Exposure to Trimethyltin Chloride Induces Pyroptosis and Immune Dysfunction in Grass Carp CIK Cells by Activating the NF-κB Pathway Through Oxidative Stress.

Trimethyltin chloride (TMT) is a highly toxic organotin pollutant frequently found in aquatic environments, posing a significant threat to the ecological system. The kidney plays a vital role in the body's detoxification processes, and TMT present in the environment tends to accumulate in the kidneys. However, it remained unclear whether exposure to different doses of TMT could induce pyroptosis and immune dysfunction in grass carp kidney cells (CIK cells). For this purpose, after assessing the half-maximal inhibitory concentration (IC50) of TMT on CIK cells, we established a model for exposure of CIK cells at varying concentrations of TMT. CIK cells were treated with various doses of TMT (2.5, 5, 10 µM) for 24 h. Oxidative stress levels were measured using kits and fluorescence methods, whereas the expression of related genes was verified through western blot and quantitative real-time PCR (qRT-PCR). The results indicated that TMT exposure led to oxidative stress, with increased levels of ROS, H2O2, MDA, and GSH, and inhibited activities of T-AOC, SOD, and CAT. It activated the NF-κB pathway, leading to the upregulation of NF-κB p65, NF-κB p50, GSDMD, NLRP3, ASC, and Caspase-1. Furthermore, TMT exposure also resulted in increased expression of cytokines (IL-18, IL-6, IL-2, IL-1ß, and TNF-α) and decreased expression of antimicrobial peptides (LEAP2, HEPC, and ß-defensin). In summary, exposure to TMT induces dose-dependent oxidative stress that activates the NF-κB pathway, leading to pyroptosis and immune dysfunction in grass carp CIK cells.

Trimethyltin chloride induces apoptosis and DNA damage via ROS/NF-κB in grass carp liver cells causing immune dysfunction.

Trimethyltin chloride (TMT), a common component in fungicides and plastic stabilizers, presents environmental risks, particularly to fish farming. The precise toxicological mechanisms of TMT in L8824 grass carp liver cells remain undefined. Our study investigates TMT's effects on these cells, focusing on its potential to induce hepatotoxicity via oxidative stress and NF-κB pathway activation. First, we selected 0, 3, 6, and 12 µM as the challenge doses, according to the inhibitory concentration of 50% (IC50) of TMT. Our results demonstrate that TMT decreases cell viability dose-dependently and triggers oxidative stress, as evidenced by increased ROS staining and MDA content. Concurrently, it inhibited the antioxidant activities of T-AOC, T-SOD, CAT, and GSH. The activation of the NF-κB pathway was confirmed by gene expression changes. Furthermore, we observed an increase in cell apoptosis rate by AO/EB staining and cell flow cytometry, and the downregulation of Bcl-2 and the upregulation of Bax, Cytc, Caspase-9, and casp3 verified that TMT passed through the BCL2/BAX/casp3 pathway induces apoptosis. DNA damage was validated by the comet assay and γH2AX gene overexpression. Lastly, our data showed increased expression of TNF-α, IL-1ß, IL-6, and INF-γ and decreased antimicrobial peptides, validating immune dysfunction. In conclusion, our findings establish that TMT induces apoptosis and DNA damage via ROS/NF-κB in grass carp liver cells, causing immune dysfunction. This study provides novel insights into the toxicology research of TMT and sheds light on the immunological effects of TMT toxicity, enriching our understanding of the immunotoxicity of TMT on aquatic organisms and contributing to the protection of ecosystems.

Trimethyltin chloride exposure induces apoptosis and necrosis and impairs islet function through autophagic interference.

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 ß cell) function.

[Three cases of occupational acute trimethyltin chloride poisoning].

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.

Deep Learning-Based Segmentation of Morphologically Distinct Rat Hippocampal Reactive Astrocytes After Trimethyltin Exposure.

As regulators of homeostasis, astrocytes undergo morphological changes after injury to limit the insult in central nervous system (CNS). Trimethyltin (TMT) is a known neurotoxicant that induces reactive astrogliosis in rat CNS. To evaluate the degree of reactive astrogliosis, the assessment relies on manual counting or semiquantitative scoring. We hypothesized that deep learning algorithm could be used to identify the grade of reactive astrogliosis in immunoperoxidase-stained sections in a quantitative manner. The astrocyte algorithm was created using a commercial supervised deep learning platform and the used training set consisted of 940 astrocytes manually annotated from hippocampus and cortex. Glial fibrillary acidic protein-labeled brain sections of rat TMT model were analyzed for astrocytes with the trained algorithm. Algorithm was able to count the number of individual cells, cell areas, and circumferences. The astrocyte algorithm identified astrocytes with varying sizes from immunostained sections with high confidence. Algorithm analysis data revealed a novel morphometric marker based on cell area and circumference. This marker correlated with the time-dependent progression of the neurotoxic profile of TMT. This study highlights the potential of using novel deep learning-based image analysis tools in neurotoxicity and pharmacology studies.

TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome.

Trimethyltin chloride (TMT) is an organotin heat stabilizer that is widely used in the production of plastics, and has strong toxicity. Here, the effect of trimethyltin chloride on mouse kidneys and its related mechanism were studied by taking TMT mouse with drinking water as a model. Histological examination and TUNEL results showed that the trimethyltin chloride group had typical apoptosis and necroptosis characteristics. Therefore, the level of oxidative stress was detected,and the expression of related genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot methods. The results showed that oxidative stress was activated (MDA,SOD,CAT,T-AOC), released ROS, activated NF-κB pathway,activated inflammasome (NLRP3,Caspase-1,ASC), and inflammasome-secreted inflammatory factors (IL-1ß). The expression of apoptosis (BCL-2, BAX, Caspase-3, Caspase-9) and necroptosis (RIPK1, RIPK33, MLKL, Caspase-8) increased.In addition, HEK293T human embryonic kidney cells were treated with trimethyltin chloride, and the results were similar to the tissue. In conclusion, TMT can induce oxidative stress, activate NF-κB pathway, and induce apoptosis and necroptosis through inflammasomes.

Autophagy in Neurons of the Prefrontal Cortex and Hippocampus of Rats after Trimethyltin Chloride Intoxication.

Ultrastructural studies of the hippocampus and the prefrontal cortex of rats were performed 7, 30, and 50 days after their damage by neurotoxicant trimethyltin chloride (TMT). Significant damage to neurons was observed in both brain structures. In the hippocampus, a large number of autophagosomes (0.9±0.1 per µm2) appeared in the soma of neurons, dendrites, and axons in 7 days after intoxication. In addition, we observed the appearance of hyperchromic neurons with abnormal structure of mitochondria. In the prefrontal cortex, damaged neurons also contained autophagosomes, but their number was significantly lower (0.3±0.1 per µm2). The number of autophagosomes decreased with increasing the time after TMT administration: 30 days after injection, the content of autophagosomes in the hippocampus was 0.10±0.01 per µm2, while in the prefrontal cortex, autophagosomes were no longer found. We hypothesized that autophagy in the hippocampus was not effective enough to prevent neuronal death caused by the neurotoxicant.

[Follow up analysis of 6 patients with severe trimethyltin chloride poisoning for 4 years].

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.

[Characteristics of clinical, Magnetic Resonance Imaging and electroencephalogram after trimethyltin chloride poisoning].

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.

[Clinical analysis of sequelae of acute trimethyltin oxide poisoning].

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.

[Electromyography analysis in 13 patients with acute trimethyltin chloride poisoning].

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.

Chronic trimethyltin chloride exposure and the development of kidney stones in rats.

We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague-Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg(-1) day(-1). Transient behavioral changes were observed in the high-dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H(+)/K(+)-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg(-1) day(-1) dose group and 3 out of 9 rats in the 131.3 µg kg(-1) day(-1) dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones.

Quantitative proteomics reveals the neurotoxicity of trimethyltin chloride on mitochondria in the hippocampus of mice.

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.

PK2/PKRs pathway is involved in the protective effect of artemisinin against trimethyltin chloride-induced hippocampal injury.

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.

ROS/ER stress contributes to trimethyltin chloride-mediated hepatotoxicity; Tea polyphenols alleviate apoptosis and immunosuppression.

Trimethyltin chloride (TMT) is an organotin-based contaminant present in the water environment that poses a great threat to aquatic organisms and humans. The liver is the detoxification organ of the body and TMT exposure accumulates in the liver. Tea polyphenol (TP) is a natural antioxidant extracted from tea leaves and has been widely used as a food and feed additive. To investigate the mechanism of toxicity caused by TMT exposure on grass carp hepatocytes (L8824 cells) and the mitigating effect of TP, we established a hepatocyte model of TMT toxicity and/or TP treatment. L8824 cells were treated with 0.5 µM of TMT and/or 4 µg/mL of TP for 24 h and assayed for relevant indices. The results showed that TMT exposure caused oxidative stress, resulting in increased intracellular ROS content, resulting in intracellular ROS accumulation and increased MDA content, and inhibiting the activities of T-AOC, SOD, CAT, and GSH. Meanwhile, TMT exposure activated the endoplasmic reticulum apoptotic signaling pathway, resulting in abnormal expression of GRP78, ATF-6, IRE1, PERK, Caspase-3 and Caspase-12. In addition, TMT exposure also led to up-regulation of cytokines IL-1ß, IL-6, TNF-α, and decreased expression of IL-2, IFN-γ, and antimicrobial peptides Hepcidin, ß-defensin, and LEAP2. However, the addition of TP could mitigate the above changes. In conclusion, TP can alleviate TMT exposure-mediated hepatotoxicity by inhibiting ROS/ER stress in L8824 cells. In addition, this trial enriches the cytotoxicity study of TMT and provides a new theoretical basis for the use of TP as a mitigating agent for TMT.

Postnatal exposure to trimethyltin chloride induces retinal developmental neurotoxicity in mice via glutamate and its transporter related changes.

Exposure to toxic substances during postnatal period is one of the major factors causing retinal developmental defects. The developmental toxicity of trimethyltin chloride (TMT), a byproduct of an organotin compound widely used in agriculture and industrial fields, has been reported; however, the effect on the mammalian retina during postnatal development and the mechanism have not been elucidated to date. We exposed 0.75 and 1.5 mg/kg of TMT to neonatal ICR mice (1:1 ratio of male and female) up to postnatal day 14 and performed analysis of the retina: histopathology, apoptosis, electrophysiological function, glutamate concentration, gene expression, and fluorescence immunostaining. Exposure to TMT caused delayed eye opening, eye growth defect and thinning of retinal layer. In addition, apoptosis occurred in the retina along with b-wave and spiking activity changes in the micro-electroretinogram. These changes were accompanied by an increase in the concentration of glutamate, upregulation of astrocyte-related genes, and increased expression of glial excitatory amino acid transporter (EAAT) 1 and 2. Conversely, EAAT 3, 4, and 5, mainly located in the neurons, were decreased. Our results are the first to prove postnatal retinal developmental neurotoxicity of TMT at the mammalian model and analyze the molecular, functional as well as morphological aspects to elucidate possible mechanisms: glutamate toxicity with EAAT expression changes. These mechanisms may suggest not only a strategy to treat but also a clue to prevent postnatal retina developmental toxicity of toxic substances.

Melatonin ameliorates trimethyltin chloride-induced cardiotoxicity: The role of nuclear xenobiotic metabolism and Keap1-Nrf2/ARE axis-mediated pyroptosis.

Trimethyltin chloride (TMT) is a stabilizer for polyvinyl chloride plastics that causes serious health hazards in nontarget organisms. Melatonin (MT) exhibits powerful protective effects in cardiac diseases. As a new environmental pollutant, TMT-induced cardiotoxicity and the protective effects of MT remain unclear. To explore this, the mice were treated with TMT (2.8 mg/kg) and/or MT (10 mg/kg) for 7 days. Firstly, the histopathological and ultrastructural evaluation showed that TMT induced cardiac damage, tumescent rupture and nuclear pyknosis. Moreover, TMT elevated the expressions of pyroptosis genes NLRP3, ASC and Cas1 and inflammation factors IL-6, IL-17 and TNFα. Secondly, TMT reduced antioxidant enzymes (GSH, CAT and T-AOC) via decreasing the expression of genes associated with the Keap1-Nrf2/ARE pathway to increase oxidative stress. Thirdly, TMT decreased the expression of genes associated with the ARE-driven drug metabolizing enzymes (DMEs), including Akr7a3, Akr1b8, and Akr1b10. Besides, TMT upregulated the mRNA expression of nuclear Xenobiotic metabolism on cytochrome P450s enzymes via increasing the expression of CAR, PXP, and AHR genes. Furthermore, MT treatment mitigated the aforementioned adverse changes induced by TMT. Overall, these results demonstrated that TMT caused pyroptosis and inflammation to aggravate cardiac damage via inducing excessive oxidative stress, imbalance of DMEs homeostasis, and nuclear Xenobiotic metabolism disorder, which could be alleviated by MT.

Trans-Anethole Alleviates Trimethyltin Chloride-Induced Impairments in Long-Term Potentiation.

Trans-anethole is an aromatic compound that has been studied for its anti-inflammation, anticonvulsant, antinociceptive, and anticancer effects. A recent report found that trans-anethole exerted neuroprotective effects on the brain via multiple pathways. Since noxious stimuli may both induce neuronal cell injury and affect synaptic functions (e.g., synaptic transmission or plasticity), it is important to understand whether the neuroprotective effect of trans-anethole extends to synaptic plasticity. Here, the effects of trimethyltin (TMT), which is a neurotoxic organotin compound, was investigated using the field recording method on hippocampal slice of mice. The influence of trans-anethole on long-term potentiation (LTP) was also studied for both NMDA receptor-dependent and NMDA receptor-independent cases. The action of trans-anethole on TMT-induced LTP impairment was examined, too. These results revealed that trans-anethole enhances NMDA receptor-dependent and -independent LTP and alleviates TMT-induced LTP impairment. These results suggest that trans-anethole modulates hippocampal LTP induction, prompting us to speculate that it may be helpful for improving cognitive impairment arising from neurodegenerative diseases, including Alzheimer's disease.

Different Activation of IL-10 in the Hippocampus and Prefrontal Cortex During Neurodegeneration Caused by Trimethyltin Chloride.

Anti-inflammatory cytokine interleukin-10 (IL-10) plays a crucial role in controlling the resolution of inflammation. In this study, we aimed to assess gene expression and the level of IL-10 in the hippocampus and prefrontal cortex of rats, after a single injection of neurotoxicant trimethyltin chloride (TMT). It was shown that 4 weeks after the treatment with TMT, the level of IL-10 in the prefrontal cortex, but not in the hippocampus of TMT-treated rats, was increased. However, expression level of IL-10 mRNA was upregulated both in the hippocampus and in the prefrontal cortex 3 weeks after the injection. Concomitantly, within the same post-treatment period, the expression level of the cyclooxygenase-2 was upregulated in both brain structures, indicating the induction of neuroinflammation. Considering that TMT leads to the death of neurons mainly in the hippocampus, we assume that in contrast to the prefrontal cortex, the level of anti-inflammatory cytokine IL-10 in the hippocampus is not sufficiently increased to prevent the damaging effect of the neurotoxicant. Therefore, an exogenous increase in the level of IL-10 may be useful for the survival of neurons in conditions of neurotoxic damage to the hippocampus.

Effect of Trimethyltin chloride on proliferation and cell cycle of intestinal porcine epithelial cells.

Trimethyltin chloride (TMT) is a highly toxic substance produced by organotin heat stabilizers in the synthesis of polyvinyl chloride (PVC) products. TMT is widely used in industry and agriculture. The aim of this study was to investigate the effects of TMT-induced cytotoxicity in intestinal porcine epithelial cells (IPEC-J2). Our study showed that TMT induced a decline in cell viability of IPEC-J2, caused cell shrinkage and rounded cell morphology, reduced the number of proliferating cells and the expression of proliferating cell nuclear antigen (PCNA), and increased lactate dehydrogenase (LDH) activity in cell supernatants. Simultaneously, TMT lowered the mRNA expression of Cyclin B1, and Cyclin D1, but increased P21 and P27 expression. The cell cycle progression was arrested from the G1 to the S phase. Furthermore, the mRNA expression of Bax/Bcl-2 ratio and the protein expression of cleaved Caspase-9 and cleaved Caspase-3 were significantly increased after TMT treatment, while the ratio of advanced apoptotic cells was elevated. These results indicated that TMT blocked the cell cycle, inhibited IPEC-J2 proliferation, and induced apoptosis.