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Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. β‐Amyloid (Aβ) oligomers are considered the principal neurotoxic species in AD brains. The M1 muscarinic ACh receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro‐cognitive activity but cause many adverse off‐target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease‐modifying efficacy in female AD mice. Experimental Approach Nine‐month‐old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg·kg−1·day−1) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment. Key Results: VU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in Aβ oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced Aβ oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non‐amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of β‐secretase 1 (BACE1), whereas it enhanced the expression of the α‐secretase ADAM10 in APPswe hippocampus. Conclusion and Implications: Using M1 mAChR PAMs can be a viable disease‐modifying approach that should be exploited clinically to slow AD in women. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent type of dementia, disproportionately affecting females, who make up nearly 60% of diagnosed cases. In AD patients, the accumulation of beta-amyloid (Aβ) in the brain triggers a neuroinflammatory response driven by neuroglia, worsening the condition. We have previously demonstrated that VU0486846, an orally available positive allosteric modulator (PAM) targeting M1 muscarinic acetylcholine receptors, enhances cognitive function and reduces Aβ pathology in female APPswe/PSEN1ΔE9 (APP/PS1) mice. However, it remained unclear whether these improvements were linked to a decrease in neuroglial activation. To investigate, we treated nine-month-old APP/PS1 and wildtype mice with VU0486846 for 8 weeks and analyzed brain slices for markers of microglial activation (ionized calcium binding adaptor molecule 1, Iba1) and astrocyte activation (Glial fibrillary acidic protein, GFAP). We find that VU0486846 reduces the presence of Iba1-positive microglia and GFAP-positive astrocytes in the hippocampus of female APP/PS1 mice and limits the recruitment of these cells to remaining Aβ plaques. This study sheds light on an additional mechanism through which novel M1 mAChR PAMs exhibit disease-modifying effects by reducing neuroglial activation and underscore the potential of these ligands for the treatment of AD, especially in females. [Display omitted] • Activation of M1 mAChR with VU0486846 reduces Aβ plaques in female APP/PS1 mice. • VU0486846 reduces microgliosis around Aβ plaques in the hippocampus of APP/PS1 mice. • VU0486846 decreases astrocyte reactivity around hippocampal plaques in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment. There are currently no available disease modifying treatments for HD patients. We have previously shown that pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) signaling rescues motor deficits, improves cognitive impairments and mitigates HD neuropathology in male zQ175 HD mice. Mounting evidence indicates that sex may influence HD progression and we have recently reported a sex-specific pathological mGluR5 signaling in Alzheimer's disease (AD) mice. Here, we compared the outcomes of treatment with the mGluR5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine) in both male and female symptomatic zQ175 mice. We found that female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Unlike males, chronic CTEP treatment did not improve the grip strength nor reverse the cognitive decline of female zQ175 mice. However, CTEP reduced the number of huntingtin aggregates, improved neuronal survival and decreased microglia activation in the striatum of both male and female zQ175 mice. Together, our results indicate that mGluR5 antagonism can reduce HD neuropathology in both male and female zQ175 HD mice, but sex has a clear impact on the efficacy of the treatment and must be taken into consideration for future HD drug development. [ABSTRACT FROM AUTHOR]

Benzotriazole ultraviolet‐stabilizers (BZT‐UVs) are commonly used as additives to protect from light‐induced degradation in a variety of consumer goods. Despite their widespread presence in aquatic ecosystems, information on the effects of these compounds remains largely unknown. The objectives of the present study were to evaluate the chronic effects of 2 BZT‐UVs alone and in a mixture, 2‐(2H‐benzotriazol‐2‐yl)‐4,6‐bis(1‐methyl‐1‐phenylethyl)phenol (UV‐234) and 2‐(2H‐benzotriazol‐2‐yl)‐4,6‐di‐tert‐pentylphenol (UV‐328), in juvenile rainbow trout (Oncorhynchus mykiss) chronically exposed (for 28 d) through the diet. Chemical analyses of livers from exposed trout suggested liver accumulation and potential metabolism of the 2 compounds. Hepatic RNA‐sequencing analyses revealed specific effects of each compound on gene transcription profiles; UV‐234 affected mainly genes involved in cellular metabolism, whereas UV‐328 induced the transcription of ribosomal proteins and downregulated genes involved in immune responses. Both compounds regulated iron homeostasis genes in an opposite manner. The mixture of both BZT‐UVs did not produce significant evidence of additive or synergistic effects. Environ Toxicol Chem 2020;39:852–862. © 2020 Her Majesty the Queen in Right of Canada. Environmental Toxicology and Chemistry © 2020 SETAC [ABSTRACT FROM AUTHOR]

There is a risk of exposure of aquatic organisms to silver nanoparticles (AgNPs) from discharges of municipal and industrial wastewater. In the present study, yellow perch ( Perca flavescens) were exposed to environmentally relevant concentrations (1 mg/L and 100 mg/L) of AgNPs and silver ions (Ag+) in static-renewal experiments conducted over 96 h and 10 d. The greatest accumulation of total Ag occurred in the liver of P. flavescens, and there was >10-fold more accumulation in the treatments with Ag+ relative to the AgNP treatments. Residues of total Ag increased with concentration and duration of exposure in liver, gill, and muscle. Both exposures caused a 2-fold induction of gene expression for metallothionein ( mt) in liver tissue after 96 h of exposure and reductions in levels of oxidized glutathione (GSSG) in liver after 10 d of exposure. Both AgNPs and Ag+ decreased the expression of heat-shock proteins ( hsp70). Exposure to the high concentration of AgNPs for 10 d significantly increased lipid peroxidation in gill tissue, as indicated by the thiobarbituric acid reactive substances (TBARS) assay. There was a negative correlation between mean levels of GSSG and TBARS for both gill and liver tissue when data for all treatments were combined. It is significant that these biological responses were observed in P. flavescens exposed to AgNPs, even though accumulation of total Ag was at least 10-fold lower relative to the treatments with Ag+. Environ Toxicol Chem 2017;36:1211-1220. © 2016 SETAC [ABSTRACT FROM AUTHOR]

Despite the North American production ban of polychlorinated biphenyls (PCBs), PCBs are ubiquitous in the environment and in wildlife tissues. Chelydra serpentina serpentina (common snapping turtle) have been used as environmental indicators of PCB pollution upwards of 40 years given their high site fidelity and high trophic position. Despite their long use as indicators of PCB contamination, the effects of PCBs in reptiles remain largely unknown. In this study, we performed two experiments to assess i) bioaccumulation and ii) toxicity of PCBs to 1-month-old C. s. serpentina , to aid in interpretation of PCB burdens. Food pellets were spiked at an environmentally relevant concentration (0.45 μg/g) of the PCB mixture Aroclor 1254 to model hepatic bioaccumulation and depuration, through feeding, for 31 days and clean food for 50 days, respectively. No significant differences in PCB concentrations were observed in liver tissue over the course of the experiment, suggesting that juvenile turtles can likely metabolize low environmentally occurring concentrations of PCBs. Additionally, a dose-response experiment, performed to determine hepatic toxicity and bioaccumulation in juvenile C. s. serpentina, showed a 1.8-fold increase in hepatic expression of cyp1a when fed A1254-spiked pellets (12.7 μg/g; range 0–12.7 μg/g). This gene induction correlates with the significant increase of group 3 PCB congeners measured in the turtle liver, which are known to be metabolized by CYP1A. This study indicates that C. s. serpentina may be a good environmental indicator for PCBs, while more research is needed to assess the effects of body burdens in wild C. s. serpentina. Image 1 • First investigation of the effects of PCBs on juvenile turtles' toxicity and transcription. • Environmentally relevant concentrations of PCBs can be cleared from the turtle liver. • Induction of cyp1a indicates activation of this pathway for hepatic PCB detoxification. • Snapping turtles show resilience to changes in oxidative stress and endocrine disruption. [ABSTRACT FROM AUTHOR]

Abstract Multiple metabolic, immune and reproductive effects have been reported in fish residing in effluent-impacted sites. Natural stressors such as parasites also have been shown to impact the responses of organisms to chronic exposure to municipal effluent in the St. Lawrence River (Quebec, Canada). In order to comprehensively evaluate the cumulative impacts of anthropogenic and natural stressors on the health of yellow perch, differential mRNA transcription profiles were examined in juvenile females collected from effluent-impacted and upstream sites with low or high infection levels of the larval trematode Apophallus brevis. Transcriptomics was used to identify biological pathways associated with environmental exposure. In total, 3463 isoforms were differentially transcribed between sites. Patterns reflecting the combined effects of stressors were numerically dominant, with a majority of downregulated transcripts (68%). The differentially expressed transcripts were associated with 27 molecular and cellular functions ranging from cellular development to xenobiotic metabolism and were involved in the development and function of 13 organ systems including hematological, hepatic, nervous, reproductive and endocrine systems. Based on RNA-seq results, sixteen genes were measured by qPCR. Significant differences were observed for six genes in fish exposed to both stressors combined, whereas parasites and effluent individually impacted the transcription of one gene. Lysozyme activity, lipid peroxidation, retinol-binding protein and glucose-6-phosphate dehydrogenase were selected as potential biomarkers of effects to study specific pathways of interest. Lipid peroxidation in perch liver was different between sites, parasite loads, and for combined stressors. Overall, results indicated that juvenile yellow perch responded strongly to combined parasite and effluent exposure, suggesting cumulative effects on immune responses, inflammation and lipid metabolism mediated by retinoid receptors. The present study highlight the importance of using a comprehensive approach combining transcriptomics and endpoints measured at higher levels of biological organization to better understand cumulative risks of contaminants and pathogens in aquatic ecosystems. Graphical abstract Unlabelled Image Highlights • Combined effects of effluent and parasite may result in stronger impacts on hosts than individually. • RNA seq used to study the interactions between municipal effluent exposure and parasite infection in fish. • Differential transcript profiles in fish from effluent/upstream sites and low/high parasitic loads • Immune function, inflammation, lipid and retinol metabolisms mainly were impacted. • Fish responded strongly to parasite and effluent exposure combined suggesting cumulative effects. [ABSTRACT FROM AUTHOR]