Feasibility study of PET/CT for the detection and localization of nervous system damage caused by trimethyltin chloride

doi:10.21203/rs.3.rs-4973147/v1

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Feasibility study of PET/CT for the detection and localization of nervous system damage caused by trimethyltin chloride

https://doi.org/10.21203/rs.3.rs-4973147/v1

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Trimethyltin chloride (TMT), an organotin compound with potent neurotoxicity, is widely used as a heat stabilizer for plastics. however, the precise pathogenic mechanism of TMT remains incompletely elucidated, and there persists a dearth of sensitive detection methodologies for early diagnosis of TMT. In this study, Sprague-Dawley rats were treated with 10 mg/kg TMT to simulate acute exposure in humans. Micro-positron emission tomography/computed tomography (Micro-PET/CT) and molecular imaging quantitative analysis tools were employed to calculate the uptake rate of 18F-2-fluoro-D-deoxy-glucose in each functional region of brain tissue. At the same time, the neurobehavioral test and neuropathological results of the experimental rats were compared, aiming to assess the feasibility of PET/CT in the detection and localization of TMT nervous system damage from many aspects. The results showed that TMT decreased glucose uptake in a wide range of brain tissues in rats, and impaired the memory, muscle strength, coordination ability and emotion of rats. Moreover, TMT induced neuronal damage within the cerebral cortex, hippocampal CA1, CA3 and DG regions as well as the cerebellum while also promoting gliosis surrounding the hippocampus. PET/CT imaging results are highly consistent with behavioral and pathological results. In conclusion, TMT induces a widespread reduction in energy metabolism across various brain regions, and PET/CT can serve as a sensitive detection method for TMT-induced encephalopathy.

Biological sciences/Neuroscience

Earth and environmental sciences/Environmental social sciences

Health sciences/Health occupations

trimethyltin chloride

animal model

positron emission computed tomography (PET-CT)

neurobehavioral experiments

brain tissue

metabolism

The trimethyltin chloride (TMT) compound is a crucial constituent in mechanical tin compounds and finds extensive usage due to its excellent performance as a plastic heat stabilizer, low dosage requirement, and high transparency^1,2. TMT exhibits high toxicity, being soluble in both lipids and water, volatile under heat conditions, and capable of entering the body through various routes³. As plastic products, especially polyvinyl chloride, are widely used in the production of building materials such as water pipes, plastic films, packaging bags and other daily products, excessive exposure to TMT is not only easy to occur in the fields of occupational health such as plastic processing and laboratories, but also common in people's daily life^4,5.

TMT can cause multi-system and multi-organ damage, but previous studies mostly focused on kidney and cardiac toxicity^6-8. It is worth noting that TMT has strong neurotoxicity, which can cause dizziness, headache, memory loss, mania, hallucinations, hearing impairment, limb tremor, epileptic seizures, coma and even death^9-11. However, the study of neurotoxicity is still in its nascent stage with an incomplete understanding of the underlying pathogenic mechanisms. To date, only a limited number of cases involving brain CT or MRI imaging have been reported with a relatively low positive detection rate^12,13. At present, there is still a lack of sensitive and accurate early detection methods for TMT poisoning.

Functional damage often precedes organic tissue damage. Normal brain function is closely associated with energy metabolism, wherein glucose serves as the primary source of energy. 18F-2-Fluro-D-deoxy-glucose (18F-FDG) can be employed as a marker for assessing brain glucose metabolism and is frequently utilized in Positron Emission Tomography/Computed Tomography (PET/CT). It has been widely used in oncology, neurology and other fields^14,15, but there has been no report on the evaluation of the application of PET/CT in TMT poisoning.

In this study, we employed Micro-PET/CT to dynamically observe changes in overall brain glucose metabolism imaging and anatomical imaging in rats exposed to TMT and normal control rats at different time points, and then the 18F-FDG uptake rate in each functional region of brain tissue was calculated by molecular imaging quantitative analysis tools. At the same time, the neurobehavioral indexes and neuropathological results of the experimental rats were compared, aiming to evaluate the feasibility of PET/CT in detecting and localizing nervous system damage caused by TMT from multiple aspects. This study aims to provide a new evaluation method for diagnosing and treating TMT poisoning while shedding light on its underlying mechanisms.

Animals

48 specific pathogen free healthy Sprague-Dawley rats [Guangdong Medical Laboratory Animal Center, Laboratory animal use License number: [SYXK (Guangdong) 2019-0048], half male and half female, aged 6–7 weeks, weighing 180–220 g, were provided by Guangdong Medical Laboratory Animal Center. The feeding conditions of rats were in line with the requirements of GB 14925 − 2010 "Laboratory animal environment and facilities", and they had free access to food and water. At the end of the experiment, all experimental animals were sacrificed under anesthesia with sodium pentobarbital. This study was approved by the Experimental Animal Ethics Committee of Guangdong province hospital for occupational disease prevention and treatment. All methods were performed in accordance with relevant guidelines and regulations. All methods are reported in accordance with ARRIVE guidelines.

Reagents and main equipment

TMT (Sigma Company, USA) dissolved in saline; Sodium pentobarbital (Beijing Solaibao Technology Co., LTD.); 18F-FDG (radiochemical purity > 95.0%, Department of Radiology, the First Affiliated Hospital of Sun Yat-sen University); HE staining solution set, Nicil staining solution set, and myelin staining solution set (Wuhan Saiwell Biotechnology Co., LTD.). Micro-PET/CT scanner, Inveon research workplace 4.2 software (Siemens Medical Solutions, Germany); PMOD 4.2 software (PMOD, Switzerland); Spontaneous activity (open field) experimental analysis system, diving platform avoidance integrated analysis system, Morris water maze system (Guangzhou Feidi Biological Technology Co., LTD.).

Animal grouping and experimental design

The experimental rats were randomly divided into the model group (n = 8) and the control group (n = 8). The rats in the model group were given a single intraperitoneal injection of 10 mg/kg body weight TMT¹⁶, while the rats in the control group were given a single intraperitoneal injection of the same volume of 0.9% sodium chloride solution. The following experiments were performed: 1) PET/CT scans were performed on the 1st and 7th day after modeling; 2) Morris water maze test was performed continuously from day 1 to day 6 after modeling. 3) The step down test, coat hater test and open field test were performed on the first and seventh days after modeling. During the experiment, the body weight, appetite, fur and activity of rats in each group were observed and recorded. At the end of the experiment, the brain histopathology was observed.

PET/CT scan and Imaging analysis

The rats were fasted for 8 h and deprived of water for 4 h before PET examination. The rats were anesthetized by intraperitoneal injection of 0.3% sodium pentobarbital (at a dose of 1 mL /kg body weight). About 20min later, Micro-PET/CT scans were performed: CT scan for 5min, PET scan for 10min, and still images were acquired using Inveon research workplace 4.2 software for 20min. The scanning range was from cranial top to neck. Scanning parameters: voltage 80 kV, current 500 µA, the scanning process was under anesthesia.

The PET images of each rat were automatically identified and delineated by PMOD 4.2 software, and the standardized uptake value (SUV) was calculated, SUV = CT· VT/WT· 1/ID· Ws, where CT represents the radioactivity in local tissues. VT and WT represent body weight and volume, the ratio of the two represents the density of the local tissue (1g/cc), ID represents the injection dose (µCi), Ws represents the body weight (g) of the examined rat, and SUV has no specific list.

Behavioral experiments

Before all behavioral experiments, the experimental animals were transported to the behavioral laboratory and acclimated to the environment for 2 to 3 hours to reduce animal stress.

Morris water maze: Rats were trained for 5 consecutive days, each rat was trained 4 times a day, and the water entry points were randomly selected from the four quadrants each time, and the training interval was 20 minutes. The time of successful landing on the platform was recorded as the latency period. Twenty-four hours after the end of the last acquired training, the platform was removed, and the quadrant opposite to the platform (target quadrant) was selected as the water entry point. The rats were tested, and the latency or the number of crossing the platform and the retention percentage of the target quadrant were recorded¹⁷. The pool has a diameter of 1600mm and a height of 80mm.

Open field test: The rats were placed in the center of the open field, and the video recording system was turned on quickly for 10 minutes. After the experiment ended, each rat's test site was meticulously cleansed with 75% ethanol to ensure cleanliness and eliminate odor. The total distance, average speed, activity time in the central area, activity distance in the central area, activity time in the peripheral area, activity distance in the peripheral area, and activity time in the four corners of the rats were recorded¹⁸. The open field size was 1000mm×1000mm×500mm cube.

Step down test: The rats were put into the passive conditioning box to adapt for 5min. After the adaptation, the 60V alternating current was turned on, and the rats would generally jump on the insulated platform to avoid the shock, and the training was recorded for 5min. After 24h of training, the rats were placed on the insulated platform while the power was on. The latency (the first time of jumping off the platform to be electrified) and the number of errors within 5min (the number of jumping off the insulated platform) were recorded ¹⁹.

Coat hater test: The device is self-made, similar in shape to a coat hater, with a horizontal length of 30cm and a distance of 40cm from the ground. The forepaw of the rat was made to grasp the center of the horizontal part of the coat rack and observed for 30s. Rats were assigned 0 points for falling from the hashing within 10s, 1 point for front PAWS hanging from the hashing, 2 points for attempting to climb on the hashing, 3 points for front PAWS and at least one hind paw hanging from the hashing, 4 points for limbs and tail wrapping around the hashing, and 5 points for attempting to escape to the end of the horizontal part. Used to evaluate limb muscle strength and coordination ability²⁰.

Histopathological examination of the brain

After PET/CT scan and behavioral test, the rats were anesthetized by intraperitoneal injection of 0.3% sodium pentobarbital (at a dose of 1 mL /kg body weight), and blood was collected through the abdominal aorta. After death, the brain tissues of the rats were quickly stripped and washed with precooled PBS buffer. Half of the brain tissue was cut for routine fixation, dehydration, paraffin embedding and sectioning at 4 µm. Then Hematoxylin-Eosin (HE) staining, Nissl staining, and Luxol Fast Blue (LFB) staining were performed. The pathological changes were observed under light microscope. The remaining brain tissue was stored in the refrigerator at -80℃.

Statistical analysis

Statistical analysis was performed using SPSS 26.0 software. The measurement data conforming to normal distribution or approximately normal distribution were analyzed by student t-test. The Mann-Whitney U (also called Wilcoxon) test was used for count data or measurement data that did not obey normal distribution. Data were presented as mean ± standard deviation, with a significance level set at α = 0.05.

Recognized indications of TMT poisoning encompass tremor, hyperexcitability, aggressive demeanor, weight reduction, and convulsions²¹. In this study, we observed that the rats in the model group had spasms 30 minutes after TMT exposure, and the spasms disappeared several hours later. Starting from the second day after exposure, the rats had obvious aggression, irritability, slight tremor of the head, and a few had strong convulsions, limb weakness, rigidity, and epistaxis, and the symptoms continued to death. The body weight of the rats in the control group exhibited a gradual increase, while the rats in the model group demonstrated a significant decrease in body weight. By the 7th day following TMT exposure, the body weight of rats in the model group (172.26±27.24) was significantly lower compared to that of the control group (251.11±33.22) (Fig. 1).

TMT caused memory impairment, muscle weakness, mild anxiety and depression symptoms in rats

Patients with TMT poisoning are often accompanied by symptoms such as memory loss, limb weakness, and temperament change²². Accordingly, we conducted a series of behavioral tests on rats in the model group and the control group. The results showed that TMT exposure caused significant damage to the learning and memory ability of rats. With the extension of the days of morris water maze training, the time of TMT exposed rats to find the escape platform was prolonged. After the platform was removed, the rats did not explore the area where the platform existed, but swam without direction, and the times of crossing the position of the platform were significantly reduced (P<0.05). (Fig. 2 a-e). In addition, the Step down test showed that the time from the platform to the electric bar (latency) was significantly reduced and the number of shocks (errors) was significantly increased in TMT exposed rats (P<0.05), while the normal control rats almost did not jump off the platform (Fig. 2 l-m). These two experiments suggest that TMT may affect both long-term and short-term memory. The open field test showed that TMT had little effect on the overall activity (total distance and average speed) of rats (Fig. 2 f-g). On the 7th day after TMT exposure, due to the weakening of muscle strength, the rats moved slowly in the central area, resulting in an increase in the time of activity in the central area (P<0.05), but a reduction in the distance in the central area (P<0.05), indicating that the activity of the rats in the central area decreased after TMT exposure. It is suggested that TMT has a certain effect on the mood of rats and may cause anxiety and depression symptoms. (Fig. 2 h-k). Furthermore, The results of coat hater test showed that the muscle strength of rats was weakened 24 hours after TMT exposure (P<0.05), and the muscle strength was further weakened and the coordinated movement ability was poor on the 7th day (P<0.05), suggesting that TMT damage the muscle strength and coordinated movement ability of rats. (Fig. 2 n).

TMT resulted in a significant reduction in 18F-FDG uptake across a broad range of brain tissue in rats

PET/CT imaging showed that the 18F-FDG uptake in the brain tissue of the model group was slightly reduced compared with the control group at 24 hours after TMT exposure. By the 7th day, there was a significant decrease in 18F-FDG uptake throughout the brain tissue of the model group, as compared to the control group (Fig. 3).

The standardized uptake value (SUV) is the most commonly employed quantitative tool for assessing 18F-FDG uptake. At 24 hours after TMT modeling, there was a slight decrease in SUV values in each brain region compared to the control group, but this difference was not statistically significant (P>0.05). However, on the 7th day post-modeling, the model group exhibited significantly lower SUV values than the control group in various regions including bilateral striatum, auditory cortex, cingulate cortex, frontal association cortex, medial prefrontal cortex, motor cortex, orbitofrontal cortex, retrosplenial cortex, somatosensory cortex, visual cortex, hippocampus antero dorsal, and septum (all P<0.05). Additionally, the right accumbens, entorhinal cortex, insular cortex, hippocampus posterior, olfactory, colliculus superior, cerebellum, colliculus inferior and thalamus also displayed significantly lower SUV values compared to those of the control group (all P<0.05) (Table 1). Functional description of the regions of difference (Supplementary Table S1).

TMT caused pathological damage in cerebral cortex, cerebellum and hippocampus

The freshly dissected brain tissue of the control group and the model group exhibited a pale pink color, with no apparent signs of edema, congestion, or pallor in the brain of the model group (Fig. 4). The average brain organ coefficient of the model group (10.05±0.16) g/kg was significantly higher than that of the control group (7.64±0.08) g/kg (t=3.91, P=0.002).

The HE staining showed that more neurons in the cerebral cortex of rats were shrunk at 24 hours and 7 days after TMT modeling. Pyramidal cell necrosis was rare in the CA2, CA3 and DG areas of the hippocampus, and the number of peripheral glial cells was slightly increased. A large number of Purkinje cells in the cerebellar cortex were shrunken. No obvious abnormality was found in the control group. (Fig. 5a). The results of Nissl staining showed that more neurons in the cerebral cortex of rats were shrunk at 24 hours and 7 days after TMT modeling. The pyramidal cells in CA1, CA3 and DG areas of hippocampus were more irregularly arranged and the number of cells was reduced. The arrangement of Purkinje cells in the cerebellar cortex was slightly irregular, and most Purkinje cells were shrunken. No obvious abnormality was found in the control group. (Fig. 5b). However, the results of LFB staining showed that there was no significant demyelination in the brain and cerebellum of rats 24 hours and 7 days after TMT compared with the control group. (Fig. 5c).

TMT is a highly toxic chemical that can be used as an organic synthesis reagent for the preparation of other organotin compounds. Since TMT is widely used as a heat stabilizer for plastics due to its good effect and high transparency, it is not only easy to expose TMT in the production process, but also easy to cause TMT to migrate into water and food during the circulation and use of plastic products, posing a threat to public health²³. Although a growing body of evidence has pointed out the harmful effects of TMT, the mechanism of neurotoxicity caused by TMT is still in the exploratory stage, and there is a lack of sensitive imaging detection methods for early TMT poisoning. In this study, we used Micro-PET/CT to quantify and locate the brain energy metabolism of TMT exposed rats, and found that PET/CT of TMT exposed rats had abnormalities in the early stage, and the abnormal brain functional areas were highly consistent with the symptoms of TMT neurotoxicity. PET/CT can be used as a sensitive method to detect TMT poisoning, and the decrease of brain glucose metabolism is the key cause of TMT induced central nervous system damage.

The reported cases of TMT poisoning present with initial nonspecific symptoms such as dizziness, headache, and fatigue. Subsequently, some cases exhibit additional manifestations of toxic encephalopathy including memory loss, altered consciousness, epilepsy, aggressive behavior, mania, and other neuropsychiatric symptoms^24,25. In a few instances, hallucinations and hearing abnormalities have also been observed^26,27. In this study, rats exposed to TMT displayed spasms, aggressive behavior, irritability, slight head tremor; while severe symptoms such as convulsions, limb weakness, rigidity, and epistaxis were also noted. Furthermore, the behavioral experiments revealed that TMT induced impairments in long-term and short-term memory, muscle strength, motor coordination ability, and emotional responses in rats. The findings align with the outcomes of prior investigations.

MRI serves as a valuable tool for diagnosing various forms of toxic encephalopathy and effectively assessing the patient's condition. However, in clinical studies on TMT poisoning, it has been observed that the MRI examination yields a relatively low positive rate, with an overall abnormality rate of approximately 13%, and lacks specificity in lesion identification. Electroencephalogram plays a supplementary role in the clinical diagnosis and prognosis assessment of different types of toxic encephalopathy; however, previous reports indicate an abnormality rate of only about 50%^11,12. Researchers have followed up 6 patients with TMT poisoning after 2 years, and found that the initial MRI of these patients was not significantly abnormal, but the head MRI results 2 years later showed significant atrophy of bilateral temporal lobe, hippocampus, insular lobe, cerebellum and ventricular enlargement^28,29. This suggests that there may be non-organic brain damage in TMT patients before it progresses to substantial damage.

Some scholars posit that TMT acts as a potent metabolic inhibitor, suppressing mitochondrial ATP synthesis and impeding the phosphorylation cascade involved in oxidative phosphorylation. Consequently, these neuropsychiatric symptoms arise from aberrant alterations in biological metabolism due to disruptions in neuronal ATP synthesis^30,31. Glucose serves as an indispensable energy source for the adult brain, with its catabolism and anabolism intricately linked to energy production, neurotransmission, management of oxidative stress, and cellular component growth and repair^32,33. 18F-FDG PET/CT can analyze brain glucose metabolism and provide anatomical location, which is an effective method to evaluate brain metabolism^34,35. Therefore, 18F-FDG Micro-PET/CT analysis of TMT exposed rats showed that glucose uptake in a wide range of regions of the brain was decreased after TMT exposure.

The hippocampus is widely recognized for its close association with memory function. Previous studies have predominantly focused on the hippocampus due to its sensitivity to TMT^36-38, as shown by Micro-PET/CT results, the glucose uptake value of the hippocampus is significantly reduced. Additionally, other memory-related areas such as the entorhinal cortex, medial prefrontal cortex, retrosplenial cortex, and somatosensory cortex also exhibited significantly reduced glucose uptake The insular cortex, orbitofrontal cortex, cingulate cortex, and frontal cortex are extensively interconnected and play vital roles in emotion generation, processing, regulation as well as various activities including addiction, aggression, fear response modulation, error monitoring problem-solving, and social cognition. The observed mental abnormalities in TMT-poisoned patients and TMT-exposed rats are likely associated with reduced glucose uptake within these regions. Numerous studies have highlighted the critical involvement of the dorsal hippocampus in acute epilepsy onset, suggesting a potential association between seizures and convulsions induced by TMT poisoning with this brain region.

Previous studies have demonstrated that exposure to TMT induces neurodegeneration^39,40. Although the main function of olfactory nerve is to transmit odor, it has been reported that olfactory dysfunction is a prodromal symptom of Parkinson's disease and Alzheimer's disease, which can be explained by the decrease of glucose uptake value of olfactory nerve. The presence of hallucinations and tinnitus in poisoning cases is associated with abnormal energy metabolism in corresponding functional areas. Research indicates that the superior colliculus serves as a higher center for vision, while the visual cortex processes visual information; thus, reductions in signals within the visual cortex may give rise to visual hallucinations. The striatum, somatosensory cortex, and thalamus play crucial roles in perceiving and processing sensory information from the body, regulating movement, attention, and consciousness. Additionally, both the motor cortex and cerebellum are involved in planning, controlling, and executing voluntary movements, aligning well with the neuropsychiatric symptoms induced by TMT.

Pathological studies have been conducted on various brain regions of rats exposed to TMT, revealing extensive neurotoxicity in areas such as the olfactory region, hippocampus, amygdala, cortex, cerebellum, pons, inferior colliculus and superior colliculus, hypoglossal nucleus, and thalamus. These findings are consistent with our PET-CT conclusions^41,42. In this study, it was also observed that neurons in the cerebral cortex, hippocampal CA1, CA3 and DG areas and cerebellum were damaged after TMT exposure, and increased glial cells could be observed around the hippocampus^43,44. In addition, it was found that the brain coefficient of the exposed rats was significantly higher than that of the control group, but there was no obvious edema or congestion in the appearance of brain tissue and pathological section, which was considered to be caused by the weight loss of the exposed rats. It has been reported that the head CT of patients with TMT poisoning showed demyelinating degeneration of the white matter⁴⁵. Therefore, we used LFB staining to observe the morphological structure and pathological changes of the nerve myelin sheath, but unfortunately no demyelinating injury was observed. In summary, although there are some slight changes in brain histopathological examination, the area and obvious degree of changes are far less extensive than those of PET-CT.

In conclusion, when there is no obvious organic damage in the early stage of TMT poisoning, PET/CT examination can detect early abnormal functional changes in brain tissue, which is highly consistent with the symptoms shown by clinical patients and exposed rats, and precede pathological and conventional imaging changes. This study is an exploration of the application of PET/CT in the diagnosis and evaluation of TMT, however, certain limitations should be acknowledged. Further research is warranted to elucidate the underlying mechanism responsible for reduced brain energy intake caused by TMT. Nevertheless, these results undeniably support the feasibility of utilizing PET/CT technology for detecting TMT poisoning, thereby suggesting its potential as a valuable tool for early diagnosis, differential diagnosis, and disease assessment of toxic encephalopathy induced by TMT.

Acknowledgments and Contributions

This work was supported by the Guangzhou Science and Technology Program (Grant No. 201804010063 [to Ming Huang]) and National Key Clinical Specialty Construction Project, China (Grant No. 2011-09 [to Ming Huang]).

Anqing Liu (first author): Methodology, Investigation, Formal analysis, Writing - Original Draft. Qingqiang Tu: Software, Investigation, Supervision. Ming Huang:(corresponding author): Conceptualization, Project administration, Funding acquisition.

Competing interests

The authors report no biomedical financial interests or potential conflicts of interest.

Data availability

Data are provided in the manuscript, tables, and supplementary information files.

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Tables 1 to 2 are available in the Supplementary Files section

No competing interests reported.

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Editorial decision: Revision requested
15 Oct, 2024
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Editor invited by journal
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Feasibility study of PET/CT for the detection and localization of nervous system damage caused by trimethyltin chloride

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