Toxicology Mechanisms and Methods最新文献

Nanoparticles (NPs) are particles of matter that are between 1 to 100 nm in diameter. They are suggested to cause toxic effects in both humans and environment thorough different mechanisms. However, their toxicity profile may be different from the parent material. Titanium dioxide (TiO₂) NPs are widely used in cosmetic, pharmaceutical and food industries. As a white pigment, the use of TiO₂ is used in food coloring, industrial paints, clothing and UV filters has increased tremendously in recent years. Melatonin, on the other hand, is a well-known antioxidant and may prevent oxidative stress caused by a variety of different substances, including NPs. In the current study, we aimed to comparatively investigate the effects of normal-sized TiO₂ (220 nm) and nano-sized TiO₂ (21 nm) on cytopathology, cytotoxicity, oxidative damage (lipid peroxidation, protein oxidation and glutathione), genotoxicity (8-hydroxydeoxyguanosine), apoptosis (caspase 3, 8 and 9) and epigenetic alterations (global DNA methylation, H3 acetylation) on 3T3 fibroblast cells. In addition, the possible protective effects of melatonin, which is known to have strong antioxidant effects, against the toxicity of TiO₂ were also evaluated. Study groups were: a. the control group; b. melatonin group; c. TiO₂ group; d. nano-sized TiO₂ group; e. TiO₂ + melatonin group and f. nano-sized TiO₂ + melatonin group. We observed that both normal-sized and nano-sized TiO₂ NPs showed significant toxic effects. However, TiO₂ NPs caused higher DNA damage and global DNA methylation compared to normal-sized TiO₂ whereas normal-sized TiO₂ led to lower H3 acetylation vs. TiO₂ NPs. Melatonin showed partial protective effect against the toxicity caused by TiO₂ NPs.

An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells via adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.

Nanoparticles have been shown to inhibit major life cycle stages of ticks, indicative of the promising application of nanomaterials against hard ticks. The study thus probed into one of the alternative options to curtail Hyalomma by employing nanocomposites consisting of pyrethroids (cypermethrin and deltamethrin) coated nanoparticles of iron oxides and iron sulfides keeping alongside the evaluation of their toxicity through plant and mammalian cell lines. The nanoparticles used in this study were roughly spherical in morphology and exhibited various size dimensions upon characterization using SEM, EDX, and FTIR. The application of nanomaterials on female ovipositioning tick showed a decline up to 15% (females ovipositioned) in deltamethrin-coated FeO NPs, whereas this decline was up to 18% in Cyp-FeS NPs and up to 5% in Cyp-FeO NPs. Similarly, the larval hatching was also impacted, leading to a hatching percentage of 5% and only 1% by application of Cyp-FeS NPs and Cyp-FeO NPs, respectively. Similarly, the larval groups had LC₉₀ of 4.1 and 4.73 mg/L for the Cyp-FeO NPs and Cyp-FeS NPs groups. The delta-FeO NPs and delta-FeS NPs demonstrated a promising effect against adult ticks, showing LC₅₀= 3.5 mg/L, LC₉₀= 6.7 mg/L and LC₅₀= 3.8 mg/L, LC₉₀= 7.9 mg/L, respectively. MTT assay revealed that the pyrethroids coupled with iron oxide nanoparticles showed the least cytotoxicity even at the highest concentration (10^-1 µL) among other nanomaterials. The study thus concluded a safer spectrum of non-target effects of pyrethroids-coated nanomaterials in addition to their significant anti-tick activity.

Comprehensive analysis of multi-omics data can reveal alterations in regulatory pathways induced by cellular exposure to chemicals by characterizing biological processes at the molecular level. Data-driven omics analysis, conducted in a dose-dependent or dynamic manner, can facilitate comprehending toxicity mechanisms. This study introduces a novel multi-omics data analysis designed to concurrently examine dose-dependent and temporal patterns of cellular responses to chemical perturbations. This analysis, encompassing preliminary exploration, pattern deconstruction, and network reconstruction of multi-omics data, provides a comprehensive perspective on the dynamic behaviors of cells exposed to varying levels of chemical stimuli. Importantly, this analysis is adaptable to any number of omics layers, including site-specific phosphoproteomics. We implemented this analysis on multi-omics data obtained from HepG2 cells exposed to a range of caffeine doses over varying durations and identified six response patterns, along with their associated biomolecules and pathways. Our study demonstrates the effectiveness of the proposed multi-omics data analysis in capturing multidimensional patterns of cellular response to chemical perturbation, enhancing understanding of pathway regulation for chemical risk assessment.

Imidacloprid (IMI), a widely used pesticide in agriculture and a potential food contaminant, poses significant health concerns. This study sought to comprehensively evaluate its neurotoxic effects while investigating the potential protective role of alpha-lipoic acid (ALA), a naturally occurring dietary antioxidant renowned for its capacity to combat oxidative stress, support cardiovascular health, and maintain optimal nerve function. In this study, 28 rats were divided evenly into four groups and administered oral treatments of corn oil, IMI, IMI + ALA, and ALA, respectively. The results of the study indicated that rats exposed to IMI exhibited significant neurobehavioral impairments, decreased levels of antioxidant enzymes and acetylcholinesterase activity, reduced expression of HO-1 and Nrf2, and increased levels of pro-inflammatory cytokines like IL-6 and TNF-α in their hippocampal tissues. Furthermore, histopathological analysis of the brain tissues, specifically cortex and hippocampus, from the IMI-treated group revealed varying degrees of neuronal degeneration. In contrast, rats co-administered ALA alongside IMI showed noticeable improvements in all the assessed toxicological parameters. This study underscores the vital significance of ALA as a potential therapeutic adjunct in mitigating the adverse neurobehavioral consequences of insecticide exposure. By harnessing the Nrf2/HO-1 pathway, ALA demonstrates its ability to shield against IMI-induced neurotoxicity, offering a promising avenue for enhancing public health and safety. As a result, our findings advocate for the incorporation of ALA as a daily dietary supplement to fortify resilience against oxidative stress-related neurobehavioral deficits linked to pesticide exposure, thereby advancing our understanding of neuroprotection strategies in the face of environmental challenges.

Fluorosis, a chronic condition brought on by excessive fluoride ingestion which, has drawn much scientific attention and public health concern. It is a complex and multifaceted issue that affects millions of people worldwide. Despite decades of scientific research elucidating the causes, mechanisms, and prevention strategies for fluorosis, there remains a significant gap between scientific understanding and public health implementation. While the scientific community has made significant strides in understanding the etiology and prevention of fluorosis, effectively translating this knowledge into public health policies and practices remains challenging. This review explores the gap between scientific research on fluorosis and its practical implementation in public health initiatives. It suggests developing evidence-based guidelines for fluoride exposure and recommends comprehensive educational campaigns targeting the public and healthcare providers. Furthermore, it emphasizes the need for further research to fill the existing knowledge gaps and promote evidence-based decision-making. By fostering collaboration, communication, and evidence-based practices, policymakers, healthcare professionals, and the public can work together to implement preventive measures and mitigate the burden of fluorosis on affected communities. This review highlighted several vital strategies to bridge the gap between science and public health in the context of fluorosis. It emphasizes the importance of translating scientific evidence into actionable guidelines, raising public awareness about fluoride consumption, and promoting preventive measures at individual and community levels.

Background: Iron is one of the essential metals that functions as a cofactor in various biological cascades in the brain. However, excessive iron accumulation in the brain may lead to neurodegeneration and may show toxic effects. Quercetin, a pigment flavonoid compound, has been proven to be a potent antioxidant and anti-inflammatory that can inhibit lipid peroxidation during metal-induced neurotoxicity. Although iron-induced neuroinflammation and neurodegeneration have been reported in many studies, but the proof for its exact mechanisms needs to be explored.

Purpose: The key target of the study was to explore the neuroprotective effect of quercetin after oral exposure of iron in rats and explore its underlying molecular mechanisms.

Results: The outcomes of the study have shown that oral exposure to ferrous sulfate may modulate behavioral paradigms such as locomotor activity, neuromuscular coordination, and increased anxiety level. The pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), apoptotic protein (caspase 3), beta-amyloid and phosphorylated tau were found to be increased on iron exposure. Also, the expressions of ferritin heavy and light chain, BACE-1 and GFAP expressions were altered. These behavioral, structural, and biochemical alterations in the brain were significantly and dose-dependently reversed by treatment with quercetin.

Conclusion: The current study provides a fundamental understanding of molecular signaling pathways, and structural proteins implicated in iron-induced neurotoxicity along with the ameliorative effects of quercetin.

Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg⁰, Hg⁺ and Hg²⁺) and organic forms (chiefly CH₃Hg⁺ or MeHg⁺). The main route of human, mammals and bird exposure occurs via predatory fish ingestion. Occupational exposure to Hg⁰ (and Hg²⁺) can also occur; furthermore, in gold mining areas the exposure to inorganic Hg can also be high. The toxicity of electrophilic forms of Hg (E⁺Hg) is mediated by disruption of thiol (-SH)- or selenol (-SeH)-containing proteins. The therapeutic approaches to treat methylmercury (MeHg⁺), Hg⁰ and Hg²⁺ are limited. Here we discuss the potential use of ebselen as a potential therapeutic agent to lower the body burden of Hg in man. Ebselen is a safe drug for humans and has been tested in clinical trials (for instance, brain ischemia, noise-induce hearing loss, diabetes complications, bipolar disorders) at doses varying from 400 to 3600 mg per day. Two clinical trials with ebselen in moderate and severe COVID are also approved. Ebselen can be metabolized to an intermediate with -SeH (selenol) functional group, which has a greater affinity to electrophilic Hg (E⁺Hg) forms than the available thiol-containing therapeutic agents. Accordingly, as observed in vitro and rodent models in vivo, Ebselen exhibited protective effects against MeHg⁺, indicating its potential as a therapeutic agent to treat MeHg⁺ overexposure. The combined use of ebselen with thiol-containing molecules (e.g. N-acetylcysteine and enaramide)) is also commented, because they can have synergistic protective effects against MeHg⁺.