Household air pollution (HAP) arising from combustion of biomass fuel (BMF) is a leading cause of morbidity and mortality in low-income countries. Air pollution may stimulate pro-inflammatory responses by activating diverse immune cells and cyto/chemokine expression, thereby contributing to diseases. We aimed to study cellular immune responses among women chronically exposed to HAP through use of BMF for domestic cooking. Among 200 healthy, non-smoking women in rural Bangladesh, we assessed exposure to HAP by measuring particulate matter 2.5 (PM₂.₅), black carbon (BC) and carbon monoxide (CO), through use of personal monitors RTI MicroPEM™ and Lascar CO logger respectively, for 48 h. Blood samples were collected following HAP exposure assessment and were analyzed for immunoprofiling by flow cytometry, plasma IgE by immunoassay analyzer and cyto/chemokine response from monocyte-derived-macrophages (MDM) and -dendritic cells (MDDC) by multiplex immunoassay. In multivariate linear regression model, a doubling of PM₂.₅ was associated with small increments in immature/early B cells (CD19⁺CD38⁺) and plasmablasts (CD19⁺CD38⁺CD27⁺). In contrast, a doubling of CO was associated with 1.20% reduction in CD19⁺ B lymphocytes (95% confidence interval (CI) = -2.36, −0.01). A doubling of PM₂.₅ and BC each was associated with 3.12% (95%CI = −5.85, −0.38) and 4.07% (95%CI = −7.96, −0.17) decrements in memory B cells (CD19⁺CD27⁺), respectively. Exposure to CO was associated with increased plasma IgE levels (beta(β) = 240.4, 95%CI = 3.06, 477.8). PM₂.₅ and CO exposure was associated with increased MDM production of CXCL10 (β = 12287, 95%CI = 1038, 23536) and CCL5 (β = 835.7, 95%CI = 95.5, 1576), respectively. Conversely, BC exposure was associated with reduction in MDDC-produced CCL5 (β = −3583, 95%CI = −6358, −807.8) and TNF-α (β = −15521, 95%CI = −28968, −2074). Our findings suggest that chronic HAP exposure through BMF use adversely affects proportions of B lymphocytes, particularly memory B cells, plasma IgE levels and functions of antigen presenting cells in rural women.

Fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) is counted as an organic manganese (Mn)-derived compound. The toxic effects of Mn (alone and complexed) on dopaminergic (DA) neurotransmission have been investigated in both cellular and animal models. However, the impact of environmentally relevant Mn exposure on DA neurodevelopment is rather poorly understood. In the present study, the MMT dose of 100 μM (about 5 mg Mn/L) caused up-regulation of DA-related genes in association with cell body swelling and increase in the number of DA neurons of the ventral diencephalon subpopulation DC2. Furthermore, our analysis identified significant brain Mn bioaccumulation and enhancement of total dopamine levels in association with locomotor hyperactivity. Although DA levels were restored at adulthood, we observed a deficit in the acquisition and consolidation of memory. Collectively, these findings suggest that developmental exposure to low-level MMT-derived Mn is responsible for the selective alteration of diencephalic DA neurons and with long-lasting effects on fish explorative behaviour in adulthood.

Excessive exposure to cobalt (Co) is known to make adverse impact on the nervous system, but its detailed mechanisms of neurotoxicity have yet to be determined. In this study, C57BL/6 mice (0, 4, 8, 16 mg/kg CoCl₂, 30 days) and human neuroblastoma H4 cells (0, 100, 400, 600 μM CoCl₂) were used as in vivo and in vitro models. Our results revealed that CoCl₂ intraperitoneal injection caused significant impairments in learning and memory, as well as pathological damage in the nervous system. We further certificated the alteration of m⁶A methylation induced by CoCl₂ exposure. Our findings demonstrate for the first time, significant differences in the degree of m⁶A modification, the biological function of m⁶A-modified transcripts between cortex and H4 cell samples. Specifically, MeRIP-seq and RNA-seq elucidate that CoCl₂ exposure results in differentially m⁶A-modified and expressed genes, which were enriched in pathways involving synaptic transmission, and central nervous system (CNS) development. Mechanistic analyses revealed that CoCl₂ remarkably changed m⁶A modification level by affecting the expression of m⁶A methyltransferase and demethylase, and decreasing the activity of demethylase. We observed variation of m⁶A modification in neurodegenerative disease-associated genes upon CoCl₂ exposure and identified regulatory strategy between m⁶A and potential targets mRNA. Our novel findings provide novel insight into the functional roles of m⁶A modification in neurodegenerative damage caused by environmental neurotoxicants and identify Co-mediated specific RNA regulatory strategy for broadening the epigenetic regulatory mechanism of RNA induced by heavy metals.

The present study was performed to evaluate the neurobehavioural deficit induced by nonylphenol (NP), a well-known xenobiotic chemical. The neurotoxic mechanism from oxidative stress and serotonin-related progress was also investigated. Caenorhabditis elegans was exposed at different levels of NP ranging from 0 to 200 μg L⁻¹ for 10 days. The results revealed that from a relatively low concentration (i.e., 10 μg L⁻¹), significant effects including decreased head thrashes, body bends and forging behaviour could be observed, along with impaired learning and memory behaviour plasticity. The level of reactive oxygen species (ROS) in head was significantly elevated with the increase of NP concentrations from 10 to 200 μg L⁻¹. Through antioxidant experiment, the oxidative damage caused by NP restored to some extent. At a NP concentration of 200 μg L⁻¹, the significant increased expression of stress-related genes, including sod-1, sod-3, ctl-2, ctl-3 and cyp-35A2 gene, was observed from integrated gene expression profiles. In addition, in comparison with wild-type N2 worms, the ROS accumulation was increased significantly with the mutation of sod-3. Tryptophan hydroxylase (TPH) in ADF and NSM neurons sharply decreased at the concentrations of 10–200 μg L⁻¹. The transcription of TPH synthesis-related genes and serotonin-related genes were both suppressed, including tph-1, cat-1, cat-4, ser-1, and mod-5. Overall, these results indicated that NP could induce neurotoxicity on Caenorhabditis elegans through excessive induction of ROS and disturbance synthesis of serotonin. The conducted research opened up new avenues for more effective exploration of neurotoxicity caused by NP.

This study investigated the role of nocturnal melatonin secretion in the cognitive performance of diurnal animals. An initial experiment measured the cognitive performance in Indian house crows treated for 11 days with 12 h light at 1.426 W/m² (∼150 lux) coupled with 12 h of 0.058 W/m² (∼6-lux) dim light at night (dLAN) or with absolute darkness (0 lux dark night, LD). dLAN treatment significantly decreased midnight melatonin levels and negatively impacted cognitive performance. Subsequently, the role of exogenous melatonin (50 μg; administered intraperitoneally half an hour before the night began) was assessed on the regulation of cognitive performance in two separate experimental cohorts of crows kept under dLAN; LD controls received vehicle. Exogenous melatonin restored its mid-night levels under dLAN at par with those under LD controls, and improved the cognitive performance, as measured in the innovative problem-solving, and spatial and pattern learning-memory efficiency tests in dLAN-treated crows. There were concurrent molecular changes in the cognition-associated brain areas, namely the hippocampus, nidopallium caudolaterale and midbrain. In particular, the expression levels of genes involved in neurogenesis and synaptic plasticity (bdnf, dcx, egr1, creb), and dopamine synthesis and signalling (th, drd1, drd2, darpp32, taar1) were restored to LD control levels in crows treated with illuminated nights and received melatonin. These results demonstrate that the maintenance of nocturnal melatonin levels is crucial for an optimal higher-order brain function in diurnal animals in the face of an environmental threat, such as light pollution.

The interrelationships among long-term ambient air pollution exposure, emotional distress and cognitive decline in older adulthood remain unclear. Long-term exposure may impact cognitive performance and subsequently impact emotional health. Conversely, exposure may initially be associated with emotional distress followed by declines in cognitive performance. Here we tested the inter-relationship between global cognitive ability, emotional distress, and exposure to PM₂.₅ (particulate matter with aerodynamic diameter <2.5 μm) and NO₂ (nitrogen dioxide) in 6118 older women (aged 70.6 ± 3.8 years) from the Women’s Health Initiative Memory Study. Annual exposure to PM₂.₅ (interquartile range [IQR] = 3.37 μg/m³) and NO₂ (IQR = 9.00 ppb) was estimated at the participant’s residence using regionalized national universal kriging models and averaged over the 3-year period before the baseline assessment. Using structural equation mediation models, a latent factor capturing emotional distress was constructed using item-level data from the 6-item Center for Epidemiological Studies Depression Scale and the Short Form Health Survey Emotional Well-Being scale at baseline and one-year follow-up. Trajectories of global cognitive performance, assessed by the Modified-Mini Mental State Examination (3MS) annually up to 12 years, were estimated. All effects reported were adjusted for important confounders. Increases in PM₂.₅ (β = -0.144 per IQR; 95% CI = −0.261; −0.028) and NO₂ (β = −0.157 per IQR; 95% CI = −0.291; −0.022) were associated with lower initial 3MS performance. Lower 3MS performance was associated with increased emotional distress (β = −0.008; 95% CI = −0.015; −0.002) over the subsequent year. Significant indirect effect of both exposures on increases in emotional distress mediated by exposure effects on worse global cognitive performance were present. No statistically significant indirect associations were found between exposures and 3MS trajectories putatively mediated by baseline emotional distress. Our study findings support cognitive aging processes as a mediator of the association between PM₂.₅ and NO₂ exposure and emotional distress in later-life.

Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6–11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (−1.25; −2.10, −0.40), house crowding (−0.39; −0.62, −0.16), and child environmental tobacco smoke (ETS) (−0.89; −1.42, −0.35), were all associated with lower CPM scores. Indoor PM₂.₅ exposure was associated with lower N-Back scores (−0.09; −0.16, −0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This first comprehensive and systematic study of many prenatal and childhood environmental risk factors suggests that unfavourable child nutrition, family crowdedness and child indoor air pollution and ETS exposures adversely and cross-sectionally associate with cognitive function. Unexpected associations were also observed and maybe due to confounding and reverse causality.

Non-optimum ambient temperature has been associated with a variety of health outcomes in the elderly population. However, few studies have examined its adverse effects on neurocognitive function. In this study, we explored the temperature-cognition association in elderly women. We investigated 777 elderly women from the German SALIA cohort during the 2007–2010 follow-up. Cognitive function was evaluated using the CERAD-Plus test battery. Modelled data on daily weather conditions were assigned to the residential addresses. The temperature-cognition association over lag 0–10 days was estimated using multivariable regression with distributed lag non-linear model. The daily mean temperature ranged between −6.7 and 26.0 °C during the study period for the 777 participants. We observed an inverse U-shaped association in elderly women, with the optimum temperature (15.3 °C) located at the 68th percentile of the temperature range. The average z-score of global cognitive function declined by −0.31 (95%CI: 0.73, 0.11) for extreme cold (the 2.5th percentile of temperature range) and −0.92 (95%CI: 1.50, −0.33) for extreme heat (the 97.5th percentile of temperature range), in comparison to the optimum temperature. Episodic memory was more sensitive to heat exposure, while semantic memory and executive function were the two cognitive domains sensitive to cold exposure. Individuals living in an urban area and those with a low educational level were particularly sensitive to extreme heat. In summary, non-optimum temperature was inversely associated with cognitive function in elderly women, with the effect size for heat exposure particularly substantial. The strength of association varied by cognitive domains and individual characteristics.

Evidence is emerging that environmental exposure to bisphenol S (BPS), a substitute for bisphenol A (BPA), to humans and wildlife is on the rise. However, research on the neurobehavioral effects of this endocrine disruptive chemical is still in its infancy. In this study, we aimed to investigate the effects of long-term exposure to environmentally relevant concentrations of BPS on recognition memory and its mechanism(s) of action, especially focusing on the glutamatergic/ERK/CREB pathway in the brain. Adult female zebrafish were exposed to the vehicle, 17β-estradiol (E2, 1 μg/L), or BPS (1, 10 and 30 μg/L) for 120 days. Fish were then tested in the object recognition (OR), object placement (OP), and social recognition tasks (SR). Chronic exposure to E2 and 1 μg/L of BPS improved fish performance in OP task. This was associated with an up-regulation in the mRNA expression of several subtypes of metabotropic and ionotropic glutamate receptors, an increase in the phosphorylation levels of ERK1/2 and CREB, and an elevated transcript abundance of several immediate early genes involved in synaptic plasticity and memory formation. In contrast, the exposure to 10 and 30 μg/L of BPS attenuated fish performance in all recognition memory tasks. The impairment of these memory functions was associated with a marked down-regulation in the expression and activity of genes and proteins involved in glutamatergic/ERK/CREB signaling cascade. Collectively, our study demonstrated that the long-term exposure to BPS elicits hermetic effects on the recognition memory in zebrafish. Furthermore, the effect of BPS on the recognition memory seems to be mediated by the glutamatergic/ERK/CREB signaling pathway.

Fluoride is capable of inducing neurotoxicity, but its mechanisms remain elusive. This study aimed to explore the roles of endoplasmic reticulum (ER) stress and autophagy in sodium fluoride (NaF)-induced neurotoxicity, focusing on the regulating role of ER stress in autophagy. The in vivo results demonstrated that NaF exposure impaired the learning and memory capabilities of rats, and resulted in histological and ultrastructural abnormalities in rat hippocampus. Moreover, NaF exposure induced excessive ER stress and associated apoptosis, as manifested by elevated IRE1α, GRP78, cleaved caspase-12 and cleaved-caspase-3, as well as defective autophagy, as shown by increased Beclin1, LC3-II and p62 expression in hippocampus. Consistently, the in vitro results further verified the findings of in vivo study that NaF induced excessive ER stress and defective autophagy in SH-SY5Y cells. Notably, inhibition of autophagy in NaF-treated SH-SY5Y cells with Wortmannin or Chloroquine decreased, while induction of autophagy by Rapamycin increased the cell viability. These results were correlated well with the immunofluorescence observations, thus confirming the pivotal role of autophagic flux dysfunction in NaF-induced cell death. Importantly, mitigation of ER stress by 4-phenylbutyrate in NaF-treated SH-SY5Y cells inhibited the expressions of autophagy markers, and decreased cell apoptosis. Taken together, these data suggest that neuronal death resulted from excessive ER stress and autophagic flux dysfunction contributes to fluoride-elicited neurotoxicity. Moreover, the autophagic flux dysfunction was mediated by excessive ER stress, which provided novel insight into a better understanding of fluoride-induced neurotoxicity.