Tributyltin induces apoptosis in mammalian cells in vivo: a scoping review.

The present review aimed to evaluate the apoptotic effect of tributyltin (TBT) exposure on mammalian tissues and cells in vivo. A search was conducted in specialized literature databases including Embase, Medline, Pubmed, Scholar Google, and Scopus for all manuscripts using the following keywords: "tributyltin", "apoptosis", "mammals", "mammalian cells', "eukaryotic cells", 'rodents', "rats", "mice" and "in vivo" for all data published until September 2023. A total of 16 studies were included. The studies have demonstrated that TBT exposure induces apoptosis in cells from various mammalian organs or tissues in vivo. TBT is capable to increase apoptotic cells, to activate proapoptotic proteins such as calpain, caspases, bax and beclin-1 and to inhibit antiapoptotic protein bcl-2. Additionally, TBT alters the ratio of bcl-2/bax which favor apoptosis. Therefore, the activation of enzymes such as calpain induces apoptosis mediated by ERS and caspases through the intrinsic apoptosis pathway. This review has demonstrated that TBT exposure induces apoptosis in mammalian tissues and cells in vivo.

PBAT is biodegradable but what about the toxicity of its biodegradation products?

CONTEXT: Poly(butylene adipate-co-terephthalate) (PBAT) is a biodegradable plastic. It was introduced to the plastics market in 1998 and since then has been widely used around the world. The main idea of this research is to perform quantum chemical calculations to study the potential toxicity of PBAT and its degradation products. We analyzed the electron transfer capacity to determine its potential toxicity. We found that biodegradable products formed with benzene rings are as good electron acceptors as PBAT and OOH•. Our results indicate that the biodegradation products are potentially as toxic as PBAT. This might explain why biodegradation products alter the photosynthetic system of plants and inhibit their growth. From this and other previous investigations, we can think that biodegradable plastics could represent a potential environmental risk. METHODS: All DFT computations were performed using the Gaussian16 at M062x/6-311 + g(2d,p) level of theory without symmetry constraints. Electro-donating (ω-) and electro-accepting (ω +) powers were used as response functions.

Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin.

This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.

Development of methodology for the visual identification of Tributyltin (TBT) in antifouling paint matrices.

Organotin compounds (OTC), mainly tributyltin (TBT), have been used since the 1970s as biocides in the composition of antifouling paints. Due to its physical-chemical characteristics, TBT has high toxicity to the marine environment affecting non-target organisms. The present study aims to develop a method of direct visual identification of TBT in antifouling paints using the cyclopalladate complex, 4- (2-thiazolylazo) resorcinol (TAR-Pd), synthesized in our laboratory. Tests were performed in blank and in the paint matrix with the following OTC: TBT-O; TBT-Cl; TPT-Cl; DBT-Cl (tributyltin oxide, tributyltin chloride, triphenyltin chloride, dibutyltin chloride), in addition to the SnCl4 and SnCl2 compounds (tin IV chloride and tin II chloride), all at a concentration of approximately 20 g/ kg of dry paint). The test was performed by applying paint samples to test bodies and scraping a few tens of milligrams of the dry paint film. The scraped paint samples were submitted to the test, showing a different staining reaction for the TBT-Cl and SnCl4 samples concerning blank and other samples (TBT-O, TPT, DBT-Cl, and SnCl2). Solution tests were performed to characterize reaction products by spectroscopy in the visible band. The method developed has potential for application in real samples, being selective for TBT-Cl and SnCl4 in an acid medium, obtaining a limit of detection, in the range of 1-10 mg/kg dry paint.

The effects of electrochemical pretreatment and curing environment on strength and leaching of stabilized/solidified contaminated sediment.

Stabilization and solidification (S/S) is known to improve the structural properties of sediment and reduce contaminant mobility, enabling the utilization of dredged contaminated sediment. Further reduction of contaminants (e.g., tributyltin (TBT) and metals) can be done using electrochemical treatment prior to S/S and could potentially minimize contaminant leaching. This is the first study on how electrochemical pretreatment affects the strength and leaching properties of stabilized sediments. It also investigates how salinity and organic carbon in the curing liquid affect the stabilized sediment.The results showed that the electrolysis reduced the content of TBT by 22% and zinc by 44% in the sediment. The electrolyzed stabilized samples met the requirements for compression strength and had a reduced surface leaching of zinc. Curing in saline water was beneficial for strength development and reduced the leaching of TBT compared to curing in fresh water. The results indicate that pretreatment prior to stabilization could be beneficial in reducing contaminant leaching and recovering metals from the sediment. The conclusion is that a better understanding of the changes in the sediment caused by electrochemical treatment and how these changes interact with stabilization reactions is needed. In addition, it is recommended to investigate the strength and leaching behavior in environments similar to the intended in situ conditions.

Trace metal and TBT pollution in the Gulf and Oman: spatial variation and hot spots.

This review assesses trace metal concentrations in nearshore and offshore bottom sediments in the Arabian Gulf and Oman focusing particularly on targeted monitoring studies of point sources of contamination near industrial zones (sometimes with ports) and desalination and power plants (often co-located). Concerns have been raised about harmful impacts from accumulation of metals in the semi-enclosed Gulf. The sediment trace metal contaminants of the greatest concern are highlighted with maximum levels of toxic trace metals such as As, Cd, Cu, Pb, Hg, Ni, Zn, and TBT recorded near port and ship repair yards/dry docks as well as industrial and power/desalination plant discharge outfalls. The levels of metals such as Cd, Pb, and Hg exceeding sediment quality guidelines at identified hot spots are of concern. Efforts to mitigate future impacts are recommended.

Effects of endocrine disruptors on the electrical activity of leptin receptor neurons in the dorsomedial hypothalamus and anxiety-like behavior in male mice.

There is increasing concern about the effects of endocrine disrupting chemicals (EDCs) on human health. Recently, some EDCs are suggested to affect energy metabolism leading to increased risk of obesity. Obesogenic effects of some EDCs on adipogenesis have been reported, however, there is no study examining their potential actions on the brain circuits controlling feeding and metabolism. We have investigated effects of tributyltin (TBT) and dichlorodiphenyltrichloroethane (p,p'-DDT) on electrical activity on dorsomedial hypothalamic leptin receptor neurons (DMHLepR), morphological adaptations in neuronal anatomy of DMHLepR, locomotion, and anxiety-like behaviors in mice. Twenty-three Lep-Cre transgenic mice were intracranially injected with GFP virus. Control animals received intraperitoneal corn oil alone while group 2 and 3 received TBT (25 µg/kg) and p,p'-DDT (2 mg/kg) for one month. Locomotor activity and anxiety-like behavior of the animals were determined by open field test. Electrophysiological effects of TBT and p,p'-DDT on DMHLepR neurons were determined by patch clamp method. Neuronal anatomy was determined by confocal microscopy. Spontaneous firing frequency of DMHLepR neurons of TBT group of mice was significantly higher than both p,p'-DDT and control groups (p < 0.01). TBT and p,p'-DDT significantly decreased frequency of the spontaneous inhibitory post-synaptic currents to DMHLepR neurons compared to the control group (p < 0.05). The time spent in the center and the number of entrances to the center by the TBT-administered mice were significantly lower than other groups (p < 0.01). The total distance traveled and mean speed of the control group of mice were significantly higher than the p,p'-DDT- and TBT-administered animals (p < 0.0001). c-Fos activity of the p,p'-DDT- and TBT-administered animals were significantly elevated compared to the control group (p < 0.001), while no change in the number of dendritic spines were observed. In conclusion, this study demonstrates that exposure to TBT and p,p'-DDT alters electrical activity in DMHLepR neurons and behavioral state in mice.

The effect of acute toxicity from tributyltin on Liza haematocheila liver: Energy metabolic disturbance, oxidative stress, and apoptosis.

Tributyltin (TBT), a highly toxic and persistent organic pollutant, is widely distributed in coastal waters. Liza haematocheila (L. haematocheila) is one of bony fish distributing coincident with TBT, and exposure risk of TBT to this fish is unknown. In this study, L. haematocheila was exposed to TBT of 0, 3.4, 6.8, and 17.2 µg/L for 48 h to explore hepatic response mechanism. Our results showed that Sn content in livers increased after 48 h of exposure. HSI and histological changes indicated that TBT suppressed liver development of L. haematocheila. TBT reduced ATPase activities. The increased RB in blood and the reduced TBC were measured after exposure to TBT. T-AOC and antioxidant enzymes SOD, CAT, and GPx activities were inhibited while MDA content was increased. Liver cells showed apoptosis characteristics after TBT exposure. Furthermore, transcriptome analysis of livers was performed and the results showed energy metabolism-related GO term (such as ATPase complex and ATPase dependent transmembrance transport complex), oxidative stress-related GO term (such as Celllular response to oxidative stress and Antioxidant activity), and apoptosis-related GO term (such as Regulation of cysteine-type endopeptidase activity involved in apoptosic signaling pathway). Moreover, we found six energy metabolism-related differentially expressed genes (DEGs) including three up-regulated DEGs (atnb233, cftr, and prkag2) and three down-regulated DEGs (acss1, abcd2, and smarcb1); five oxidative stress-related DEGs including one up-regulated DEG (mmp9) and four down-regulated DEG (prdx5, hsp90, hsp98, and gstf9); as well as six apoptosis-related DEGs including five up-regulated DEGs (casp8, cyc, apaf1, hccs, and dapk3) and one down-regulated DEG (bcl2l1). Our transcriptome data above further confirmed that acute stress of TBT led energy metabolic disturbance, oxidative stress, and apoptosis in L. haematocheila livers.

Tributyltin degrading microbial enzymes: A promising remediation approach.

Brazil is one of the countries most impacted along the entire coastline by the presence of tributyltin (TBT), a biocide used in antifouling paints. Despite being banned since 2008, its use is still registered in the country, and it is possible to find recent inputs of this substance in places under the influence of shipyards, marinas, and fishing ports. In this study, a bacterium isolated from TBT-contaminated sediment from Santos and São Vicente Estuarine System (SESS) in Brazil, identified as Achromobacter sp., proved to be resistant to this compound. Furthermore, its crude enzymatic extract presented the ability to reduce up to 25 % of the initial TBT concentration in the liquid phase in 1 h, demonstrating to be a simple, fast, effective procedure and a potential tool for the environmental attenuation of TBT.

Molecular and biochemical responses to tributyltin (TBT) exposure in the American oyster: Triggers of stress-induced oxidative DNA damage and prooxidant-antioxidant imbalance in tissues by TBT.

Environmental pollution increases due to anthropogenic activities. Toxic chemicals in the environment affect the health of aquatic organisms. Tributyltin (TBT) is a toxic chemical widely used as an antifouling paint on boats, hulls, and ships. The toxic effect of TBT is well documented in aquatic organisms; however, little is known about the effects of TBT on DNA lesions in shellfish. The American oyster (Crassostrea virginica, an edible and commercially important species) is an ideal marine mollusk to examine the effects of TBT exposure on DNA lesions and oxidative/nitrative stress. In this study, we investigated the effects of TBT on 8'-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of pro-mutagenic DNA lesion), double-stranded DNA (dsDNA), dinitrophenyl protein (DNP, a biomarker on reactive oxygen species, ROS), 3-nitrotyrosine protein (NTP, a biomarker of reactive nitrogen species, RNS), catalase (CAT, an antioxidant), and acetylcholinesterase (AChE, a cholinergic enzyme) expressions in the gills and digestive glands of oysters. We also analyzed extrapallial (EF) fluid conditions. Immunohistochemical and qRT-PCR results showed that TBT exposure significantly increased 8-OHdG, dsDNA, DNP, NTP, and CAT mRNA and/or protein expressions in the gills and digestive glands. However, AChE mRNA and protein expressions, and EP fluid pH and protein concentrations were decreased in TBT-exposed oysters. Taken together, these results suggest that antifouling biocide-induced production of ROS/RNS results in DNA damage, which may lead to decreased cellular functions in oysters. To the best of our knowledge, the present study provides the first molecular/biochemical evidence that TBT exposure results in oxidative/nitrative stress and DNA lesions in oysters.

NMR technique revealed the metabolic interference mechanism of the combined exposure to cadmium and tributyltin in grass carp larvae.

Widespread human activity has resulted in the presence of different pollutants in the aquatic environment that does not exist in isolation. The study of the effects of contamination of aquatic organisms is of great significance. To assess the individual and combined toxicity of cadmium (Cd) and tributyltin (TBT) to aquatic organisms, juvenile grass carp (Ctenopharyngodon idella) were exposed to Cd (2.97 mg/L), TBT (7.5 µg/L), and their mixture MIX. The biological response was evaluated by nuclear magnetic resonance (NMR) analysis of plasma metabolites. Plasma samples at 1, 2, 4, 8, 16, 32, and 48 days post-exposure were analyzed using detection by NMR technique. The typical correlation analysis (CCA) analysis revealed that TBT had the greatest effect on plasma metabolism, followed by MIX and Cd. The interference pathway to grass carp was similar to that of TBT and MIX. Both Cd and TBT exposure alone or in combination can lead to metabolic abnormalities in TCA cycle-related pathways and interfere with energy metabolism. These results provide more detailed information for the metabolic study of pollutants and data for assessing the health risks of Cd, TBT, and MIX at the metabolic level.

First assessment of butyltins (BuTs) contamination of the Montenegrin coast (Southeast Adriatic): Tributyltin (TBT) poses a threat to the marine ecosystem.

This study presents the first assessment of butyltins (BuTs) pollution of the Montenegrin coast. The distribution of tributyltin (TBT), dibutyltin (DBT) and monobutyltin (MBT) was investigated in mussels, sediments and water overlying sediment after the sediment resuspension. The results showed that the investigated sites (marinas, ports, shipyards) are contaminated with BuTs (19-402 ng (Sn)/g in mussels; 43-20,641 ng (Sn)/g in sediments; 9-566 ng (Sn)/L in overlying waters). The measured TBT concentrations indicate that toxic effects on marine organisms are expected at most locations. The simultaneous analysis of BuTs and total Sn in sediment cores allowed the assessment of TBT historical input, while it was demonstrated that resuspension of contaminated sediments leads to the release of all BuTs into the water column. This study shows that, despite the ban of TBT-based antifouling paints more than a decade ago, pollution of the marine environment with TBT is still a problem and regular monitoring remains essential.

Combinatorial pathway disruption is a powerful approach to delineate metabolic impacts of endocrine disruptors.

The prevalence of metabolic diseases, such as obesity, diabetes, metabolic syndrome and chronic liver diseases among others, has been rising for several years. Epidemiology and mechanistic (in vivo, in vitro and in silico) toxicology have recently provided compelling evidence implicating the chemical environment in the pathogenesis of these diseases. In this review, we will describe the biological processes that contribute to the development of metabolic diseases targeted by metabolic disruptors, and will propose an integrated pathophysiological vision of their effects on several organs. With regard to these pathomechanisms, we will discuss the needs, and the stakes of evolving the testing and assessment of endocrine disruptors to improve the prevention and management of metabolic diseases that have become a global epidemic since the end of last century.

The ecotoxicology of marine tributyltin (TBT) hotspots: A review.

Tributyltin (TBT) was widely used as a highly efficient biocide in antifouling paints for ship and boat hulls. Eventually, TBT containing paints became globally banned when TBT was found to cause widespread contamination and non-target adverse effects in sensitive species, with induced pseudohermaphroditism in female neogastropods (imposex) being the best-known example. In this review, we address the history and the status of knowledge regarding TBT pollution and marine TBT hotspots, with a special emphasis on the Norwegian coastline. The review also presents a brief update on knowledge of TBT toxicity in various marine species and humans, highlighting the current understanding of toxicity mechanisms relevant for causing endocrine disruption in marine species. Despite observations of reduced TBT sediment concentrations in many marine sediments over the recent decades, contaminant hotspots are still prevalent worldwide. Consequently, efforts to monitor TBT levels and assessment of potential effects in sentinel species being potentially susceptible to TBT in these locations are still highly warranted.

Surgical treatment of primary tracheobronchial tumors: 16-year experience in a single center.

Background: Primary tracheobronchial tumor (TBT) is a rare disease, and the prognostic factors of surgical treatment have not been well identified. Methods: Patients with primary TBT and accepted surgical treatment between January 2004 and January 2020 at our institution were retrospectively analyzed. The univariate analysis and multivariate analysis were conducted on the malignant cases. The overall survival (OS) was analyzed using Kaplan-Meier method, and potential prognostic factors were analyzed using Cox regression analysis. Results: A total of 69 patients (29 males and 40 females) were included. The median follow-up duration was 75.7 months (1.2-177.4 months). The most common histology was adenoid cystic carcinoma (ACC) (37.7%) followed by squamous cell carcinoma (SCC) (23.2%). For patients with malignant tumors, the estimated 5-year OS of the overall population was 77.2% and the estimated 5-year OS of SCC patients was 73.8% especially. The univariate Cox regression analysis identified that age and tumor size had significant effects on OS. The multivariate analysis showed that age (≤50 or >50 years) was independent prognostic factor for OS (P<0.05). Conclusions: Age is independent factor affecting the OS of primary TBT treated by surgery. And patients of TBT with younger age should be much more referred for surgery.

Removal of organotin compounds and metals from Swedish marine sediment using Fenton's reagent and electrochemical treatment.

Metal and tributyltin (TBT) contaminated sediments are problematic for sediment managers and the environment. This study is the first to compare Fenton's reagent and electrochemical treatment as remediation methods for the removal of TBT and metals using laboratory-scale experiments on contaminated dredged sediment. The costs and the applicability of the developed methods were also compared and discussed. Both methods removed > 98% TBT from TBT-spiked sediment samples, while Fenton's reagent removed 64% of the TBT and electrolysis 58% of the TBT from non-spiked samples. TBT in water phase was effectively degraded in both experiments on spiked water and in leachates during the treatment of the sediment. Positive correlations were observed between TBT removal and the added amount of hydrogen peroxide and current density. Both methods removed metals from the sediment, but Fenton's reagent was identified as the most potent option for effective removal of both metals and TBT, especially from highly metal-contaminated sediment. However, due to risks associated with the required chemicals and low pH level in the sediment residue following the Fenton treatment, electrochemical treatment could be a more sustainable option for treating larger quantities of contaminated sediment.

Temporal evolution of imposex and butyltin contamination in Gemophos viverratus from São Vicente (Cabo Verde) - a countercurrent trend on the world scenario.

Organotin (OT) based Antifouling Systems (AFS) were globally banned by the AFS Convention since 2008, but the Republic of Cabo Verde did not ratify this Convention, nor did it develop a national legislation to control OT-AFS. Gemophos viverratus imposex and butyltin tissue contamination were assessed around the São Vicente Island (Cabo Verde) in 2019 and compared with the data available from 2012. The vas deferens sequence index (VDSI), the relative penis length (RPL), the percentage of females with imposex (%I) and the percentage of sterilized females (%S) in 2019 ranged from 0 to 4.0, 0-84.4%, 0-100% and 0-5.1%, respectively, whilst TBT reached maximum values of ≈30 ng TBT-Sn g-1 dw in the whelk tissues. These values are very similar to those registered in 2012, which indicates that TBT pollution has not decreased over the years, in contrast to the declining trend observed worldwide.

Tributyltin and high-refined carbohydrate diet lead to metabolic and reproductive abnormalities, exacerbating premature ovary failure features in the female rats.

Exposure to the obesogen tributyltin (TBT) alone or high carbohydrate diet (HCD) alone leads to obesity and reproductive complications, such as premature ovary failure (POF) features. However, little is known about interactions between TBT and nutrition and their combined impact on reproduction. In this study, we assessed whether acute TBT and HCD exposure results in reproductive and metabolic irregularities. Female rats were treated with TBT (100 ng/kg/day) and fed with HCD for 15 days and metabolic and reproductive outcomes were assessed. TBT and HCD rats displayed metabolic impairments, such as increased adiposity, abnormal lipid profile and triglyceride and glucose (TYG) index, worsening adipocyte hypertrophy in HCD-TBT rats. These metabolic consequences were linked with reproductive disorders. Specifically, HCD-TBT rats displayed irregular estrous cyclicity, high follicle-stimulating hormone (FSH) levels, low anti-Müllerian hormone (AMH) levels, reduction in ovarian reserve, and corpora lutea (CL) number, with increases in atretic follicles, suggesting that HCD-TBT exposure exacerbated POF features. Further, strong negative correlations were observed between adipocyte hypertrophy and ovarian reserve, CL number and AMH levels. HCD-TBT exposure resulted in reproductive tract inflammation and fibrosis. Collectively, these data suggest that TBT plus HCD exposure leads to metabolic and reproductive abnormalities, exacerbating POF features in female rats.

Long-term monitoring of Nucella lapillus imposex in Ria de Aveiro (Portugal): When will a full recovery happen?

Nucella lapillus imposex has been monitored in Ria de Aveiro (Portugal) in order to understand the evolution of organotin (OT) pollution after the EU ban on OT-based antifouling systems (OT-AFS). A rapid decrease of imposex occurred, but a countercurrent tendency upsurged recently (2018-2019) with a slight increase of imposex at some sites, instead of a continuous decline towards a complete recovery. In 2018 the vas deferens sequence index ranged between 0.6 and 1.0 across stations and the percentage of females with imposex varied from 63 to 100%. In 2019 these parameters varied between 0.4 and 1.0 and 37-100%, while the concentration of butyltins (TBT, DBT, MBT) in the dogwhelk tissues were < 1 ng Sn g-1 dw. Although N. lapillus imposex levels are low they are indicative of OT pollution. The full recovery of N. lapillus imposex in the future is uncertain and a cause for concern.

Comparison of biomarker responses after acute and chronic bioassays in Lumbriculus variegatus.

Differential biomarker responses may occur after acute or chronic bioassays when animals are unfed. In many aquatic species, food deprivation may lead to a pro-oxidant condition. However, information about its effects on the oligochaete Lumbriculus variegatus, a bioindicator organism for water and sediment toxicity tests, is almost completely lacking. Acute (48 h) and chronic (21 days) bioassays were performed using unfed L. variegatus to assess the impact of food deprivation on several biomarkers related to the redox cellular status. Results showed that food deprivation inhibited the antioxidant enzymes superoxide dismutase and catalase, whilst levels of total glutathione (t-GSH) and lipid peroxidation processes increased with respect to controls. The same biomarkers were evaluated in unfed organisms exposed to tributyltin (TBT), nano-goethite or a binary mixture of both, for 48 h and 21 days. After 48 h, the organisms were able to cope with chemical stressors by enhancing antioxidant defences and lipid peroxidation processes were not observed. After 21 days, both TBT and the binary mixture induced the most noxious effects. At this time, the antioxidant enzymatic defences were still higher than controls, but levels of t-GSH were significantly decreased and lipid peroxidation was found. Therefore, differential biomarker responses were observed between starved organisms for 21 days and those simultaneously exposed to other chemical stressors. The activity of the enzyme acetylcholinesterase was also determined, but it remained unchanged in all cases.