Astaxanthin treatment reduces kidney damage and facilitates antioxidant recovery in lithium-intoxicated rats.

OBJECTIVE: This study aimed to evaluate the protective effects of astaxanthin against lithium-induced nephrotoxicity, focusing on histopathological changes, oxidative stress modulation, and alteration in the expression of key proteins related to apoptosis and inflammation. METHODS: In this study, 56 male rats were utilized and divided into experimental groups subjected to lithium-induced nephrotoxicity, with and without astaxanthin treatment, over 14 and 28 days. The parameters assessed included oxidative stress markers (MDA, GSH, SOD), protein expression levels of BCL-2, BAX, TNF- α, PI3K, NF-κ B-p65, IL-1ß, and comprehensive histopathological examinations to evaluate the integrity of renal tissue. RESULTS: Lithium exposure led to significant renal damage, as evidenced by histological distortions in renal architecture, increased oxidative stress indicated by elevated MDA levels, and dysregulated expressions of apoptotic and inflammatory proteins. Notably, histopathological analysis revealed glomerular and tubular degeneration in lithium-treated groups. Astaxanthin treatment effectively mitigated these effects, demonstrating its efficacy in reducing lipid peroxidation, rebalancing apoptotic proteins, suppressing pro-inflammatory cytokines, and preserving renal histological structure. The concurrent use of lithium and astaxanthin showed a considerable amelioration of lithium-induced damage, suggesting astaxanthin's role in attenuating the nephrotoxic effects of lithium, both at a molecular and structural level. CONCLUSION: Astaxanthin demonstrates significant renoprotective effects against lithium-induced nephrotoxicity, suggesting its utility as an effective adjunctive therapy. Through its potent antioxidative, anti-inflammatory, and anti-apoptotic actions, astaxanthin effectively reduces renal damage associated with lithium treatment, underscoring its potential for enhancing renal health in patients receiving lithium therapy.

Epidemiology studies on effects of lithium salts in pregnancy are confounded by the inability to control for other potentially teratogenic factors.

INTRODUCTION: In bipolar women who took lithium during pregnancy, several epidemiology studies have reported small increases in a rare fetal cardiac defect termed Ebstein's anomaly. METHODS: Behavioral, environmental, and lifestyle-associated risk factors associated with bipolar disorder and health insurance status were determined from an Internet search. The search was conducted from October 1, 2023, through October 14, 2023. The search terms employed included the following: bipolar, bipolar disorder, mood disorders, pregnancy, congenital heart defects, Ebstein's anomaly, diabetes, hypertension, Medicaid, Medicaid patients, alcohol use, cigarette smoking, marijuana, cocaine, methamphetamine, narcotics, nutrition, diet, obesity, body mass index, environment, environmental exposures, poverty, socioeconomic status, divorce, unemployment, and income. No quotes, special fields, truncations, etc., were used in the searches. No filters of any kind were used in the searches. RESULTS: Women who remain on lithium in the United States throughout their pregnancy are likely to be experiencing mania symptoms and/or suicidal ideation refractory to other drugs. Pregnant women administered the highest doses of lithium salts would be expected to have been insufficiently responsive to lower doses. Any small increases in the retrospectively determined risk of fetal cardiac anomalies in bipolar women taking lithium salts cannot be disentangled from potential developmental effects resulting from very high rates of cigarette smoking, poor diet, alcohol abuse, ingestion of illegal drugs like cocaine or opioids, marijuana smoking, obesity, and poverty. CONCLUSIONS: The small risks in fetal cardiac abnormalities reported in the epidemiology literature do not establish a causal association for lithium salts and Ebstein's anomaly.

Toxicological effects and mechanisms of lithium on growth, photosynthesis and antioxidant system in the freshwater microalga Chromochloris zofingiensis.

The growing prevalence of lithium (Li) batteries has drawn public attention to Li as an emerging pollutant. The present study investigates the toxicity of Li+ on Chromochloris zofingiensis, examining physiological, biochemical and omics aspects. Results reveal hormesis effects of Li+ on C. zofingiensis growth. At Li+ concentrations below 5 mg L-1, Li+ can enhance chlorophyll content, mitochondrial activity, and antioxidant capacity, leading to increased dry cell weight and cell number. Conversely, when it exceeded 10 mg L-1, Li+ can reduce chlorophyll content, induce oxidative stress, and disrupt chloroplast and mitochondria structure and function, ultimately impeding cell growth. In addition, under 50 mg L-1 Li+ stress, microalgae optimize absorbed light energy use (increasing Fv/Fm and E TR ) and respond to stress by up-regulating genes in starch and lipid biosynthesis pathways, promoting the accumulation of storage components. Weighted gene co-expression network analysis indicates that peptidylprolyl cis/trans isomerase, GTPase and L-ascorbate oxidase might be the key regulators in response to Li+ stress. This research marks the toxic effects and molecular mechanisms of Li+ on freshwater microalga, which would improve our understanding of Li's toxicology and contributing to the establishment of Li pollution standards.

Concentration-dependent effects of lithium on Daphnia magna: Life-history profiles and integrated biomarker response implementation.

The growing use of lithium (Li) in industrial and energy applications and increasing demand worldwide has inevitably resulted in its wide dispersal, representing a significant threat to aquatic systems. Unfortunately, as a ubiquitous emerging contaminant, the comprehensive toxicological information regarding Li at multifarious levels is limited. To diminish this gap, this work was focused to explore Li-induced cascading effects on Daphnia magna as a key species in freshwater ecosystems. Specifically, the organisms were chronically exposed to gradient Li concentrations with emphasis on characterizing life-history traits from individual to population scale, primarily as observed by a markedly concentration-dependent decrease along exposure gradients. In parallel, a robust set of biomarkers relating to energy reserves, antioxidant and biotransformation enzymes, cellular damage, ionoregulation and neurotoxicity were assayed for further understanding potential underlying mechanisms. As a result, biomarker alterations were characterized by significant decreases in energy storage and enzymatic profiles of antioxidant and biotransformation systems, not only triggering an imbalance between reactive oxygen species (ROS) generation and elimination under Li exposure, but compromising the fecundity fitness of phenotypical costs. In contrast, malondialdehyde (MDA) levels were remarkably enhanced as a consequence of inefficient antioxidant and biotransformation capacity leading to lipid peroxidation (LPO). Additionally, Li exerted a dose-dependent biphasic effect on the activities of superoxide dismutase (SOD), Na+,K+-ATPase and acetylcholinesterase (AChE) by interfering with inherent balance. In terms of responsive patterns and dose-effect trends, the integrated biomarker response indices (IBRv2) and star plots were consistent with the differences in biomarker profiles, not only presenting comprehensively biological effects in a visualized form, but signaling the importance of progressive induced changes in an integrative way. Overall, these findings highlighted the need for elucidating Li-produced impacts from a comprehensive perspective, providing valuable insights into better understanding the toxicity of Li in relation to aquatic ecosystem functioning and ecological relevance.

Lithium salts cytotoxicity and accumulation in melanoma cells in vitro.

Boron neutron capture therapy is a perspective selective technology for the destruction of cancer cells, while the use of lithium instead of boron may represent a new and promising vector for the development of neutron capture therapy (NCT). The aim of the study was a comparative assessment of the cytotoxicity of various lithium salts, as well as an analysis of the accumulation of lithium in tumor cells in vitro to determine the possibility of using lithium in NCT. The cytotoxicity of lithium salts was determined using MTT-test and colony forming assay on human fibroblasts BJ-5ta, human skin melanoma SK-Mel-28, and mouse skin melanoma B16 cell lines. An assessment of lithium concentration in cells was performed using inductively coupled plasma atomic emission spectrometry. Our results showed that three different lithium salts at a concentration of 40 µg/ml are not toxic for both tumor and normal cells. The highest uptake values were obtained on murine melanoma B16 cells when exposed to lithium carbonate (0.8 µg/106 cells); however, human melanoma SK-Mel-28 cells effectively accumulated both lithium carbonate and lithium citrate (about 0.46 µg/106 cells for two salts). Thus, our results demonstrate a range of non-toxic doses of lithium salts and a high uptake of lithium by tumor cells, which indicates the possibility to use the lithium in NCT.

Differential Regulation of Wnt/ß-catenin Signaling in Acute and Chronic Epilepsy in Repeated Low Dose Lithium-Pilocarpine Rat Model of Status Epilepticus.

Epilepsy is a chronic neurological complication characterized by unprovoked seizure episodes due to the imbalance between excitatory and inhibitory neurons. The epileptogenesis process has been reported to be involved in chronic epilepsy however, the mechanism underlying epileptogenesis remains unclear. Recent studies have shown the possible involvement of Wnt/ß-catenin signaling in the neurogenesis and neuronal reorganization in epileptogenesis. In this study, we used repeated low dose lithium-pilocarpine model of status epilepsy (SE) to study the involvement of Wnt/ß-catenin signaling at acute and chronic stages post SE induction. The acute study ranged from day 0 to day 28 post SE induction and the chronic study ranged from day 0 to day 56 post SE induction. Several neurobehavioral parameters and seizure score and seizure frequency was analysed until the end of the study. The proteins involved in the regulation of Wnt/ß-catenin signaling and downstream cascading were analysed using western blot and quantitative real-time PCR analysis. The Wnt/ß-catenin pathway was found inactive in acute SE, while the same was found activated at the chronic stage. Our findings suggest that the activated Wnt/ß-catenin signaling in chronic epilepsy might be the possible mechanism underlying epileptogenesis as indicated by increased neuronal count, increased synaptic density, astrogliosis and apoptosis in chronic epilepsy. These findings can help target the Wnt/ß-catenin pathway differentially depending upon the type of epilepsy. The acute stage characterized by SE can be improved by targeting GSK-3ß levels and the chronic stage characterized by temporal lobe epilepsy can be improved by targeting ß-catenin and disheveled proteins.

Lithium Treatment Induces Cardiac Dysfunction in Mice.

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes' size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.

Lithium impacts the function of hematopoietic stem cells via disturbing the endoplasmic reticulum stress and Hsp90 signaling.

Lithium (Li) has been widely used in clinical therapy and new Li-ion battery industry. To date, the impact of Li on the development of immune cells is largely unknown. The aim of this study was to investigate the impact of Li on hematopoiesis. C57BL/6 (B6) mice were treated with 50 ppm LiCl, 200 ppm LiCl, or the control via drinking water for 3 months, and thereafter the hematopoiesis was evaluated. Treatment with Li increased the number of mature lymphoid cells while suppressing the number of mature myeloid cells in mice. In addition, a direct action of Li on hematopoietic stem cells (HSC) suppressed endoplasmic reticulum (ER) stress to reduce the proliferation of HSC in the bone marrow (BM), thus leading to fewer HSC in mice. On the other hand, the suppression of ER stress by Li exposure increased the expression of Hsp90, which promoted the potential of lymphopoiesis but did not impact that for myelopoiesis in HSC in the BM of mice. Moreover, in vitro treatment with Li also likely disturbed the ER stress-Hsp90 signaling, suppressed the proliferation, and increased the potential for lymphopoiesis in human HSC. Our study reveals a previously unrecognized toxicity of Li on HSC and may advance our understanding for the immunotoxicology of Li.

Dendritic reorganization in the hippocampus, anterior temporal lobe, and frontal neocortex of lithium-pilocarpine induced Status Epilepticus (SE).

Status Epilepticus (SE) is a distributed network disorder, which involves the hippocampus and extra-hippocampal structures. Epileptogenesis in SE is tightly associated with neurogenesis, plastic changes and neural network reorganization facilitating hyper-excitability. On the other hand, dendritic spines are known to be the excitatory synapse in the brain. Therefore, dendritic spine dynamics could play an intricate role in these network alterations. However, the exact reason behind these structural changes in SE are elusive. In the present study, we have investigated the aforementioned hypothesis in the lithium-pilocarpine treated rat model of SE. We have examined cytoarchitectural and morphological changes using hematoxylin-eosin and Golgi-Cox staining in three different brain regions viz. CA1 pyramidal layer of the dorsal hippocampus, layer V pyramidal neurons of anterior temporal lobe (ATL), and frontal neocortex of the same animals. We observed macrostructural and layer-wise alteration of the pyramidal layer mainly in the hippocampus and ATL of SE rats, which is associated with sclerosis in the hippocampus. Sholl analysis exhibited partial dendritic plasticity in apical and basal dendrites of pyramidal cells as compared to the saline-treated weight-/age-matched control group. These findings indicate that region-specific alterations in dendritogenesis may contribute to the development of independent epileptogenic networks in the hippocampus, ATL, and frontal neocortex of SE rats.

Behavioural and biochemical responses of the sea snail Tritia reticulata to lithium concentration gradient.

Lithium (Li) is present in many modern technologies, most notably in rechargeable batteries. Inefficient recycling strategies for electronic waste containing this element may result in its release into aquatic systems, which may induce harmful effects on wildlife. The present study evaluated the effect of Li contamination on the gastropod Tritia reticulata exposed to different concentrations of Li (100, 200, 500 and 1000 µg L-1) for 21 days. Biochemical analyses showed that this species was not significantly affected by this contaminant at the cellular level, as no significant differences were observed in terms of metabolism, oxidative stress, and neurotoxicity. Results further revealed that snails attempted to avoid Li accumulation by burying in the sediment at a faster rate when exposed to the highest concentrations (500 and 1000 µg L-1). More research is needed to fully assess the response of T. reticulata to Li contamination, such as investigating longer exposure periods or other endpoints.

The influence of temperature on the effects of lead and lithium in Mytilus galloprovincialis through biochemical, cell and tissue levels: Comparison between mono and multi-element exposures.

Lead (Pb) and lithium (Li) are metals which have been detected in the environment and, at high concentrations, can induce toxic effects that disturb the growth, metabolism or reproduction of organisms along the entire trophic chain. The impacts of these metals have scarcely been investigated using marine bivalves, especially when acting as a mixture. The present study aimed to investigate the influence of temperature on the ecotoxicological effects caused by Pb and Li, acting alone and as a mixture, on the mussel species Mytilus galloprovincialis after 28 days of exposure. The impacts were evaluated under actual (17 °C) and projected (+4 °C) warming conditions, to understand the influence of temperature rise on the effects of the metals (both acting alone or as a mixture). The results obtained showed that the increased temperature did not influence the accumulation of metals. However, the biomarkers evaluated showed greater responses in mussels that are exposed to metals under increased temperature (21 °C). The IBR index showed that there is a comparable toxic effect of Li and Pb separately, while exposure to a mixture of both pollutants causes a significantly higher stress response. Overall, the results obtained revealed that temperature may cause extra stress on the mussels and exposure to the metal mixture caused the greatest impacts compared to each metal acting alone.

Are lithium batteries so eco-friendly? Ecotoxicological impacts of lithium in estuarine bivalves.

Lithium (Li) is now widely used in green energies/clean technologies; however, due to its inefficient recycling and treatment, it is an emerging contaminant in aquatic systems. Bivalves, such as clams, are considered good bioindicators of pollution, hence we evaluated the biochemical effects of Li in the clam Venerupis corrugata. Clams were exposed (14 days) to an increasing Li gradient (0, 200, 400, 800 µg/L). Bioconcentration capacity tended to decrease with increasing Li exposure possibly due to efforts to eliminate Li from the cells, to avert damage. No influences on the clams' metabolic capacity and protein content were observed. Antioxidant and detoxification defences were activated, especially at 400 and 800 µg/L of Li, avoiding lipid damage, while protein injuries were observed at higher concentrations. Furthermore, a loss of redox balance was observed. This study highlights the importance of preventing and regulating Li discharges into the environment, avoiding adverse consequences to aquatic ecosystems.

Encefalopatía posterior reversible: una complicación de la intoxicación por litio / Posterior reversible encephalopathy: a complication of lithium toxicity

Las intoxicaciones en nuestro medio se presenta con una incidencia de 45.1 por cada 100,000 habitantes. Una de las principales causas son las intoxicaciones por psicofármacos dentro de las cuales esta el litio. Este medicamento es utilizado para el manejo del trastorno afectivo bipolar. En la literatura existen diferentes factores de riesgo para la intoxicación por litio como: condiciones que favorezcan la hipovolemia, uso de diuréticos, antihipertensivos, hiponatremia , interacciones medicamentosas y ajuste de dosis. Alrededor del 75 a 90% de los pacientes tratados crónicamente con litio pueden tener niveles tóxicos durante su tratamiento. Como tal la intoxicación puede cursar con diferentes complicaciones renales, cardiovasculares y neurológicas, dentro de estas últimas ésta la encefalopatía. Presentamos el caso de una paciente que ingresa con toxicidad crónica y presenta como complicación neurológica una encefalopatía posterior reversible. El objetivo de este reporte es sensibilizar al personal medico sobre esta complicación poco frecuente pero asociada a gran morbimortalidad. (AU)

Intoxications in our enviroment has an incidence of 45.1 for each 100.000 habitants. One of the main causes are psychopharmaceuticals, one of which is lithium. This drug is used in the management of bipolar disorder. There are several risk factors depicted on literature for this intoxication, such as: conditions that favor hipovolemia, diurethic and antihypertensive use, hiponatremia, drug interactions and lithium dose adjustment. About 75 to 90% of patients chronically treated with lithium can reach toxic levels during their treatment. Lithium intoxication can present with complications affecting different systems such as renal, cardiovascular and nervious, last one includying encephalopathy. We will discuss the case of a patient that presents with chronic lithuim toxicity and develops posterior reversible encephalopathy as a neurologic complication. The goal of this case report is to sensitize medical staff with this unfrequent but dangerous complication. (AU)

New insight into the toxic effects of lithium in the ragworm Perinereis cultrifera as revealed by lipidomic biomarkers, redox status, and histopathological features.

Lithium (Li) is a toxic monovalent alkaline metal used in household items common to industrial applications. The present work was aimed at investigating the potential toxic effects of LiCl on the redox status, fatty acid composition, and histological aspects of the marine ragworm Perinereis cultrifera. Sea worms were exposed to LiCl graded doses (20, 40, and 80 mg/L) for 48 h. Compared with the control group, the saturated fatty acids (SFA) decreased while monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) increased upon exposure to LiCl. The increase in PUFA n-3 and PUFA n-6 was concomitant to an increase in docosahexaenoic (DHA: C22:6n-3), eicosapentaenoic (EPA: C20:5n-3), and docosapentaenoic acid (C22:5n-6) fatty acids. Results showed that LiCl-treated specimens accumulate lithium with increasing exposure gradient. Indeed, the exposure to LiCl doses promoted oxidative stress with an increase of the ferric reducing antioxidant power (FRAP), malondialdehyde (MDA), hydrogen peroxide (H2O2), advanced oxidation protein product (AOPP), and protein carbonyl (PCO) as well as the enzymatic and non-enzymatic antioxidants (non-protein thiols (NPSH), catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione S-transferase (GST), and metallothionein (MT)) levels in all treated groups. Our biochemical findings have been affirmed by the histopathological observations showing hyperplasia and loss of the intestine structure in treated specimens. Overall, our findings give new insights on the toxic effect of LiCl on the redox status of P. cultrifera body tissue and highlighted the usefulness of the FA composition as an early sensitive bioindicators to better understand LiCl mechanism of toxicity in marine polychaetes.

[A case of lithium intoxication with reversible parkinsonism].

A 73-year-old man, who had been treated for bipolar disorder since he was 39 years old, was admitted because he had developed difficulty in walking and moving his hands for the past 2 months. He was suspected of having Parkinson's syndrome. On admission, his blood lithium level was at the upper limit of normal (1.34 mEq/l), but his food intake gradually decreased and his communication difficulties worsened. On the sixth day of hospitalization, his blood lithium level was in the toxic range (2.44 mEq/l). His general condition, including motor symptoms, improved after lithium medication was discontinued and infusions (normal saline) were started. On the 24th day of admission, he was transferred to the psychiatry department for a psychotropic medication adjustment. It is important to note that chronic intoxication can occur even at the upper limit of the therapeutic range and that salt reduction at the start of the inpatient diet may be a trigger for intoxication.

Ecotoxicity Evaluation of Fire-Extinguishing Water from Large-Scale Battery and Battery Electric Vehicle Fire Tests.

Electrified transport has multiple benefits but has also raised some concerns, for example, the flammable formulations used in lithium-ion batteries. Fires in traction batteries can be difficult to extinguish because the battery cells are well protected and hard to reach. To control the fire, firefighters must prolong the application of extinguishing media. In this work, extinguishing water from three vehicles and one battery pack fire test were analyzed for inorganic and organic pollutants, including particle-bound polycyclic aromatic hydrocarbons and soot content. Additionally, the acute toxicity of the collected extinguishing water on three aquatic species was determined. The vehicles used in the fire tests were both conventional petrol-fueled and battery electric. For all of the tests, the analysis of the extinguishing water showed high toxicity toward the tested aquatic species. Several metals and ions were found in concentrations above the corresponding surface water guideline values. Per- and polyfluoroalkyl substances were detected in concentrations ranging between 200 and 1400 ng L-1. Flushing the battery increased the concentration of per- and polyfluoroalkyl substances to 4700 ng L-1. Extinguishing water from the battery electric vehicle and the battery pack contained a higher concentration of nickel, cobalt, lithium, manganese, and fluoride compared with the water samples analyzed from the conventional vehicle.

Acute-on-Chronic Lithium Toxicity: A Simulation Case for Emergency Medicine Residents.

Introduction: Simulation-based education has become standard within emergency medicine training. Toxicological clinical presentations are challenging to identify and treat in the emergency department. Recognizing that active teaching methods are superior to standard lecture for learner retention, we created an experiential simulation case for education on lithium toxicity. The case was written after an extensive literature review followed by consultation with a medical toxicologist and an expert in simulation-based education. Methods: Fifty-three residents participated in a simulation scenario involving a lithium-poisoned patient over the course of eight simulation sessions. The scenario ran approximately 10 minutes and was followed by postevent debriefing. Debriefing was facilitated by an emergency medicine attending with specialized training in simulation-based education. Following the completion of the scenario, residents received an anonymous educational quality improvement survey assessing residents' perception of their ability to recognize and manage lithium toxicity as well as their comfort level with the lithium-poisoned patient. Results: After the simulation, residents reported an increased comfort level with managing lithium-poisoned patients. Residents also self-reported an increased ability to recognize the signs and symptoms of lithium toxicity. Additionally, residents cited the case's educational importance and a desire to include this specific scenario in future simulation sessions. Discussion: Compared to other disease processes, toxicological overdoses are infrequently seen in the emergency department. Health care simulation can effectively portray lithium toxicity for emergency medicine resident education in a safe, controlled environment to increase repetitive practice in caring for this challenging population.

How will different scenarios of rising seawater temperature alter the response of marine species to lithium?

Marine ecosystems are suffering from the gradual rise in temperature due to climate change. Warming scenarios and the intensification of extreme climate events, such as marine heatwaves (MHWs), have been negatively affecting marine organisms. In addition, they are also threatened by anthropogenic pollution. Lithium (Li) is an emerging pollutant that has become a major concern due to its increasing use in a variety of applications. Understanding its influence on marine environments in combination with warming scenarios is crucial, as very little is known about its impact on marine organisms, especially when also considering the increasingly concerning impacts of climate change. With this in mind, this research aimed to assess how different scenarios of increasing temperature may affect the response of Mytilus galloprovincialis to Li. Mussels bioaccumulation levels, as well as physiological and biochemical biomarkers were analyzed after 28 days of exposure to Li under different temperature scenarios (control - 17 °C; warming - 21 °C and marine heatwave - MHW). The results indicate that mussels accumulated Li, independently of the temperature scenario. The respiration rate was higher in contaminated mussels than in the non-contaminated ones, with no differences among temperature scenarios. Furthermore, the metabolic rate decreased in non-contaminated mussels exposed to 21 °C and MHW, while mussels exposed to the combination of Li and MHW presented the highest metabolic rate. The mussels exposed to MHW and Li evidenced the highest cellular damage but Li was not neurotoxic in M. galloprovincialis. This study highlighted that MHW + Li was the most stressful condition, inducing clear negative effects in this species that can impair the growth and reproduction of an entire population. In general, the presented results highlight the importance of future studies in which it is necessary to combine the effects of pollutants and climate change scenarios, namely extreme weather events such as MHWs.

The binary combined toxicity of lithium, lead, and manganese on the proliferation of murine neural stem cells using two different models.

As persistent environmental pollutants, more than thirty metals impose a potential global threat to the environment and humans, which has raised scientific concerns. Although the toxic effects of metals had been extensively studied, there is a paucity of information on their mixture toxicity. In this study, we examined the individual and binary combined toxicity of three common metals such as lithium (Li), lead (Pb), and manganese (Mn) on the proliferation of murine neural stem cells (mNSCs), respectively. Li, Pb, and Mn reduced cell proliferation at the concentration of 5.00 mM, 2.50 µM, and 5.00 µM, respectively (all p < 0.050), in a dose-dependent manner of each metal solely on mNSCs with the cytotoxicity rank as Pb > Mn > Li. Furthermore, the interactions of metal mixtures on mNSCs were determined by using response-additivity and dose-additivity models. Pb + Mn mixtures showed a more than additive effect (synergistic) of toxicity in both two methods. In the dose-additivity method, Pb + Li and Li + Mn mixtures exhibited synergistic effects in the compound with a high ratio of Li (25.0% Pb/75.0% Li, 75.0% Li/25.0% Mn), whereas they are antagonistic in the lower or equal ratio of Li (such as 75.0% Pb/25.0% Li, 25.0% Li/75.0% Mn). Besides, the interactions of Li + Mn mixtures showed some discrepancies between different endpoints. In conclusion, our study highlights the complexity of the mixtures' interaction patterns and the possible neuroprotective effect of Li under certain conditions. In the future, more research on different levels of metal mixtures, especially Li metal, is necessary to evaluate their underlying interactions and contribute to establishing risk assessment systems.