Effects Of Chronic Exposure Research Articles

MiR-153-3p via PIK3R1 Is Involved in Cigarette Smoke-Induced Neurotoxicity in the Brain.

Cigarettes contain various chemicals that cause damage to nerve cells. Exposure to cigarette smoke (CS) causes insulin resistance (IR) in nerve cells. However, the mechanisms for a disorder in the cigarette-induced insulin signaling pathway and in neurotoxicity remain unclear. Therefore, we evaluated, by a series of pathology analyses and behavioral tests, the neurotoxic effects of chronic exposure to CS on C57BL/6 mice. Mice exposed to CS with more than 200 mg/m3 total particulate matter (TPM) exhibited memory deficits and cognitive impairment. Pathological staining of paraffin sections of mouse brain tissue revealed that CS-exposed mice had, in the brain, neuronal damage characterized by thinner pyramidal and granular cell layers and fewer neurons. Further, the exposure of SH-SY5Y cells to cigarette smoke extract (CSE) resulted in diminished insulin sensitivity and reduced glucose uptake in a dose-dependent fashion. The PI3K/GSK3 insulin signaling pathway is particularly relevant to neurotoxicity. microRNAs are involved in the PI3K/GSK3β/p-Tau pathway, and we found that cigarette exposure activates miR-153-3p, decreases PI3K regulatory subunits PIK3R1, and induces Tau hyperphosphorylation. Exposure to an miR-153 inhibitor or to a PI3K inhibitor alleviated the reduced insulin sensitivity caused by CS. Therefore, our results indicate that miR-153-3p, via PIK3R1, causes insulin resistance in the brain, and is involved in CS-induced neurotoxicity.

Lethal and sublethal effects of chronic exposure to insecticide residues on reared Alphitobius diaperinus

Abstract Edible insects such as lesser mealworm (Alphitobius diaperinus) are a promising new protein source for food and feed. The feed substrate on which these insects are reared may be contaminated with residues of insecticides originating from agricultural products that may impact insect performance. In this study, two generations of A. diaperinus were chronically exposed to spinosad (2.0 and 0.2 mg/kg) and imidacloprid (0.1 and 0.01 mg/kg) in the substrate. The aim was to determine sublethal effects on performance measures (total biomass (yield), mean individual weight, number of alive individuals) of larvae, pupae, and adult beetles, as well as pupation and eclosion. Exposure to spinosad at 2.0 mg/kg resulted in significant adverse effects on most performance measures of larvae, of both generations. Imidacloprid caused a reduction in yield and mean individual weight of the larvae as compared to the control at 0.1 mg/kg, while an increase in those measures was observed at 0.01 mg/kg. Significant adverse effects on adult beetles were only observed for imidacloprid at 0.1 mg/kg, and no significant effects of this insecticide on pupation and eclosion were observed. The concentrations of tested substances in larval samples were negligible for both generations, however, transfer from substrate to larval biomass was higher in the offspring generation relative to the parent generation. More research is needed to fully assess the hazard of insecticide residues to cause sublethal effects on A. diaperinus, for which method development for more cost-efficient designs is required.

Central sleep apnea and exposure to ambient hydrogen sulfide emissions from massive strandings of decomposing sargassum in the Caribbean

BackgroundSargassum invasion of Caribbean and American shorelines is a recurring environmental hazard. Potential health effects of long-term chronic exposure to sargassum gaseous emissions, notably hydrogen sulfide (H2S), are overlooked. H2S plays an important role in neurotransmission and is involved in generating and transmitting respiratory rhythm. Central sleep apnea (CSA) has been attributed to the depression of respiratory centers. ObjectiveEvaluate the effects of exposure to sargassum-H2S on CSA. MethodsThis study, set in the Caribbean, describes the clinical and polysomnographic characteristics of individuals living and/or working in areas impacted by sargassum strandings, in comparison with non-exposed subjects. Environmental exposure was estimated by the closest ground H2S sensor. Multivariate linear regression was applied to analyze CSA changes according to cumulative H2S exposure over time. Effects of air pollution and other sargassum toxic compounds (NH3) on CSA were also controlled. ResultsAmong the 685 study patients, 27 % were living and/or working in sargassum impacted areas. Compared with non-exposed patients, exposed ones had similar sleep apnea syndrome risk factors, but had increased levels of CSA events (expressed as absolute number or % of total sleep apnea). Multivariate regression retained only male gender and mean H2S concentration over a 6-month exposure period as independent predictors of an increase in CSA events. A minimal exposure length of 1 month generated a significant rise in CSA events, with the latter increasing proportionally with a cumulative increase in H2S concentration over time. ConclusionThis pioneer work highlights a potential effect of sargassum-H2S on the central nervous system, notably on the modulation of the activity of the brain's respiratory control center. These observations, jointly with previous studies from our group, constitute a body of evidence strongly supporting a deleterious effect of sargassum-H2S on the health of individuals chronically exposed to low to moderate concentration levels over time.

Biochemical, histological and transcriptomic analyses for the immunological organs provide insights into heat stress-induced disease susceptibility in Largemouth Bass

Aquaculture of Largemouth Bass (LMB, Micropterus salmoides), an economically important species, is badly affected by the outbreak of bacterial diseases in summer. However, the mechanisms underlying heat-induced disease susceptibility remain largely unknown. In this study, after exposure to 34 °C for 1, 7 and 14 d, the head kidney, spleen and blood of LMB were sampled for biochemical and histological assays to explore the effects of heat exposure on the oxidative and immunological indices. Compared to the controls maintained at 28 °C, chronic heat exposure (34 °C for 14 d) induced oxidative stress, caused cell apoptosis and decreased expression of the immunological genes in the head kidney and spleen tissues; and attenuated the blood immunological indices. Consistent with the impaired immunological functions, chronic heat exposure predisposed LMB to Aeromonas hydrophila infection and significantly (p < 0.001) increased tissue bacterial load. Furthermore, the effects of chronic heat exposure (heat), A. hydrophila infection (infection) and heat exposure followed by A. hydrophila infection (heat + infection) on gene expression in the head kidney and spleen of LMB were characterized by RNA sequencing. The results indicated that chronic heat exposure facilitated the bacteria-elicited changes in expression of the genes involved in a couple of metabolic and signaling pathways in both tissues. Upon heat + infection, the pathways involved in energy production and nutrients biosynthesis were enhanced, whereas those associated with the host cell functions such as cell-cell interactions and cell signaling were depressed. Our data provide new insights into the mechanisms underlying heat-induced disease susceptibility in LMB.

Chronic Morphine Induces Adaptations in Opioid Receptor Signaling in a Thalamostriatal Circuit That Are Location Dependent, Sex Specific, and Regulated by μ-Opioid Receptor Phosphorylation.

Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in the DMS. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation) in male, but not female, mice. At MThal cell bodies, chronic morphine treatment decreased subsequent morphine activation of potassium conductance (morphine tolerance) in both male and female mice. In knock-in mice expressing phosphorylation-deficient MORs, chronic morphine treatment resulted in tolerance to, rather than facilitation of, subsequent morphine signaling at MThal-DMS terminals, suggesting phosphorylation deficiency unmasks adaptations that counter the facilitation observed at presynaptic terminals in wild-type mice. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry, and sex.

Abstract 14831: Low Positive Social Determinants of Health Exposure Amplifies the Association Between Allostatic Load and Risk of Cardiovascular Mortality in Cancer and Non-Cancer Patients

Introduction: Allostatic load (AL) is a measure of the biological “wear and tear” or physiological effects of chronic toxic stress exposure and the body’s adaptive responses over time. High AL is associated with an increased risk of death from cardiovascular disease and cancer. Hypothesis: We examined Positive Social Determinants of Health (PSDOH) exposure as a moderator for the effect of AL on the risk of cardiovascular-related death (CVD) among adults with and without a history of cancer. Methods: We conducted a retrospective cohort analysis of the National Health and Nutrition Examination Survey (NHANES) years 1999 through 2010 linked and followed up with the National Death Index through December 31, 2019. We fit age, race, and sex-adjusted Fine &amp; Gray models to calculate sub-distribution hazard ratios (SHR) of CVD among adults exposed to high versus low levels of PSDOH, stratified by high and low AL status. AL was calculated using a nine-point score previously defined in NHANES literature that uses a combination of serum biomarkers as well as body mass index and blood pressure. PSDOH was calculated using a seven-point score previously defined in NHANES literature examining positive exposures of home ownership, health insurance, educational attainment greater than high school, food security, being above the federal poverty level, health care access, and living with a partner. Results: Among 22,775 eligible participants in this study, 1,939 (8.5%) had a history of cancer. In the full cohort, age, race, and sex-adjusted models found that low PSDOH exposure was associated with a 38% increased risk of CVD among high AL adults (SHR: 1.38, 95% CI: 1.22 - 1.56) and a 57% increased risk among low AL adults (SHR: 1.57, 95% CI: 1.32 - 1.87). Cancer history-stratified adjusted models are presented in Table 1. Conclusions: Low PSDOH exposure amplified the association between AL and CVD in all cohorts, with the highest increases in risk being seen among adults with a history of cancer.

The Impact of Soluble BCMA and BCMA Gain on Anti-BCMA Immunotherapies in Multiple Myeloma

B cell maturation antigen (BCMA) targeting chimeric antigen receptor T cells (CAR T) and bispecific T cell engagers (TCE) have remarkable efficacy in multiple myeloma (MM). While BCMA antigen escape, driven by TNFRSF17 deletions or mutations, is a mediator of anti-BCMA CAR T/ TCE resistance, the majority of patients retain BCMA surface expression at progression. Furthermore, patients with high disease burden and extramedullary disease associated with poorer response to anti-BCMA therapies, have high levels of soluble BCMA (sBCMA). The mechanisms mediating this resistance, and in particular the contribution of sBCMA, have not been fully elucidated. In order to assess the effect of sBCMA on anti-BCMA CAR T function, we measured CAR T cells activation with an in-house manufactured anti-BCMA CAR transduced with an NFAT-GFP reporter gene after co-culture with increasing concentrations of sBCMA (0-2500 ng/mL). sBCMA bound to CAR scFv in a dose dependent manner, effectively competing with the fluorophore tagged BCMA peptide binding. Despite their stable engagement, sBCMA failed to induce the expression of GFP, CD69, CD25, or 41BB on CAR T cells. To further examine the functional effect of sBCMA on CAR T cytotoxicity, we generated isogenic OPM2 cell lines with distinct BCMA expression profiles: OPM2 over-expressing BCMA (OPM2_BCMA high) generated by lentiviral transduction of TNFRSF17, and Cas9 BCMA knockout OPM2 (OPM2_BCMA -/-). OPM2_BCMA high cells exhibited one-log-fold increase in surface BCMA expression and 10-fold increase in sBCMA and were more resistant to CAR T mediated lysis. In addition, in co-culture assays, elevated sBCMA impaired OPM2 target cell lysis by anti-BCMA CAR T in a dose dependent-manner. To gain insight into the effect of chronic sBCMA exposure on CAR T, we exposed anti-BCMA CAR T to OPM2 cells secretome in the absence of direct cell to cell contact in a trans-well co-culture system. On day 24, CAR T in co-culture with OPM2_BCMA high (sBCMA levels of 2343 ng/mL) significantly contracted with no viable cells, while CAR T in culture with parental OPM2 (sBCMA level of 267 ng/mL) did persist with up-regulated TIM3 and TIGIT. In contrast CAR T cultured with OPM2_BCMA -/- remained viable with no expression of exhaustion markers. In examining the impact of sBCMA on TCE activity, sBCMA level as low as 50 ng/mL in vitro impaired anti-BCMA TCE binding to K562 cells transduced to stably express BCMA (K562_wtBCMA) . Consistent results were found in cytotoxicity assays wherein the addition of 2 ng/mL of sBCMA was sufficient to induce a reduction in anti-BCMA TCE mediated cytotoxicity of K562_wtBCMA cells by healthy donor peripheral blood mononuclear cells. To identify genomic events that lead to elevated sBCMA expression and subsequent resistance to CAR T/TCE, we conducted bulk whole genome sequencing (100X) on CD138+ bone marrow MM cells obtained from 40 MM patients treated with anti-BCMA CAR T/ TCE. Structural variants (SVs) at or adjacent to TNFRSF17 locus were identified in four patients. These included i) focal copy number gain of TNFRSF17 (3 copies) in a patient who progressed within 3 months post anti-BCMA TCE, ii) subclonal duplication of TNFRSF17 locus in another patient (n=1), as well as iii) focal copy number losses 5‘ or 3‘ to the TNFRSF17 gene locus (n=2). In addition to SVs affecting TNFRSF17 locus, we also identified mutations involving TNFRSF17 transcriptional regulators. Notably, MM clones at progression 4 months post anti-BCMA TCE (n=1) harboured copy number gains (3 copies) of POU2AF1 gene on chr11q23. POU2AF1 encodes a key transcriptional regulator of TNFRSF17 expression. Indeed, sBCMA level from this patient was significantly elevated at relapse at a level (638 ng/mL) correlated with resistance to anti-BCMA TCE. In addition, we identified translocation involving MAP3K14 encoding the NF-kB regulator NIK in a patient with short remission post anti-BCMA CAR T. Of interest, analysis of the CoMMpass dataset revealed significantly higher BCMA transcripts in patients with translocations involving MAP3K14 locus. Our findings highlight the impact of sBCMA levels and its chronicity of exposure on anti-BCMA TCE and CAR T activities in MM. We further identified structural genomic events driving TNFRSF17 over-expression and their correlation to sBCMA levels facilitating tumoral immunotherapeutic escape.

Maternal exposure to polystyrene microplastics impairs social behavior in mouse offspring with a potential neurotoxicity

As plastic production has been increasing steadily, environmental pollution resulting from microplastics (MPs) continues to draw considerable attention of the researchers. Several studies have reported that MPs are risk factors for various cellular and systemic dysfunctions. However, the effects of chronic MP exposure from the embryonic stage to adulthood on mouse brain remain unclear. Accordingly, determining the impacts of maternal exposure to MPs on mouse offspring was the main goal of this study. To this end, single cells of primary cortical neurons were isolated from mouse embryos. Subsequently, the cells were exposed to 2 µm polystyrene microplastics (PS-MPs), which resulted in a notable reduction in dendritic length, and PS-MPs cannot pass through the cellular membrane of neurons. Moreover, exposure to PS-MPs caused the proliferation increase and apoptosis in primary cortical neuronal cells. We then evaluated the neurotoxicity associated with chronic PS-MP exposure from the embryonic stage to adulthood in C57BL/6 J mouse offspring. PS-MPs were found to accumulate in the digestive and excretory organs of the offspring but not in the brain tissue. However, offspring exposed to PS-MPs exhibited no differences in the levels of expression of genes related to brain cell markers or synaptic organization. Nevertheless, PS-MP-exposed mice exhibited impaired social novelty preferences; however, no changes were observed in the emotional, compulsive, or cognitive behaviors. Taken together, these results demonstrate the potential neurotoxic effects of chronic exposure to PS-MPs in mouse offspring.

Workplace Harassment and Health: A Long Term Follow up.

We examine relationships between workplace harassment (WH) and onset of health conditions over a 23-year period. Participants were surveyed at seven points between 1997-2006 and again in 2020. Regression analyses (n = 921) assessed effects of chronic WH exposure on onset or recent health conditions by 2020. Growth mixture modeling revealed infrequent and chronic classes of generalized workplace harassment (GWH; 33.39% chronic) and sexual harassment (SH; 32.32% chronic). Prevalence of health conditions ranged from 3.71% for myocardial infarction to 43.06% for hypertension. Analysis via propensity score matching showed chronic WH class membership increased odds of coronary heart disease (GWH, odds ratio [OR] = 3.42, P < 0.05), arthritic/rheumatic conditions (SH, OR = 1.56, P < 0.05), and recent migraine (SH, OR = 1.68, P < 0.05). Workplace harassment is associated with coronary heart disease, arthritic/rheumatic conditions, and migraine. Worker health can be protected through strengthening and enforcing organizational and social antiharassment policies and laws.

Microplastics in river sediment: Chronic exposure of the amphipod Gammarus fossarum to polyethylene terephthalate in a microcosm

Microplastics constitute a form of particulate matter in aquatic environments, where they are a widespread pollutant. The broad range of particle sizes facilitates interactions with diverse species assemblages. Exposure to microplastics can negatively impact organisms, but similar effects also arise from exposure to naturally occurring particles, such as increased oxidative stress. It therefore remains uncertain, what effects are specific to microplastic particles, and how these effects manifest as a consequence of chronic exposure. Here we show in microcosm experiments that long-term exposure (111 days) to irregularly shaped polyethylene terephthalate (PET) fragments (10–400 µm) added to riverine sediments did not negatively impact the amphipod Gammarus fossarum’s group size, and oxygen consumption, and minimally affected proteome composition. We found that these results were consistent for male and female specimens when exposed to an environmentally relevant concentration (0.004% of sediment dry weight; dw) and an environmentally less realistic one (4% dw). In female specimens' whole proteomes, we identified two highly differentially abundant proteins, which have been associated with an organism's response to xenobiotics. We conclude that in this sentinel species exposure to PET microplastic fragments mixed into the sediment does not elicit significant stress, even at concentrations exceeding current exposure levels in the environment.

The Effects of Stress on Hippocampal Neurogenesis and Behavior in the Absence of Lipocalin-2.

Lipocalin-2 (LCN2) is an acute phase protein able to bind iron when complexed with bacterial siderophores. The recent identification of a mammalian siderophore also suggested a physiological role for LCN2 in the regulation of iron levels and redox state. In the central nervous system, the deletion of LCN2 induces deficits in neural stem cells proliferation and commitment, with an impact on the hippocampal-dependent contextual fear discriminative task. Additionally, stress is a well-known regulator of cell genesis and is known to decrease adult hippocampal cell proliferation and neurogenesis. Although voluntary running, another well-known regulator of neurogenesis, is sufficient to rescue the defective hippocampal neurogenesis and behavior in LCN2-null mice by promoting stem cells' cell cycle progression and maturation, the relevance of LCN2-regulated hippocampal neurogenesis in response to stress has never been explored. Here, we show a lack of response by LCN2-null mice to the effects of chronic stress exposure at the cellular and behavioral levels. Together, these findings implicate LCN2 as a relevant mediator of neuronal plasticity and brain function in the adult mammalian brain.

P013 The Effect of Noise Exposure during Sleep on the Cortisol Awakening Response

Abstract Introduction Environmental noise could negatively impact the sleep and well-being of nearby residents. This study tested for overnight noise exposure effects on the cortisol awakening response (CAR), a potential marker of noise-related stress responses, and for differences in CAR and hair cortisol between different prior noise exposure groups. Methods A randomised controlled laboratory trial was conducted in 68 individuals from four groups; including WFN-exposed residents n=14 with and n=18 without WFN-related complaints, n=18 quiet rural control and n=18 urban traffic-noise exposed residents. Across six nights, after an initial adaptation night, participants were exposed in random order to different noise conditions, which included intermittent WFN and road traffic noise (RTN), WFN at average exposure levels throughout wake, sleep or both and a quiet control night. Salivary CAR responses were evaluated from 5 serial saliva samples collected following awakening. Hair cortisol levels were also collected. Mixed effects models were used to examine group and night effects on CAR and group effects on hair cortisol. Results There was a significant main effect of condition on CAR (p=0.038), but no significant pairwise differences between the control night and noise exposure nights, and no further differences between nights or groups on CAR or hair cortisol concentrations. Conclusions Acute in-laboratory noise-related sleep disturbance at the levels used in this study do not appear to alter acute cortisol awakening responses. A better understanding of chronic noise exposure effects and stress responses is important to help clarify and mitigate potential environmental noise exposure effects on nearby residents.

Effects of Chronic Hydrocodone Exposure and Ceftriaxone on the Expression of Astrocytic Glutamate Transporters in Mesocorticolimbic Brain Regions of C57/BL Mice.

Exposure to opioids can lead to the alteration of several neurotransmitters. Among these neurotransmitters, glutamate is thought to be involved in opioid dependence. Glutamate neurotransmission is mainly regulated by astrocytic glutamate transporters such as glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT). Our laboratory has shown that exposure to lower doses of hydrocodone reduced the expression of xCT in the nucleus accumbens (NAc) and the hippocampus. In the present study, we investigated the effects of chronic exposure to hydrocodone, and tested ceftriaxone as a GLT-1 upregulator in mesocorticolimbic brain regions such as the NAc, the amygdala (AMY), and the dorsomedial prefrontal cortex (dmPFC). Eight-week-old male mice were divided into three groups: (1) the saline vehicle control group; (2) the hydrocodone group; and (3) the hydrocodone + ceftriaxone group. Mice were injected with hydrocodone (10 mg/kg, i.p.) or saline for 14 days. On day seven, the hydrocodone/ceftriaxone group was injected with ceftriaxone (200 mg/kg, i.p.) for last seven days. Chronic exposure to hydrocodone reduced the expression of GLT-1, xCT, protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal Kinase (JNK) in NAc, AMY, and dmPFC. However, hydrocodone exposure increased the expression of G-protein-coupled metabotropic glutamate receptors (mGluR5) in the NAc, AMY, and dmPFC. Importantly, ceftriaxone treatment normalized the expression of mGluR5, GLT-1, and xCT in all these brain regions, except for xCT in the AMY. Importantly, ceftriaxone treatment attenuated hydrocodone-induced downregulation of signaling pathways such as AKT, ERK, and JNK expression in the NAc, AMY, and dmPFC. These findings demonstrate that ceftriaxone has potential therapeutic effects in reversing hydrocodone-induced downregulation of GLT-1 and xCT in selected reward brain regions, and this might be mediated through the downstream kinase signaling pathways such as AKT, ERK, and JNK.

Chronic Fluoride Exposure Induces Ovarian Dysfunction and Potential Association with Premature Ovarian Failure in Female Rats.

Chronic fluorosis has been widely investigated for its adverse effects on skeletal and neurological health; however, its impact on reproductive health, especially in females, remains underexplored. In this study, female Sprague-Dawley rats were exposed to different fluoride concentrations (0.75, 50, and 100mg/L) in their drinking water for six months. Dental fluorosis and increased urinary fluoride content were observed in fluoride-exposed rats, reflecting fluoride accumulation and exposure levels. Chronic fluorosis resulted in reduced ovary organ coefficient, indicating harmful effects on ovarian tissue. Additionally, the number of ovarian primordial and primary/secondary follicles decreased, while the number of atresia follicles increased. Furthermore, chronic fluorosis led to disrupted estrous cycles. Hormonal analysis revealed altered secretion of estrogen, progesterone, anti-Müllerian hormone, luteinizing hormone, follicular stimulating hormone, and inhibin B in response to fluoride exposure. Ultrastructural observation of ovarian granulosa cells showed evidence of apoptosis, which was further confirmed by flow cytometry. Caspase-3 activity was increased, and ATP levels were decreased, suggesting mitochondrial impairment and apoptosis induction. The mRNA and protein expression of BMP15 and GDF9, essential regulators of ovarian function, significantly decreased with increasing fluoride concentration. Furthermore, gene expression analysis identified a panel of premature ovarian failure-related genes that were downregulated in fluoride-exposed rat ovaries. These findings suggest that chronic fluoride exposure may contribute to ovarian dysfunction and possibly the pathogenesis of premature ovarian failure. Understanding the toxicological effects of chronic fluoride exposure on ovarian function is essential for identifying potential environmental risk factors affecting female reproductive health.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Impact of Chronic Exposure to Arsenate through Drinking Water on the Intestinal Barrier.

Chronic exposure to inorganic arsenic (As) [As(III) + As(V)], which affects millions of people, increases the incidence of some kinds of cancer and other noncarcinogenic pathologies. Although the oral pathway is the main source of exposure, in vivo studies conducted to verify the intestinal toxicity of this metalloid are scarce and are mainly focused on evaluating the toxicity of As(III). The aim of this study was to evaluate the effect of chronic exposure (6 months) of BALB/c mice to As(V) (15-60 mg/L) via drinking water on the different components of the intestinal barrier and to determine the possible mechanisms involved. The results show that chronic exposure to As(V) generates a situation of oxidative stress (increased lipid peroxidation and reactive species) and inflammation (increased contents of several proinflammatory cytokines and neutrophil infiltrations) in the intestinal tissues. There is also evidence of an altered expression of constituent proteins of the intercellular junctions (Cldn1, Cldn3, and Ocln) and the mucus layer (Muc2) and changes in the composition of the gut microbiota and the metabolism of short-chain fatty acids. All of these toxic effects eventually may lead to the disruption of the intestinal barrier, which shows an increased paracellular permeability. Moreover, signs of endotoxemia are observed in the serum of As(V)-treated animals (increases in lipopolysaccharide-binding protein LBP and the proinflammatory cytokine IL-1β). The data obtained suggest that chronic exposure to As(V) via drinking water affects the intestinal environment.

New sensitive LC-MS/MS method for the simultaneous determination of 13 phenolic and carboxylic acid pesticide biomarkers in human urine, including dicamba

The commercialization in 2016 of genetically engineered seeds tolerant to dicamba and/or 2,4-dichlorophenoxyacetic acid (2,4-D) has caused a rapid increase in the use of these herbicides. New questions about the reproductive and chronic health effects of long-term exposure to these herbicides have been raised. To assess exposure to dicamba and other pesticides of interest in the Heartland Study, a birth cohort study based in the United States, a new analytical method was needed. The present study describes the development and validation of this new solid phase extraction and liquid chromatography-tandem mass spectrometry method that detects simultaneously 13 pesticides or their metabolites in 250 μL of urine. More specifically, the method allows the analysis of dicamba, 2,4-D and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), which are herbicides, of malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPy), 2-diethylamino-6-methylpyrimidin-4-ol (DEAMPY) and 2-isopropyl-6-methyl-4-pyrimidinol (IMPY), which are metabolites of organophosphate insecticides, and finally of cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA), trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA), 3-Phenoxybenzoic acid (3-PBA), 4-Fluoro-3-phenoxybenzoic acid (4-F-3-PBA) and cis-3-(2,2-Dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DBCA), which are metabolites of synthetic pyrethroids insecticides. The method was validated under ISO/IEC 17025 guidance. The limit of detection (LOD) in urine samples was 0.10 μg/L for dicamba, while the LOD for other analytes ranged between 0.0038 μg/L and 0.091 μg/L. Accuracy was evaluated by analyzing samples from two External Quality Assessment Schemes, namely G-EQUAS and OSEQAS. Preliminary results obtained following the analysis of 91 urine samples taken from pregnant women enrolled in the Heartland Study are presented here. This method is suitable for human biomonitoring studies.

Effects of chronic exposure to microplastics and microplastics associated with polychlorinated biphenyl 153 on Daphnia magna

The present study investigates the potential effects and risks of polyethylene microbeads (PEMBs) and PEMBs associated with PCB-153 (PEMB-PCB) on Daphnia magna using a chronic exposure study approach. Daphnia magna were exposed to PEMBs, PCB-153, and PEMB-PCB for 21 days. Accumulation of PEMBs and PCB-153 in D. magna and effects on survival and reproduction of the organisms were measured. Overall, D. magna ingested and accumulated PEMBs and PCB-153. The accumulation of PEMBs increased with exposure time and was higher for PEMB exposure than for PEMB-PCB exposure. However, PCB-153 accumulation did not appear to increase over time. Exposure to PCB-153 in water resulted in higher PCB-153 accumulation than did PEMB-PCB exposure. Polyethylene microbeads and PCB-153 appeared to interact, resulting in a lower accumulation of PEMBs and PCB-153 and causing less effect on reproduction of D. magna. Survival of D. magna was affected by PEMBs, PCB-153, and PEMB-PCB. Results of the present study reveal potential risks of MPs to living organisms and ecosystems, especially when considering long-term exposure, which is relevant for microplastic pollution because of the persistence and continuous increase in MP abundance in the environment. More research should be conducted to understand the interactive effect mechanisms of MP and pollutant mixture exposure on organisms that would help explain the decreased accumulation of pollutants in organisms when MPs are present.

The adverse consequences of not using sunscreens.

The adverse effects of solar ultraviolet radiation (UVR) on normal skin are well established, especially in those with poorly melanized skin. Clinically, these effects may be classified as acute, such as erythema or chronic such as keratinocyte and melanocyte skin cancers. Apart from skin type genetics, clinical responses to solar UVR are dependent on geophysical (e.g., solar intensity) and behavioural factors. The latter are especially important because they may result in 'solar overload' with unwanted clinical consequences and ever greater burdens to healthcare systems. Correctly used, sunscreens can mitigate the acute and chronic effects of solar UVR exposure. Laboratory studies also show that sunscreens can inhibit the initial molecular and cellular events that are responsible for clinical outcomes. Despite public health campaigns, global trends continue to show increasing incidence of all types of skin cancer. Large-scale epidemiological studies have shown the benefits of sunscreen use in preventing skin cancer, though it is likely that sunscreen use has not been optimal in such studies. It is evident that without substantial changes in sun-seeking behaviour, sunscreen use is a very important part of the defence against the acute and chronic effects of solar exposure. Ideally, sunscreens should be able to provide the level of protection that reduces the risk of skin cancer in susceptible skin types to that observed in heavily melanized skin.

Neuro-Cardiovascular Responses to Sympathetic Stimulation in Fighter Pilots.

INTRODUCTION: The chronic effects of regular exposure to high acceleration levels (G-force) on the neuro-cardiovascular system are unclear. We compared the mean arterial pressure (MAP) and cardiac autonomic modulation between nonpilots (NP) vs. military fighter (FP) and transport (TP) pilots. Additionally, we correlated the cardiac autonomic indices with the cardiorespiratory fitness and flight experience of FP.METHODS: A total of 21 FP, 8 TP, and 20 NP performed a tilt test (TT), during which beat-to-beat blood pressure and heart rate were recorded.RESULTS: No difference was detected between groups for changes in MAP and heart rate variability indices during the TT. However, the analysis of areas under the curves showed a greater increase in MAP in FP vs. TP and NP. Conversely, there was a greater decrease in indices reflecting vagal modulation in TP vs. FP and NP (rMSSD, pNN50, and SDNN), and a greater increase in heart rate and sympathovagal balance in TP vs. other groups (LF/HF). The maximal oxygen uptake was strongly correlated with the vagal reserve in FP (r = -0.74). Moreover, the total flying hours of FP were positively correlated with resting HFnu (r = 0.47) and inversely correlated with resting LFnu (r = -0.55) and LF/HF (r = -0.46).CONCLUSION: FP had a higher pressor response to TT than TP and NP. Vagal withdrawal and sympathovagal increase induced by TT in FP were similar vs. NP and attenuated vs. TP. Greater cardiorespiratory fitness and accumulated flying hours in FP seemed to favor lower sympathetic and greater vagal modulation at rest.dos Santos Rangel MV, de Sá GB, Farinatti P, Borges JP. Neuro-cardiovascular responses to sympathetic stimulation in fighter pilots. Aerosp Med Hum Perform. 2023; 94(10):761-769.