Positive association between chlorinated paraffins and the risk of allergic diseases in children and adolescents.

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.

Long-term exposure to major constituents of fine particulate matter and neurodegenerative diseases: A population-based survey in the Pearl River Delta Region, China.

BACKGROUND: Exposure to PM2.5 has been linked to neurodegenerative diseases, with limited understanding of constituent-specific contributions. OBJECTIVES: To explore the associations between long-term exposure to PM2.5 constituents and neurodegenerative diseases. METHODS: We recruited 148,274 individuals aged ≥ 60 from four cities in the Pearl River Delta region, China (2020 to 2021). We calculated twenty-year average air pollutant concentrations (PM2.5 mass, black carbon (BC), organic matter (OM), ammonium (NH4+), nitrate (NO3-) and sulfate (SO42-)) at the individuals' home addresses. Neurodegenerative diseases were determined by self-reported doctor-diagnosed Alzheimer's disease (AD) and Parkinson's disease (PD). Generalized linear mixed models were employed to explore associations between pollutants and neurodegenerative disease prevalence. RESULTS: PM2.5 and all five constituents were significantly associated with a higher prevalence of AD and PD. The observed associations generally exhibited a non-linear pattern. For example, compared with the lowest quartile, higher quartiles of BC were associated with greater odds for AD prevalence (i.e., the adjusted odds ratios were 1.81; 95% CI, 1.45-2.27; 1.78; 95% CI, 1.37-2.32; and 1.99; 95% CI, 1.54-2.57 for the second, third, and fourth quartiles, respectively). CONCLUSIONS: Long-term exposure to PM2.5 and its constituents, particularly combustion-related BC, OM, and SO42-, was significantly associated with higher prevalence of AD and PD in Chinese individuals. ENVIRONMENTAL IMPLICATION: PM2.5 is a routinely regulated mixture of multiple hazardous constituents that can lead to diverse adverse health outcomes. However, current evidence on the specific contributions of PM2.5 constituents to health effects is scarce. This study firstly investigated the association between PM2.5 constituents and neurodegenerative diseases in the moderately to highly polluted Pearl River Delta region in China, and identified hazardous constituents within PM2.5 that have significant impacts. This study provides important implications for the development of targeted PM2.5 prevention and control policies to reduce specific hazardous PM2.5 constituents.

Toxicological evaluation and concentration of airborne PM0.1 in high air pollution period in Guangzhou, China.

The emissions and exposure limits for airborne PM0.1 are lacking, with limited scientific data for toxicity. Therefore, we continuously monitored and calculated the number and mass concentrations of airborne PM0.1 in December 2017, January 2018 and March 2018 during the high pollution period in Guangzhou. We collected PM0.1 from the same period and analyzed their chemical components. A549, THP-1 and A549/THP-1 co-cultured cells were selected for exposure to PM0.1, and evaluated for toxicological responses. Our aims are to 1) measure and analyze the number and mass concentrations, and chemical components of PM0.1; 2) evaluate and compare PM0.1 toxicity to different airway cells models at different time points. Guangzhou had the highest mass concentration of PM0.1 in December 2017, while the number concentration was the lowest. Chemical components in PM0.1 vary significantly at different time periods, and the correlation between the chemical composition or source of PM0.1 and the mass and number concentration of PM0.1 was dissimilar. Exposure to PM0.1 disrupted cell membranes, impaired mitochondrial function, promoted the expression of inflammatory mediators, and interfered with DNA replication in the cell cycle. The damage caused by exposure to PM0.1 at different times exhibited variations across different types of cells. PM0.1 in March 2018 stimulated co-cultured cells to secrete more inflammatory mediators, and CMA was significantly related to the expression of them. Our study indicates that it is essential to monitor both the mass and number concentrations of PM0.1 throughout all seasons annually, as conventional toxicological experiments and the internal components of PM0.1 may not effectively reveal the health damages caused by elevated number levels of PM0.1.

Early life exposure to F-53B induces neurobehavioral changes in developing children and disturbs dopamine-dependent synaptic signaling in weaning mice.

BACKGROUND: Previous studies have shown that F-53B exposure may be neurotoxic to animals, but there is a lack of epidemiological evidence, and its mechanism needs further investigation. METHODS: Serum F-53B concentrations and Wisconsin Card Sorting Test (WCST) were evaluated in 314 growing children from Guangzhou, China, and the association between them were analyzed. To study the developmental neurotoxicity of F-53B, experiments on sucking mice exposed via placental transfer and breast milk was performed. Maternal mice were orally exposed to 4, 40, and 400 µg/L of F-53B from postnatal day 0 (GD0) to postnatal day 21 (PND 21). Several genes and proteins related to neurodevelopment, dopamine anabolism, and synaptic plasticity were examined by qPCR and western blot, respectively, while dopamine contents were detected by ELISA kit in weaning mice. RESULTS: The result showed that F-53B was positively associated with poor WCST performance. For example, with an interquartile range increase in F-53B, the change with 95 % confidence interval (CI) of correct response (CR), and non-perseverative errors (NPE) was -2.47 (95 % CI: -3.89, -1.05, P = 0.001), 2.78 (95 % CI: 0.79, 4.76, P = 0.007), respectively. Compared with the control group, the highest exposure group of weaning mice had a longer escape latency (35.24 s vs. 51.18 s, P = 0.034) and a lesser distance movement (34.81 % vs. 21.02 %, P < 0.001) in the target quadrant, as observed from morris water maze (MWM) test. The protein expression of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) levels were decreased, as compared to control (0.367-fold, P < 0.001; 0.366-fold, P < 0.001; respectively). We also observed the upregulation of dopamine transporter (DAT) (2.940-fold, P < 0.001) consistent with the trend of dopamine content (1.313-fold, P < 0.001) in the hippocampus. CONCLUSION: Early life exposure to F-53B is associated with adverse neurobehavioral changes in developing children and weaning mice which may be modulated by dopamine-dependent synaptic plasticity.

Preclinical evaluation of drug treatment options for sleep-related epileptiform spiking in Alzheimer's disease.

Introduction: There are no published data on prospective clinical studies on drug treatment options for sleep-related epileptiform spiking in Alzheimer's disease (AD). Methods: Using video-EEG with hippocampal electrodes in 17 APP/PS1 transgenic male mice we assessed the effects of donepezil and memantine, anti-seizure drugs levetiracetam and lamotrigine, gamma-secretase inhibitor semagacestat, anti-inflammatory minocycline and adenosine receptor antagonist istradephylline on density of cortical and hippocampal spikes during sleep. Results: Levetiracetam decreased the density of hippocampal giant spikes and cortical spikes. Lamotrigine reduced cortical single spikes and spike-wave discharges but dramatically increased hippocampal giant spikes. Memantine increased cortical single spikes and spike-wave discharges dose-dependently. Memantine and istradephylline decreased total sleep time while levetiracetam increased it. Lamotrigine decreased REM sleep duration. Other drugs had no significant effects. Discussion: Levetiracetam appears promising for treating sleep-related epileptiform spiking in AD while lamotrigine should be used with caution. Donepezil at low doses appeared neutral but the memantine effects warrant further studies.

Recommendations for Preclinical Testing of Treatments Against Alzheimer's Disease-Related Epileptiform Spikes in Transgenic Rodent Models.

Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer's disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models. Transgenic rodent models of AD pathology exhibit various forms of epileptiform EEG activity related to the abnormal levels of amyloid species in the brain. Among them, large-amplitude cortical and hippocampal EEG spikes in mouse and rat AD models may be reminiscent of the subclinical epileptiform EEG spikes recorded in some AD patients. This article reports the recommendations of a multidisciplinary panel of experts on optimal EEG markers and experimental designs to measure and report epileptiform activities and their response to symptomatic and disease-modifying drugs in transgenic AD model rodents. These recommendations may harmonize future preclinical EEG studies in the drug discovery research and may increase the comparability of experimental outcomes and their translational clinical value.

Mushroom Body Extrinsic Neurons in Walking Bumblebees Correlate With Behavioral States but Not With Spatial Parameters During Exploratory Behavior.

Central place foraging insects like honeybees and bumblebees learn to navigate efficiently between nest and feeding site. Essential components of this behavior can be moved to the laboratory. A major component of navigational learning is the active exploration of the test arena. These conditions have been used here to search for neural correlates of exploratory walking in the central arena (ground), and thigmotactic walking in the periphery (slope). We chose mushroom body extrinsic neurons (MBENs) because of their learning-related plasticity and their multi-modal sensitivities that may code relevant parameters in a brain state-dependent way. Our aim was to test whether MBENs code space-related components or are more involved in state-dependent processes characterizing exploration and thigmotaxis. MBENs did not respond selectively to body directions or locations. Their spiking activity differently correlated with walking speed depending on the animals' locations: on the ground, reflecting exploration, or on the slope, reflecting thigmotaxis. This effect depended on walking speed in different ways for different animals. We then asked whether these effects depended on spatial parameters or on the two states, exploration and thigmotaxis. Significant epochs of stable changes in spiking did not correlate with restricted locations in the arena, body direction, or walking transitions between ground and slope. We thus conclude that the walking speed dependencies are caused by the two states, exploration and thigmotaxis, rather than by spatial parameters.

Response of spike-wave discharges in aged APP/PS1 Alzheimer model mice to antiepileptic, metabolic and cholinergic drugs.

Epileptic nonconvulsive spike-wave discharges (SWDs) are commonly seen in amyloid plaque bearing transgenic mice but only rarely in their wild-type littermates. To shed light on their possible treatment options, we assessed the effect of drugs with variable and known mechanisms of action on the occurrence of SWDs in aged APPswe/PS1dE9 mice. The treatments included prototypic antiepileptic drugs (ethosuximide and levetiracetam), donepezil as the typical Alzheimer drug and atropine as an antagonistic effect, GABAB antagonist CGP-35348, and alternate energy substrates beta-hydroxybutyrate (BHB), pyruvate and lactate on the occurrence of SWDs in aged APPswe/PS1dE9 mice. All agents were administered by single intraperitoneal injections at doses earlier documented to be effective and response was assessed by recording 3 h of video-EEG. Atropine at 25 mg/kg significantly decreased SWD occurrence in all behavioral states, and also resulted in altered frequency composition of SWDs and general EEG slowing during sleep. Ethosuximide at 200 mg/kg and levetiracetam at 75 mg/kg effectively suppressed SWDs only during a period of mixed behavioral states, but levetiracetam also increased SWDs in sleep. BHB at 1 g/kg decreased SWDs in sleep, while both pyruvate and lactate at the same dose tended to increase SWD number and total duration. Unexpectantly, donepezil at 0.3 mg/kg CGP-35348 at 100 mg/kg had no effect on SWDs. These findings call for re-evaluation of some prevailing theories on neural circuit alternations that underlie SWD generation and show the utility of APP/PS1 mice for testing potential new treatments for nonconvulsive epileptic activity related to Alzheimer pathology.

The Traditional Formula Kai-Xin-San Alleviates Polyglutamine-Mediated Neurotoxicity by Modulating Proteostasis Network in Caenorhabditis elegans.

The inherited polyglutamine (polyQ) expansion diseases are characterized by progressive accumulation of aggregation-prone polyQ proteins, which may provoke proteostasis imbalance and result in significant neurotoxicity. Using polyQ transgenic Caenorhabditis elegans models, we find that Kai-Xin-San (KXS), a well-known herbal formula traditionally used to treat mental disorders in China, can alleviate polyQ-mediated neuronal death and associated chemosensory deficiency. Intriguingly, KXS does not reduce polyQ aggregation in vitro as demonstrated by Thioflavin-T test, but does inhibit polyQ aggregation in C. elegans models, indicating an indirect aggregation-inhibitory mechanism. Further investigation reveals that KXS can modulate two key arms of the protein quality control system, that is, heat shock response and autophagy, to clear polyQ aggregates, but has little effect on proteasome activity. In addition, KXS is able to reduce oxidative stress, which is involved in proteostasis and neurodegeneration, but has no effect on life span or dietary restriction response. To examine potential interaction of the four component herbs of KXS, a dissection strategy was used to study the effects of differential herbal combinations in C. elegans polyQ models. While the four herbs do contribute additively to KXS function, Panax ginseng is found to be the most effective constituent. Taken together, these findings not only demonstrate the neuroprotective ability of KXS but also suggest its potential as a proteostasis regulator in protein aggregation disorders and provide an insight into the mechanism studies of traditionally used complex prescriptions and their rationality.

Characterization of Epileptic Spiking Associated With Brain Amyloidosis in APP/PS1 Mice.

Epileptic activity without visible convulsions is common in Alzheimer's disease (AD) and may contribute adversely to the disease progress and symptoms. Transgenic mice with amyloid plaque pathology also display epileptic seizures, but those are too infrequent to assess the effect of anti-epileptic treatments. Besides spontaneous seizures, these mice also display frequent epileptic spiking in epidural EEG recordings, and these have provided a means to test potential drug treatment to AD-related epilepsy. However, the origin of EEG spikes in transgenic AD model mice has remained elusive, which makes it difficult to relate electrophysiology with underlying pathology at the cellular and molecular level. Using multiple cortical and subcortical electrodes in freely moving APP/PS1 transgenic mice and their wild-type littermates, we identified several types of epileptic spikes among over 15 800 spikes visible with cortical screw electrodes based on their source localization. Cortical spikes associated with muscle twitches, cortico-hippocampal spikes, and spindle and fast-spindle associated spikes were present equally often in both APP/PS1 and wild-type mice, whereas pure cortical spikes were slightly more common in APP/PS1 mice. In contrast, spike-wave discharges, cortico-hippocampal spikes with after hyperpolarization and giant spikes were seen almost exclusively in APP/PS1 mice but only in a subset of them. Interestingly, different subtypes of spikes responded differently to anti-epileptic drugs ethosuximide and levetiracetam. From the translational point most relevant may be the giant spikes generated in the hippocampus that reached an amplitude up to ± 5 mV in the hippocampal channel. As in AD patients, they occurred exclusively during sleep. Further, we could demonstrate that a high number of giant spikes in APP/PS1 mice predicts seizures. These data show that by only adding a pair of hippocampal deep electrodes and EMG to routine cortical epidural screw electrodes and by taking into account underlying cortical oscillations, one can drastically refine the analysis of cortical spike data. This new approach provides a powerful tool to preclinical testing of potential new treatment options for AD related epilepsy.

Increased cortical beta power and spike-wave discharges in middle-aged APP/PS1 mice.

Amyloid plaque-forming transgenic mice display neuronal hyperexcitability, epilepsy, and sudden deaths in early adulthood. However, it is unknown whether hyperexcitability persists until middle ages when memory impairment manifests. We recorded multichannel video electroencephalography (EEG), local field potentials, and auditory evoked potentials in transgenic mice carrying mutated human amyloid precursor protein (APP) and presenilin-1 (PS1) genes and wild-type littermates at 14-16 months and compared the results with data we have earlier collected from 4-month-old mice. Furthermore, we monitored acoustic startle responses in other APP/PS1 and wild-type mice from 3 to 11 months of age. Independent of the age APP/PS1 mice demonstrated increased cortical power at 8-60 Hz. They also displayed over 5-fold increase in the occurrence of spike-wave discharges and augmented auditory evoked potentials compared with nontransgenic littermates. In contrast to evoked potentials, APP/PS1 mice showed normalization of acoustic startle responses with aging. Increased cortical power and spike-wave discharges provide powerful new biomarkers to monitor progression of amyloid pathology in preclinical intervention studies.

The neonicotinoid clothianidin interferes with navigation of the solitary bee Osmia cornuta in a laboratory test.

Pollinating insects provide a vital ecosystem service to crops and wild plants. Exposure to low doses of neonicotinoid insecticides has sub-lethal effects on social pollinators such as bumblebees and honeybees, disturbing their navigation and interfering with their development. Solitary Hymenoptera are also very important ecosystem service providers, but the sub-lethal effects of neonicotinoids have not yet been studied well in those animals. We analyzed the ability of walking Osmia to remember a feeding place in a small environment and found that Osmia remembers the feeding place well after 4 days of training. Uptake of field-realistic amounts of the neonicotinoid clothianidin (0.76 ng per bee) altered the animals' sensory responses to the visual environment and interfered with the retrieval of navigational memory. We conclude that the neonicotinoid clothianidin compromises visual guidance and the use of navigational memory in the solitary bee Osmia cornuta.

The neuroprotective and lifespan-extension activities of Damnacanthus officinarum extracts in Caenorhabditis elegans.

AIM OF THE STUDY: This study was aimed to evaluate the neuroprotective and anti-aging activity of extracts in Caenorhabditis elegans from the roots and leaves of Damnacanthus officinarum Huang to provide the pharmacological basis in traditional medicine. MATERIALS AND METHODS: Investigations on the neuroprotective and lifespan activity were carried out, which were observed by utilizing the following models: observing the worms' chemosensory behavior test based on the aversion index in the assay plate, neuroprotective activity of nematode by evaluating the ASH neuron survival and lifespan test in C. elegans. RESULTS: It has been shown that the ethanol, n-butanol and aqueous extracts in the roots possessed significantly neuroprotective effect both in chemosensory behavior test and ASH neuron survival model. The same extracts in the leaves showed similar activities in two models, but have less potency revealing by the data. Four candidate extracts, possessing excellent neuroprotective activity, extend lifespan in C. elegans. The n-butanol extracts in the root part showed best efficacy among them. CONCLUSION: The results show the n-butanol and aqueous extracts are the major pharmacological plant extracts. Moreover, the neuroprotective and lifespan-extension activity effects of root extracts are superior to leave extracts, supporting the traditional application of above-ground parts of DOH in treating various diseases associated with brain disorders and anti-aging.