage, cochlear hair cell and optic nerve damage caused by TMT.

Clinical analysis on 325 cases of trimethyl tin chloride-induced acute toxic encephalopathy / 中国职业医学

OBJECTIVE: To investigate the clinical characteristics of acute toxic encephalopathy caused by trimethyltin chloride(TMT). METHODS: Literatures related to TMT acute poisoning accidents occurred in China from 1998 to 2018 were collected and analyzed using the CNKI, WEIPU Database and WANFANG Database. The clinical manifestations, neuroimaging images, electroencephalography(EEG), treatment and other data were collected and analyzed. RESULTS: A total of 15 literatures were included in the study. These studies involved 15 incidents with 1 339 patients with TMT acute poisoning. Among them, 325 patients(24.3%) presented toxic encephalopathy. They were moderate to severe poisoning.The clinical manifestations were headache, dizziness, limb weakness, abnormal mental behavior and memory loss. Magnetic resonance imaging(MRI) and computed tomography(CT) were performed in 105 and 86 patients, respectively, with 29.5% and 26.7% of abnormal rate. There was no significant difference in the abnormal rate between the above two methods(P>0.05). 294 cases were examined by electroencephalogram. The abnormal rate was 93.9%, which was higher than that of the MRI and CT examination(P<0.05). Patients with toxic encephalopathy were treated with glucocorticoid. Some patients were treated with hyperbaric oxygen, nerve cell nutritional drugs and rehabilitation exercise after the conditions were stable. CONCLUSION: The patients with TMT toxic encephalopathy were moderately and severely poisoned by TMT. EEG examination is helpful for the diagnosis and treatment of TMT toxic encephalopathy.

Clinical analysis of sequelae of acute trimethyltin oxide poisoning / 中华劳动卫生职业病杂志

Objective@#Clinical analysis of sequelae of 16 patients with trimethyltin chloride (TMT) poisoning after 2 years.@*Methods@#Sixteen patients with TMT poisoning from a waste recycling company in Ganzhou City in August 2016 were enrolled. They were investigated by questionnaires and assessed by various scales after two years. 6 cases of severe poisoning were examined by head MRI. The scale includes Hamilton Anxiety Scale (HAMA) , Depression Scale (HAMD) , Simple Mental State Examination Scale (MMSE) , Activity of Daily Living (ADL) , International Cooperative Ataxia Rating Scale (ICARS) .@*Results@#16 cases of TMT poisoning still have headache, dizziness and other symptoms. Instability of walking in 4 patients with severe poisoning, and the brain MRI manifestations included obvious atrophy of temporal lobe, hippocampus, insula lobe, cerebellum and ventricle enlargement. Two patients were rated as severe mixed anxiety and depression, one as moderate mixed anxiety and depression, and one as mild anxiety. 3 cases were diagnosed as dementia and 1 case as mild cognitive impairment. Two cases were totally dependent on living ability. ICARS scores were 66 points and 63 points respectively. Two cases were mildly dependent on living ability. ICARS scores were 28 points and 6 points respectively. There were 2 cases of mild mixed anxiety and depression in mild and moderate poisoning patients, and 1 case of mild cognitive impairment in each patient. They could live independently. ICARS scores were 0.@*Conclusion@#After 2 years of TMT poisoning, some patients still have general clinical symptoms such as dizziness, headache and so on. There are also mental and intellectual symptoms such as anxiety, depression and cognitive impairment. Some of patients with severe poisoning presented with dementia and cerebellar ataxia, and even lost independent living ability.

Characteristics of clinical, Magnetic Resonance Imaging and electroencephalogram after trimethyltin chloride poisoning / 中华劳动卫生职业病杂志

Objective@#Characteristics of clinical, MRI and electroencephalogram after trimethyltin chloride (TMT) poisoning.@*Methods@#The clinical manifestations, MRI, EEG, treatment and prognosis of 16 patients with TMT poisoning were analyzed retrospectively.@*Results@#Among the 16 cases of TMT poisoning, 6 cases were severe poisoning, 4 cases were moderate poisoning, and 6 cases were mild poisoning. All patients had dizziness, headache, general fatigue, loss of appetite, nausea, vomiting and other general clinical symptoms. Six patients with severe poisoning had psychobehavioral abnormalities, including 4 patients with mania, delirium, ataxia, epileptic seizures. Glasgow was 15 points in mild and moderate poisoning. Of the 6 cases of severe poisoning, 4 cases of Glasgow were 9~11 points, and 2 cases of Glasgow were 13 points. 2 patients with severe poisoning had abnormal MRI in head, and the total abnormal rate was 12.50%. Toxic encephalopathy was considered in 1 case with abnormal signal of corpus callosum pressure, and patchy ischemic foci of left cerebral foot and mild cerebral atrophy in 1 case. The total abnormal rate of EEG was 56.25%. The abnormal rate of electroencephalogram in severe poisoning was 83.33%. There were 2 cases of severe abnormal electroencephalogram, 2 cases of moderate abnormal electroencephalogram and 1 case of slight abnormal electroencephalogram. Twelve patients were recovered and discharged from hospital. 4 cases of severe poisoning are still getting better, and there are still cerebellar ataxia symptoms such as dizziness and unstable walking.@*Conclusion@#In clinical work, attention should be paid to the identification of patients with mild and moderate TMT poisoning, and attention should be paid to the patients with severe TMT poisoning manifested by disturbance of consciousness. The positive rate of MRI test in TMT poisoning is low, and the lesion is nonspecific. Electroencephalogram test has a high positive rate in TMT poisoning, which can well reflect the degree of illness. Attention should be paid to the prevention and treatment of neurodegeneration caused by TMT poisoning.

Electromyography analysis in 13 patients with acute trimethyltin chloride poisoning / 中华劳动卫生职业病杂志

Objective@#To investigate the electromyography (EMG) characteristics and clinical significance in patients with acute trimethyltin chloride (TMT) poisoning.@*Methods@#Retrospectively analyze the EMG results of major limb nerves and muscles of 13 patients with acute TMT poisoning.@*Results@#Among the 13 patients, 10 cases had abnormal and the abnormal rate was 76.9%. The same degree of involvement of upper and lower limbs is the most common. And distal peripheral nerve damage is the most common, mainly manifested as sensory damage or mixed sensory and motor damage, with axonal injury and demyelinating lesions to almost the same degree. The peroneal nerve and median nerve were the most vulnerable, with an abnormal rate of 39.1% and 35.9%, respectively. The peroneal nerve and median nerve were damaged first but recovered slowly.The ulnar nerve first appeared damaged and recovered quickly. The sural nerve was damaged later.@*Conclusion@#Acute TMT poisoning can cause limb peripheral nerve damage. This damage is a slow, gradual process, and its recovery is also a slow process.

Wogonin Attenuates Hippocampal Neuronal Loss and Cognitive Dysfunction in Trimethyltin-Intoxicated Rats

We examined whether wogonin (WO) improved hippocampal neuronal activity, behavioral alterations and cognitive impairment, in rats induced by administration of trimethyltin (TMT), an organotin compound that is neurotoxic to these animals. The ability of WO to improve cognitive efficacy in the TMT-induced neurodegenerative rats was investigated using a passive avoidance test, and the Morris water maze test, and using immunohistochemistry to detect components of the acetylcholinergic system, brain-derived neurotrophic factor (BDNF), and cAMP-response element-binding protein (CREB) expression. Rats injected with TMT showed impairments in learning and memory and daily administration of WO improved memory function, and reduced aggressive behavior. Administration of WO significantly alleviated the TMT-induced loss of cholinergic immunoreactivity and restored the hippocampal expression levels of BDNF and CREB proteins and their encoding mRNAs to normal levels. These findings suggest that WO might be useful as a new therapy for treatment of various neurodegenerative diseases.

Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection / 한국실험동물학회지

To investigate the beneficial effects of diosgenin (DG) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DG for 21 days. Multiple types of damage were successfully induced by Aβ-42 accumulation and TMT injection into the brains of TG mice. However, DG treatment significantly reduced the number of Aβ-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DG treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75NTR expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DG could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis.

Neuroprotective Effect of Lucium chinense Fruit on Trimethyltin-Induced Learning and Memory Deficits in the Rats

In order to the neuroprotective effect of Lycium chinense fruit (LCF), the present study examined the effects of Lycium chinense fruit on learning and memory in Morris water maze task and the choline acetyltransferase (ChAT) and cyclic adenosine monophosphate (cAMP) of rats with trimethyltin (TMT)-induced neuronal and cognitive impairments. The rats were randomly divided into the following groups: naive rat (Normal), TMT injection+saline administered rat (control) and TMT injection+LCF administered rat (LCF). Rats were administered with saline or LCF (100 mg/kg, p.o.) daily for 2 weeks, followed by their training to the tasks. In the water maze test, the animals were trained to find a platform in a fixed position during 6d and then received 60s probe trial on the 7th day following removal of platform from the pool. Rats with TMT injection showed impaired learning and memory of the tasks and treatment with LCF (p<0.01) produced a significant improvement in escape latency to find the platform in the Morris water maze at the 2nd day. Consistent with behavioral data, treatment with LCF also slightly reduced the loss of ChAT and cAMP in the hippocampus compared to the control group. These results demonstrated that LCF has a protective effect against TMT-induced neuronal and cognitive impairments. The present study suggests that LCF might be useful in the treatment of TMT-induced learning and memory deficit.

Inducible nitric oxide synthase is involved in neuronal death induced by trimethyltin in the rat hippocampus / 대한수의학회지

Trimethyltin chloride (TMT) has been used as a neurotoxin for inducing brain dysfunction and neuronal death. Neuronal death in the hippocampus by TMT may generate excessive nitric oxide, but there are few studies about nitric oxide synthase enzyme involved in the synthesis of nitric oxide. The purpose of present study is to analyze the TMT toxicity in each region of rat hippocampus. To evaluate the involvement of nitric oxide, we analyzed the effects of aminoguanidine known as a selective inhibitor for inducible nitric oxide synthase on behavioral changes and the hippocampus of rat by TMT toxicity. 6-week-old male Sprague-Dawley rats were administered with a single dose of TMT (8 mg/kg b.w., i.p.) and the control group was similarly administered with distilled water. TMT + aminoguanidine-treated groups were administered with aminoguanidine (10 mg/kg or 100 mg/kg b.w., i.p.) for 3 days prior to TMT injection. The rats were sacrificed 2 days after TMT administration. In the TMT-treated group, a number of cell losses were seen in CA1, CA3 and the dentate gyrus. In the TMT + aminoguanidine-treated group, neuronal death was seen in CA1 and CA3, but reduced in the dentate gyrus compared to the TMT-treated group. Western blot analysis showed that cleaved caspase-3 expression was increased in the TMT-treated group compared to the control group. However, the expression significantly declined in the TMT + aminoguanidine-treated group. The present findings suggest that inducible nitric oxide synthase is involved in neuronal death induced by TMT.

Signal transduction in trialkyltin compounds-induced tumor cell apoptosis mechanism trialkyltin compounds-induced tumor cell apoptosis / 中国药理学通报

Aim Organotin compounds are important organometallic chemicals with a variety of technical applications.Of these compounds,the trialkyltins,especially tributyltin,triphenyltin and trimethyltin,have been proved to have the distinct ability to induce tumor cell apoptosis and significant antitumor activity.They can induce tumor cell apoptosis through Fas receptor,mitochondrial,Ca 2+,MAPKs,p53,NF-?B and caspase/p38/ROS pathway.This paper reviewed recent progress in the studies on signal transduction in tumor cell apoptosis induced by trialkyltin compounds.

Trimethyltin-Induced Hippocampal Neurodegeneration is Possibly Mediated by Induction of Apoptosis

BACKGROUND: Trimethyltin (TMT) is a neurotoxicant which produces a distinct pattern of neuronal cell death in the hippocampus following systemic administration of a single dose. However, the mechanism of selective neuronal death remains unclear. We performed this study to elucidate the underlying mechanism of TMT-induced hippocampal neu-ronal death. METHODS: The effects of trimethyltin (8.0mg/kg, I.p., single dose) on the hippocampal neurons were investi-gated in terms of changes in the neurobehavioral status, histologic, and electron microscopc findings. RESULTS: Behaviorally, TMT treatment caused stereotypic limbic system dysfunction, i.e. tremors, spontaneous seizures, vocaliza-tion, hyperactivity, hyperexcitability, intraspecific aggression as described previously. Morphologically, TMT produced prominent neurodegeneration in the dentate gyrus. Widespread, strong glial fibrillary acidic protein (GFAP) immunore-activity, which was suggestive of reactive astrogliosis, was noted throughout the hippocampal subfields. Many degener-ating neurons were TUNEL positive. Electron microscopic findings revealed characteristic features of apoptosis in the dentate granule cells. NADPH-diaphorase positive cells were spared after TMT exposure. CONCLUSIONS: It is suggested that TMT-induced hippocampal degeneration might be a useful in vivo model for the study of learning and memory, neuronal-glial interactions, and selective neuronal apoptosis.

Trimethyltin-Induced Hippocampal Neurodegeneration is Possibly Mediated by Induction of Apoptosis

BACKGROUND: Trimethyltin (TMT) is a neurotoxicant which produces a distinct pattern of neuronal cell death in the hippocampus following systemic administration of a single dose. However, the mechanism of selective neuronal death remains unclear. We performed this study to elucidate the underlying mechanism of TMT-induced hippocampal neu-ronal death. METHODS: The effects of trimethyltin (8.0mg/kg, I.p., single dose) on the hippocampal neurons were investi-gated in terms of changes in the neurobehavioral status, histologic, and electron microscopc findings. RESULTS: Behaviorally, TMT treatment caused stereotypic limbic system dysfunction, i.e. tremors, spontaneous seizures, vocaliza-tion, hyperactivity, hyperexcitability, intraspecific aggression as described previously. Morphologically, TMT produced prominent neurodegeneration in the dentate gyrus. Widespread, strong glial fibrillary acidic protein (GFAP) immunore-activity, which was suggestive of reactive astrogliosis, was noted throughout the hippocampal subfields. Many degener-ating neurons were TUNEL positive. Electron microscopic findings revealed characteristic features of apoptosis in the dentate granule cells. NADPH-diaphorase positive cells were spared after TMT exposure. CONCLUSIONS: It is suggested that TMT-induced hippocampal degeneration might be a useful in vivo model for the study of learning and memory, neuronal-glial interactions, and selective neuronal apoptosis.