Trimethyltin chloride (TMT) is a highly toxic organotin compound often used in plastic heat stabilizers, chemical pesticides, and wood preservatives. TMT accumulates mainly through the environment and food chain. Exposure to organotin compounds is associated with disorders of glucolipid metabolism and obesity. The mechanism by which TMT damages pancreatic tissue is unclear. For this purpose, a subacute exposure model of TMT was designed for this experiment to study the mechanism of damage by TMT on islet. The fasting blood glucose and blood lipid content of mice exposed to TMT were significantly increased. Histopathological and ultrastructural observation and analysis showed that the TMT-exposed group had inflammatory cell infiltration and necrosis. Then, mouse pancreatic islet tumour cells (MIN-6) were treated with TMT. Autophagy levels were detected by fluorescence microscopy. Real-time quantitative polymerase chain reaction and Western blotting were used for verification. A large amount of autophagy occurred at a low concentration of TMT but stagnated at a high concentration. Excessive autophagy activates apoptosis when exposed to low levels of TMT. With the increase in TMT concentration, the expression of necrosis-related genes increased. Taken together, different concentrations of TMT induced apoptosis and necrosis through autophagy disturbance. TMT impairs pancreatic (islet β cell) function.

Trimethyltin chloride (TMT) is a potent neurotoxin widely used as a constituent of polyvinyl chloride plastic in the industrial and agricultural fields. However, the underlying mechanisms by which TMT leads to neurotoxicity remain elusive. In the present study, we constructed a dose and time dependent neurotoxic mouse model of TMT exposure to explore the molecular mechanisms involved in TMT-induced neurological damage. Based on this model, the cognitive ability of TMT exposed mice was assessed by the Morris water maze test and a passive avoidance task. The ultrastructure of hippocampus was analyzed by the transmission electron microscope. Subsequently, proteomics integrated with bioinformatics and experimental verification were employed to reveal potential mechanisms of TMT-induced neurotoxicity. Gene ontology (GO) and pathway enrichment analysis were done by using Metascape and GeneCards database respectively. Our results demonstrated that TMT-exposed mice exhibited cognitive disorder, and mitochondrial respiratory chain abnormality of the hippocampus. Proteomics data showed that a total of 7303 proteins were identified in hippocampus of mice of which 224 ones displayed a 1.5-fold increase or decrease in TMT exposed mice compared with controls. Further analysis indicated that these proteins were mainly involved in tricarboxylic acid (TCA) cycle and respiratory electron transport, proteasome degradation, and multiple metabolic pathways as well as inflammatory signaling pathways. Some proteins, including succinate-CoA ligase subunit (Suclg1), NADH dehydrogenase subunit 5 (Nd5), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (Ndufa4l2) and cytochrome c oxidase assembly factor 7 (Coa7), which were closely related to mitochondrial respiratory electron transport, showed TMT dose and time dependent changes in the hippocampus of mice. Moreover, apoptotic molecules Bax and cleaved caspase-3 were up-regulated, while anti-apoptotic Bcl-2 was down-regulated compared with controls. In conclusion, our findings suggest that impairment of mitochondrial respiratory chain transport and promotion of apoptosis are the potential mechanisms of TMT induced hippocampus toxicity in mice.

Neuroinflammation is one of the important mechanisms of trimethyltin chloride (TMT) central neurotoxicity. Artemisinin (ARS) is a well-known antimalarial drug that also has significant anti-inflammatory effects. Prokineticin 2 (PK2) is a small molecule secreted protein that is widely expressed in the nervous system and plays a key role in the development of neuroinflammation. However, it remains unclear whether ARS can ameliorate neuroinflammation caused by TMT and whether PK2/PKRs signaling pathway plays a part in it. In this research, male Balb/c mice were administered TMT (2.8 mg/kg, i.p.) followed by immunohistochemistry to assess the expression of PK2, PKR1, and PKR2 proteins in the hippocampus. Network pharmacology was used to predict the intersection targets of ARS, central nervous system(CNS) injury and TMT. The neurobehavior of mice was evaluated by behavioral scores. Histopathological damage of the hippocampus was evaluated by HE, Nissl and Electron microscopy. Western blotting was used to identify the expression of synapse-related proteins (PSD95, SYN1, Synaptophysin), PK system-related proteins (PK2, PKR1, PKR2), and inflammation-related proteins (TNF-α, NF-κB p65). Immunohistochemistry showed that TMT resulted in elevated PK2 and PKR2 protein expression in the CA2 and CA3 regions of the hippocampus in mice, while PKR1 protein was not significantly altered. Network pharmacology showed that PK2 could interact with the intersectional targets of ARS, CNS injury, and TMT. ARS remarkably attenuated TMT-induced seizures and hippocampal histological damage. Further studies demonstrated that ARS treatment attenuated TMT-induced hippocampal ultrastructural damage, possibly by increasing the number of rough endoplasmic reticulum and mitochondria as well as upregulating the levels of synapse-associated proteins (PSD95, SYN1, Synaptophysin). Western blotting results revealed that ARS downregulated TMT-induced TNF-α and NF-κB p65 protein levels. In addition, ARS also decreased TMT-induced protein expression of PK2 and PKR2 in the mouse hippocampus, but had no significant effect on PKR1 protein expression. Our results suggested that ARS ameliorated TMT-induced abnormal neural behavior and hippocampal injury, which may be achieved by regulating PK2/PKRs inflammatory pathway and ameliorating synaptic injury. Therefore, we suggest that PK2/PKRs pathway may be involved in TMT neurotoxicity and ARS may be a promising drug that can relieve TMT neurotoxicity.

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.
目的： 了解重度三甲基氯化锡（TMT）中毒患者4年间健康变化。 方法： 于2016年8月，将赣南医学院第一附属医院收治的6例重度TMT中毒患者分别编序号为1、2、3、4、5、6号，对患者在中毒后0.5、2、4年进行随访及对比分析，随访内容包括：症状程度、《简易精神智能检查量表》（MMSE）评分及《改良Rankin量表》（mRS）评分、头颅磁共振成像（MRI）、脑电图等。 结果： 6例患者头晕、头痛、胸闷、心悸、恶心及呕吐等症状逐渐减轻。1、2、3号患者的言语障碍、记忆力下降症状逐渐加重，MMSE及mRS评分逐渐降低；4、5、6号患者言语障碍好转，但记忆力下降、MMSE及mRS评分仍平定位轻度认识功能障碍。1、2、3号患者脑萎缩加重，表现为海马、颞叶、岛叶、小脑萎缩明显及脑室扩大；4、5、6号患者脑萎缩变化不明显。 结论： 重度TMT中毒后期神经毒性症状仍然严重，且神经毒性时间长。.

Trimethyltin chloride (TMT) is acknowledged to have potent neurotoxicity. Chlorogenic acid (CGA), the most abundant polyphenol in the human diet, is well-known for its neuroprotective activity. This investigation was performed to determine the effects and mechanisms of CGA on TMT-induced neurobehavioral dysfunctions. Mice received oral administrations of CGA (30 mg kg-1) for 11 days, in which they were intraperitoneally injected with TMT (2.7 mg kg-1) once on the 8th day. The daily intake of CGA significantly alleviated TMT-induced epilepsy-like seizure and cognition impairment, ameliorating hippocampal neuronal degeneration and neuroinflammation. Oral gavage of CGA potentially exerted neuroprotective effects through JNK/c-Jun and TLR4/NFκB pathways. Microbiome analysis revealed that daily consumption of CGA raised the relative abundance of Lactobacillus in TMT-treated mice. SCFAs, the gut microbial metabolites associated with neuroprotection, were increased in the mouse hippocampus following CGA treatment. TMT-induced neurotransmitter disorders were regulated by oral gavage of CGA, especially DL-kynurenine and acetylcholine chloride. Additionally, neurotransmitters in the mouse hippocampus were found to be highly associated with the gut microbiota. Our findings provided research evidence for the neuroprotective effect of CGA on TMT-induced neurobehavioral dysfunctions.

Trimethyltin chloride (TMT) is a by-product in the synthesis of organotin, a plastic stabilizer. With the rapid development of industry, the occupational hazards caused by TMT cannot be ignored. TMT is a typical neurotoxicant, which mainly damages the limbic system and brainstem of the nervous system. Previous studies have demonstrated that the neurotoxicity induced by TMT is linked to the inhibition of energy metabolism, but the underlying mechanism remains elusive. In order to investigate the mechanism of TMT-induced inhibition of energy metabolism, C57BL/6 male mice were administered by IP injection in different TMT doses (0 mg/kg, 1.00 mg/kg, 2.15 mg/kg and 4.64 mg/kg) and times (1d, 3d and 6d), and then the changes of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level and Na+-K+-ATPase activity in cerebral cortex, cerebellum, hippocampus, pons, medulla oblongata of mice, the expressions of Na+-K+-ATPase protein, AMP-activated protein kinase (AMPK), phosphorylated AMP-activated protein kinase(p-AMPK)and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) in hippocampus and medulla oblongata were measured; the effects of TMT on the viability, the activity of SOD, glutathione (GSH) and Na+-K+-ATPase, MDA level, and the expression of PGC-1α and Na+-K+-ATPase protein in N2a cells were measured by different TMT doses and times, in order to verify the experiments in vivo. Our results found that most of the mice showed depression, tremor, epilepsy, spasm and other symptoms after TMT exposure. Moreover, with the increase of TMT dose, the activity of Na+-K+-ATPase and the expressions of AMPK protein in the hippocampus and medulla oblongata of mice decreased, and the expressions of p-AMPK protein increased. Peroxidative damage was evident in hippocampus, medulla oblongata of mice and N2a cells, and the expression of PGC-1α and Na+-K+-ATPase protein was significantly down-regulated. Therefore, it is reasonable to believe that TMT-induced neurotoxic symptoms and inhibition of energy metabolism may be related to p-AMPK and down-regulation of PGC-1α in the hippocampus and medulla oblongata.

This manuscript aimed to describe and analyze acute trimethyltin poisoning caused by exposure to polyvinyl chloride production and review the literature. Combined with an analysis of occupational hygiene survey data, the clinical data of 8 cases of acute trimethyltin poisoning were analyzed retrospectively. The clinical manifestations of acute trimethyltin poisoning are mainly related to central nervous system damage, hypokalemia and metabolic acidosis in patients with severe poisoning. Early positive potassium supplementation and symptomatic treatment are beneficial to the improvement of the condition. The early recognition of central nervous system manifestations and hypokalemia is beneficial for early diagnosis and correct treatment.

Trimethyltin (TMT) is widely used in industry and agriculture. The present study aims to clarify the effects of in vitro TMT exposure on androgen biosynthesis and metabolism in immature Leydig cells (ILCs), and to unveil the underlying mechanism. It was found that 1-10μM TMT decreased ILC androgen productions under basal conditions. TMT at 10μM decreased luteinizing hormone (LH) or 8-Br-cAMP (8BR)-stimulated androgen productions from ILCs. TMT at 10μM decreased 22R-hydroxycholesterol (22R) and androstenedione (D4)-mediated androgen productions from ILCs. TMT at 0.1-10μM down-regulated the mRNA or protein expression levels of STAR, CYP11A1, 17β-HSD3, or NR5A1. TMT at 10μM directly inhibited the enzyme activities of CYP11A1 and 17β-HSD3. In conclusion, the present study demonstrated that in vitro TMT exposure decreased ILC function of androgen production, via exerting negative effects on the mRNA/protein expression levels, or enzyme activities of STAR, CYP11A1, 17β-HSD3, or NR5A1.

Trimethyltin chloride (TMT) is a stabilizer by-product in the process of manufacturing plastic, which is a kind of very strong toxic substance, and has acute, cumulative and chronic toxicity. TMT may cause bradycardia in patients with occupational poisoning, the mechanism of which has not been reported. This study explored the mechanism of TMT resulting in bradycardia of C57BL/6 mice. TMT was administered to mice to measure heart rate, serum succinate dehydrogenase (SDH) level, and myocardial Na+/K+-ATPase activity and expression. The effects of TMT on myocardial apoptosis were observed by changing the expressions of caspase-3, Bax and Bcl-2 in myocardium. It was found that the heart rate and SDH activity in serum of mice gradually decreased with the increase of TMT dose compared with the control group. The activity and the expression of Na+/K+-ATPase in the heart tissue of mice exposed to TMT was measured and gradually decreased with the increase of dose and time. We measured the expression of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the heart tissues of TMT exposed mice and found that the expressions of Bax, caspase-3 and cleaved caspase-3 increased and the expressions of Bcl-2 decreased in the heart tissues of the TMT-exposed mice at different doses. With the extension of TMT exposure time, the expression of Bax and caspase-3 increased and the expression of Bcl-2 decreased in the heart tissues of TMT exposed mice. Our findings suggest the mechanisms of TMT resulting in bradycardia may be associated with the inhibited activity and decreased content of Na+/K+-ATPase, thus further leading to the changes of Bcl-2, Bax, caspase-3 and cleaved caspase-3 in the mice\'s ventricular tissues.

Trimethyltin chloride (TMT) is widely used as a constituent of fungicides and plastic stabilizers in the industrial and agricultural fields, and is generally acknowledged to have potent neurotoxicity, especially in the hippocampus; however, the mechanism of induction of neurotoxicity by TMT remains elusive. Herein, we exposed Neuro-2a cells to different concentrations of TMT (2, 4, and 8 μM) for 24 h. Proteomic analysis, coupled with bioinformatics analysis, revealed the important role of macroautophagy/autophagy-lysosome machinery in TMT-induced neurotoxicity. Further analysis indicated significant impairment of autophagic flux by TMT via suppressed lysosomal function, such as by inhibiting lysosomal proteolysis and changing the lysosomal pH, thereby contributing to defects in autophagic clearance and subsequently leading to nerve cell death. Mechanistically, molecular interaction networks of Ingenuity Pathway Analysis identified a downregulated molecule, KIF5A (kinesin family member 5A), as a key target in TMT-impaired autophagic flux. TMT decreased KIF5A protein expression, disrupted the interaction between KIF5A and lysosome, and impaired lysosomal axonal transport. Moreover, Kif5a overexpression restored axonal transport, increased lysosomal dysfunction, and antagonized TMT-induced neurotoxicity in vitro. Importantly, in TMT-administered mice with seizure symptoms and histomorphological injury in the hippocampus, TMT inhibited KIF5A expression in the hippocampus. Gene transfer of Kif5a enhanced autophagic clearance in the hippocampus and alleviated TMT-induced neurotoxicity in vivo. Our results are the first to demonstrate KIF5A-dependent axonal transport deficiency to cause autophagic flux impairment via disturbance of lysosomal function in TMT-induced neurotoxicity; manipulation of KIF5A may be a therapeutic approach for antagonizing TMT-induced neurotoxicity.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTB: actin beta; AGC: automatic gain control; ATG: autophagy-related; ATP6V0D1: ATPase H+ transporting lysosomal V0 subunit D1; ATP6V1E1: ATPase H+ transporting lysosomal V1 subunit E1; CA: cornu ammonis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; DCTN1: dynactin subunit 1; DG: dentate gyrus; DYNLL1: dynein light chain LC8-type 1; FBS: fetal bovine serum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IPA: Ingenuity Pathway Analysis; KEGG: Kyoto Encyclopedia of Genes and Genomes; KIF5A: kinesin family member 5A; LAMP: lysosomal-associated membrane protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRM: parallel reaction monitoring; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SYP: synaptophysin; TAX1BP1: Tax1 binding protein 1; TMT: trimethyltin chloride; TUB: tubulin.