Neurotoxicology最新文献

Parkinson's disease (PD) is a prevalent neurodegenerative disorder in which gut microbiota play a critical role in pathogenesis through the gut-brain axis. Taurine has been reported to exhibit neuroprotective properties. In this study, we employed a rotenone-induced mouse model of PD to investigate the protective effects of taurine and elucidate its underlying mechanisms. PD model mice exhibited weight loss and impaired motor function, both of which were significantly ameliorated by taurine treatment. These mice also showed a marked reduction in dopaminergic neurons alongside increased microglial and astrocyte activation in the substantia nigra. Taurine preserved dopaminergic neuron numbers and suppressed glial activation. Elevated plasma levels of LPS, IL-1β, IL-6, and TNF-α were detected in the PD model group, accompanied by intestinal barrier dysfunction, blood-brain barrier disruption, and gastrointestinal impairment. Taurine administration significantly reduced pro-inflammatory cytokine levels, improved gastrointestinal motility, and preserved the integrity of both the intestinal and blood-brain barriers. Fecal microbiota analysis revealed significant compositional alterations in PD mice. Both α- and β-diversity analyses indicated profound microbial dysbiosis in the model group, which was effectively mitigated by taurine.

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver dysfunction, driven by hyperammonemia, oxidative stress, neuroinflammation, apoptosis, and endoplasmic reticulum (ER) stress, which disrupt the hepato-encephalic axis and impair cognition and motor functions. Despite its clinical burden, effective therapies that target this multi-organ pathology remain limited. β-Caryophyllene (BCP), an antioxidant and anti-inflammatory dietary sesquiterpene, has not been evaluated for its ability to modulate liver-brain crosstalk in HE. This study investigated the hepatoprotective and neuroprotective effects of BCP in a rat model of thioacetamide (TAA)-induced HE. Rats received TAA (200 mg/kg, i.p.) for three days, followed by BCP (100-400 mg/kg) for 14 days. A comprehensive evaluation included serum biochemistry, oxidative stress indices, inflammatory cytokines, apoptosis-related proteins, neurotrophic factors (BDNF), astroglial activation marker (GFAP), ER stress regulators (GRP78, IRE1, XBP1, PERK, CHOP, ATF6), histopathology, and behavioral outcomes. TAA caused severe hepatic and cerebral injury with elevated liver enzymes, oxidative and inflammatory mediators, ER stress dysregulation, pro-apoptotic signaling, reduced BDNF and GFAP, and impaired motor and exploratory behaviors. BCP treatment dose-dependently restored biochemical and molecular parameters, suppressed oxidative stress and neuroinflammation, normalized ER stress signaling, promoted anti-apoptotic pathways, preserved BDNF and maintained astroglial status as reflected by GFAP, and improved histoarchitecture. Importantly, moderate to high doses fully restored locomotor and exploratory activity, indicating coordinated protection across the hepato-encephalic axis. Here, for the first time, the BCP concurrently mitigates hepatic and cerebral pathology via oxidative, inflammatory, apoptotic, and ER stress pathways, supporting its translational potential as a dual hepatoprotective and neuroprotective candidate for xenobiotic-induced HE and related liver-brain disorders.

Harmful chemical mixtures are pervasive in the environment, yet traditional epidemiological designs face major challenges in establishing causal links between individual chemicals or mixture exposures and health outcomes. These challenges arise from the high dimensionality and inter-correlation of exposures, their mediation through complex molecular pathways, and the practical absence of truly unexposed control groups, due to the ubiquity of synthetic chemicals. However, environmental health research is entering a new era defined by integration of epidemiological and experimental studies as well as recent advances in molecular technologies and computational modelling. Here, we introduce four approaches designed to advance our understanding of chemical mixtures and move beyond correlation to causation and intervention: 1) 'hMIX' which integrates human relevant reference mixtures with experimental evidence of adverse effects; 2) the Similar Mixture Approach (SMACH) that translates hazards of chemical mixtures to risks across populations; 3) hybrid epidemiology that bridges experimental and population-based mechanistic insights; and 4) counterfactual theoretical interventions tailored to examine the health benefits of reducing exposure to specific harmful chemicals or mixtures. We propose an integrative framework combining these four approaches to move the chemical mixture field towards causality - a critical step toward predicting and preventing chemical mixture related health effects.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, oxidative stress, neuroinflammation, and neurotransmitter imbalances. This study explored the neuroprotective potential of melatonin (MLT), alone and in combination with edaravone (EDR), in a methylmercury (MEME)-induced ALS rat model. MEME exposure effectively replicated ALS pathology, causing behavioral deficits, oxidative stress, neuroinflammation, apoptosis, and widespread structural damage in critical brain regions and the spinal cord. MLT administration at 5mg/kg (MLT5) and 10mg/kg (MLT10) significantly mitigated MEME-induced neurotoxicity in a dose-dependent manner. MLT improved motor function, reduced depressive-like behavior, and restored body weight. Biochemically, MLT enhanced antioxidant defenses, including superoxide dismutase (SOD) and catalase (CAT), reduced pro-inflammatory cytokines, interleukin-1 beta (IL-1β), increased anti-inflammatory cytokines, interleukin-10 (IL-10), and restored neurotransmitter balance like dopamine and Gamma-Aminobutyric Acid (GABA). Mechanistically, MLT activated the IGF-1 signaling pathway, promoting neuronal survival and reducing apoptosis (Caspase-3 expression). Histopathological analyses confirmed that MLT preserved neuronal and glial integrity, reduced demyelination, and restored myelin basic protein (MBP) levels in brain and cerebrospinal fluid. The combination of MLT and EDR exhibited synergistic neuroprotective effects, surpassing the efficacy of individual treatments in reducing oxidative stress, inflammation, and neuronal damage. Behavioral and biochemical improvements were paralleled by systemic recovery, as evidenced by normalized hematological parameters and reduced methylmercury accumulation in brain tissues. These findings underscore MLT, particularly in combination with EDR, as a potent therapeutic agent for ALS, offering multi-targeted neuroprotection. Future studies should explore its translational potential in clinical settings for the treatment of neurodegenerative diseases.

Previous studies showed that exposure to long-acting anticoagulant rodenticides (LAARs) can induce neuropathology in adult rats. In the current study we tested if the potent LAAR brodifacoum similarly promoted neuropathology in adult rabbits which provide a better model of human LAAR poisoning. Adult male New Zealand White rabbits were administered by gavage a single administration of brodifacoum at its LD₅₀ dose (200 μg/kg), followed by daily injections of vitamin K1 to prevent mortality due to anti-coagulation. After 3 weeks, examination of the cerebellum revealed an increase in glial cell activation, and a decrease in myelin content. A targeted lipidomics analysis was carried out to determine if brodifacoum altered the relative abundance of lipids enriched in myelin. We observed brodifacoum-dependent decreases in several sulfatides which were associated with an increase in expression of arylsulfatase A which degrades sulfatides. Daily treatment with the bile sequestrant cholestyramine, which accelerates LAAR clearance from the body, ameliorated brodifacoum -induced damage. These findings confirm that, despite daily vitamin K1 treatment, LAARs such as brodifacoum can induce neuropathology in adult animals and support the use of agents such as bile sequestrants to ameliorate those consequences.

Airborne combustion emissions from military burn pits, wildfires, and urban/industrial sources are increasingly recognized as a component of the neurotoxic exposome, with potential consequences extending beyond cardiopulmonary disease to brain health. These aerosols comprise heterogeneous mixtures of fine and ultrafine particulate matter (PM₂.₅/PM₀.₁), polycyclic aromatic hydrocarbons, volatile organic compounds, metals, and reactive gases whose composition varies with fuel type, combustion efficiency, and atmospheric aging. Evidence from experimental models, epidemiology, and exposed human cohorts supports two principal routes by which inhaled pollutants may influence the central nervous system: (i) the lung-brain axis, where pulmonary oxidative injury and systemic immune activation promote endothelial dysfunction and compromise blood-brain barrier integrity; and (ii) the olfactory (nose-to-brain) pathway, in which ultrafine and lipophilic constituents interact with the olfactory neuroepithelium and are associated with early neuroimmune changes in olfactory-connected brain regions. At the cellular level, these exposures converge on microglial and astrocytic activation, TLR-NF-κB and inflammasome signaling, mitochondrial dysfunction, and lipid peroxidation, processes that can sustain chronic neuroinflammation and plausibly interact with 'second hits' such as traumatic brain injury, psychological stress, heat stress, sleep disruption, and cardiometabolic comorbidity. Veterans and wildland firefighters represent sentinel occupational groups for defining exposure-biomarker-outcome relationships. This review brings together current evidence linking combustion-derived aerosols to neuroinflammatory and neurodegeneration-relevant mechanisms, highlighting source-specific considerations for military operational exposure, and outlines translational strategies for exposure monitoring, multi-omic biomarker discovery (blood and nasal/olfactory sampling), and early risk stratification to enable targeted prevention in vulnerable populations.