Neurotoxicology最新文献

Autism spectrum disorder (ASD), also known as autism, is a common, highly hereditary and heterogeneous neurodevelopmental disorder. The global prevalence of ASD among children continues to rise significantly, which is partially attributed to environmental pollution. It has been reported that pre- or post-natal exposure to di-(2-ethylhexyl) phthalate (DEHP) or bisphenol A (BPA), two prevalent environmental endocrine disruptors, increases the risk of ASD in offspring. Yet, the joint action mode linking DEHP and BPA with ASD is incompletely understood. This study aims to unravel the joint action mode of DEHP and BPA co-exposure on the development of ASD. An adverse outcome pathway (AOP) framework was employed to integrate data from multiple public database and construct chemical-gene-phenotype-disease networks (CGPDN) for DEHP- and BPA-related ASD. Topological analysis and comprehensive literature exploration of the CGPDN were performed to build the AOP. By analysis of shared key events (KEs) or phenotypes within the AOP or the CGPDN, we uncovered two AOPs, decreased N-methyl-D-aspartate receptor (NMDAR) and estrogen antagonism that were likely linked to ASD, both with moderate confidence. Our analysis further predicted that the joint action mode of DEHP and BPA related ASD was possibly an additive or synergistic action. Thus, we propose that the co-exposure to BPA and DEHP perhaps additively or synergistically increases the risk of ASD.

Exposure to inorganic arsenic (iAs) detrimentally affects the structure and function of the central nervous system. In-utero and postnatal exposure to iAs has been connected to adverse effects on cognitive development. Therefore, this investigation explores neurobehavioral and neurochemical effects of 0.05 and 0.10 mg/L iAs exposure during gestation and lactation periods on 90-day-old female offspring rats. The assessment of anxiety- and depressive-like behaviors was conducted through the application of an elevated plus maze and a forced swim test. The neurochemical changes were evaluated in the prefrontal cortex (PFC) through the determination of enzyme activities and α1 GABA_A subunit expression levels. Our findings revealed a notable impact of iAs exposure on anxiety and the induction of depressive-like behavior in 90-day-old female offspring. Furthermore, the antioxidant status within the PFC exhibited discernible alterations in exposed rats. Notably, the activities of acetylcholinesterase and glutamate pyruvate transaminase demonstrated an increase, while glutamate oxaloacetate transaminase activity displayed a decrease within the PFC due to the iAs treatment. Additionally, a distinct downregulation in the mRNA expression of the α1GABA_A receptor was observed in this neuronal region. These findings strongly suggest that iAs exposure during early stages of rat development causes significant modifications in brain oxidative stress markers and perturbs the activity of enzymes associated with cholinergic and glutamatergic systems. In parallel, it elicits a discernible reduction in the level of GABA receptors within the PFC. These molecular alterations may play a role in the diminished anxiety levels and the depressive-like behavior outlined in the current investigation.

Polychlorinated biphenyls are ubiquitous environmental contaminants linkedc with peripheral immune and neural dysfunction. Neuroimmune signaling is critical to brain development and later health; however, effects of PCBs on neuroimmune processes are largely undescribed. This study extends our previous work in neonatal or adolescent rats by investigating longer-term effects of perinatal PCB exposure on later neuroimmune responses to an inflammatory challenge in adulthood. Male and female Sprague-Dawley rats were exposed to a low-dose, environmentally relevant, mixture of PCBs (Aroclors 1242, 1248, and 1254, 1:1:1, 20 μg / kg dam BW per gestational day) or oil control during gestation and via lactation. Upon reaching adulthood, rats were given a mild inflammatory challenge with lipopolysaccharide (LPS, 50 μg / kg BW, ip) or saline control and then euthanized 3 hours later for gene expression analysis or 24 hours later for immunohistochemical labeling of Iba1+ microglia. PCB exposure did not alter gene expression or microglial morphology independently, but instead interacted with the LPS challenge in brain region- and sex–specific ways. In the female hypothalamus, PCB exposure blunted LPS responses of neuroimmune and neuromodulatory genes without changing microglial morphology. In the female prefrontal cortex, PCBs shifted Iba1+ cells from reactive to hyperramified morphology in response to LPS. Conversely, in the male hypothalamus, PCBs shifted cell phenotypes from hyperramified to reactive morphologies in response to LPS. The results highlight the potential for long-lasting effects of environmental contaminants that are differentially revealed over a lifetime, sometimes only after a secondary challenge. These neuroimmune endpoints are possible mechanisms for PCB effects on a range of neural dysfunction in adulthood, including mental health and neurodegenerative disorders. The findings suggest possible interactions with other environmental challenges that also influence neuroimmune systems.

Lead (Pb) is harmful to almost all organs, particularly the developmental neural system, and previous studies revealed oxidative stress played an important role in Pb neurotoxicity. Rutin, a type of flavonoid glycoside found in various plants and fruits, is widely used as a dietary supplement due to its antioxidant and anti-inflammatory properties, but whether rutin could protect against Pb neurotoxicity is unclear. In this study, we found rutin treatment significantly alleviated Pb-induced cell death, oxidative stress, and inflammation, resulting in cell survival. Moreover, rutin treatment promoted nuclear factor erythroid 2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and subsequently activated antioxidant and detoxifying enzymes expression including HO-1. Knocking down Nrf2 by siRNA transfection abolished this protection of rutin against Pb. Overall, rutin could alleviate Pb-induced oxidative stress, inflammation, and cell death by activating the Nrf2/antioxidant response elements (ARE) system.

Ozone (O₃) forms in the Earth’s atmosphere, both naturally and by reactions of man-made air pollutants. Deleterious effects of O₃ have been found in the respiratory system. Here, we examine whether O₃ alters olfactory behavior and cellular properties in the olfactory system. For this purpose, mice were exposed to O₃ at a concentration found in highly polluted city air [0.8 ppm], and the behavior elicited by social and non-social odors in habituation/dishabituation tests was assessed. In addition, the electrical responses of dopaminergic olfactory bulb (OB) neurons were also evaluated. O₃ differentially compromises olfactory perception to odors: it reduces responses to social and non-social odors in Swiss Webster mice, while this effect was observed in C57BL/6 J mice only for some non-social odors. Additionally, O₃ reduced the rate of spontaneous spike firing in periglomerular dopaminergic cells (PG-DA) of the OB. Because this effect could reflect changes in excitability and/or synaptic inputs, the ability of O₃ to alter PG-DA spontaneous activity was also tested together with cell membrane resistance, membrane potential, rheobase and chronaxie. Taken together, our data suggest the ability of O₃ to affect olfactory perception.

Inhalation of welding fumes can cause metal accumulation in the brain, leading to Parkinsonian-like symptoms. Metal accumulation and altered neurochemical profiles have been observed using magnetic resonance imaging (MRI) in highly exposed welders, being associated with decreased motor function and cognition. While MRI is impractical to use as a health risk assessment tool in occupational settings, toenail metal levels are easier to assess and have been demonstrated to reflect an exposure window of 7–12 months in the past. Yet, it is unclear whether toenail metal levels are associated with brain metal levels or changes in metabolism, which are the root of potential health concerns. This study investigates whether toenail manganese (Mn) and iron (Fe) levels, assessed at several time points, correlate with brain Mn and Fe levels, measured by MRI, as well as brain GABA, glutamate (Glu), and glutathione (GSH) levels, measured by Magnetic Resonance Spectroscopy (MRS), in seventeen Mn-exposed welders. Quantitative T1 and R2* MRI maps of the whole brain, along with GABA, Glu, and GSH MRS measurements from the thalamus and cerebellum were acquired at baseline (T0). Toenail clippings were collected at T0 and every three months after the MRI for a year to account for different exposure periods being reflected by toenail clippings and MRI. Spearman correlations of toenail metal levels were run against brain metal and metabolite levels, but no significant associations were found for Mn at any timepoint. Cerebellar GSH positively correlated with toenail Fe clipped twelve months after the MRI (p = 0.05), suggesting an association with Fe exposure at the time of the MRI. Neither thalamic GABA nor Glu correlated with toenail Fe levels. In conclusion, this study cannot support toenail Mn as a proxy for brain Mn levels or metabolic changes, while toenail Fe appears linked to brain metabolic alterations, underscoring the importance of considering other metals, including Fe, in studying Mn neurotoxicity.

The Advanced Oxidative Processes have demonstrated potential for application in the degradation of organic pollutants, such as Paraquat (PQ) from water and wastewater, due to their low price, high efficiency, and non-toxic properties. In this study, we investigated whether the photodegradation of PQ with TiO₂ nanotubes reduced its toxicity in Drosophila melanogaster. However, dietary ingestion of degradation products PQ for larvae resulted in a low axial ratio (pupal volume). In the adults, products of photodegradation of PQ exposure markedly diminished climbing ability in a time-dependent manner after 10 days of feeding. In addition, exposure of D. melanogaster to photodegradation of PQ reduced acetylcholinesterase and citrate synthase activities but improved oxidative stress, as evidenced by oxide nitric, protein carbonyl, and lactate production. These results suggest that the photodegradation of PQ with TiO₂ nanotubes produced PQ fragments with higher toxicity than PQ, while the precise mechanism of its action needs further investigation.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.