High-dose Exposure Research Articles

Analysis of the correlation between the dose exposure intensity and apatinib in advanced gastric cancer: a retrospective cohort study

BackgroundApatinib is a small molecule anti-angiogenesis targeted drug that has demonstrated significant efficacy as a late-line treatment in advanced gastric cancer in phase 3 clinical trials. This study amid to evaluate the correlation between dose exposure intensity and efficacy and safety of apatinib in the treatment of advanced gastric cancer.MethodsWe conducted an observational, retrospective cohort study of patients with advanced gastric cancer who received apatinib targeted therapy in Beijing Friendship Hospital affiliated to Capital Medical University between June 1, 2018, and June 30, 2021. Dose exposure intensity (DEI) was defined as the product of dose and continuous medication time. Patients were assigned to high-dose exposure intensity (HDEI) and low-dose exposure intensity (LDEI) cohorts. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and safety. The relationship between HDEI and LDEI and clinical outcomes was analyzed by using the Kaplan-Meier curve and χ2 test.Results61 patients were enrolled and assigned into two retrospective cohorts. The median PFS (mPFS) were 6.50 months (95% confidence interval (CI) [4.80-9.20]) and 4.10 months (95% CI [3.70-5.20]), and the median OS (mOS) were 10.70 months (95% CI [9.20-18.50]) and 7.50 months (95% CI [6.80-9.30]) for the HDEI and LDEI cohorts, respectively. The mPFS were 5.85 months (95% CI [5.00-7.00]) and 4.60 months (95% CI [4.10-5.90]), and mOS were 9.60 months (95% CI [9.10-12.40]) and 7.60 months (95% CI [7.20-10.20]) the for the 250 mg cohort and 500 mg cohorts. The mPFS were 6.65 months (95% CI [5.90-9.20]) and 4.10 months (95% CI [3.90-5.20]), and the mOS were 11.20 months (95% CI [9.20-18.50]) and 7.60 months (95% CI [7.20-9.60])for the long medication time and short medication time cohorts, respectively. The most common TRAEs of any grade were hypertension, proteinuria, and neutrophil count decreased. The incidence of grade 3-4 adverse reactions in the 500 mg cohort was higher than the 250 mg cohort (P=0.0016).ConclusionThe efficacy of apatinib in advanced gastric cancer was significantly positively correlated with dose exposure intensity, and HDEI can prolong PFS and OS. Early application of low-dose apatinib (250 mg/d) can improve patients’ tolerability, and the adverse reactions are controllable.

Maternal exposure to bisphenol A induces congenital heart disease through mitochondrial dysfunction.

Congenital heart disease (CHD) represents a major birth defect associated with substantial morbidity and mortality. Although environmental factors are acknowledged as potential contributors to CHD, the underlying mechanisms remain poorly understood. Bisphenol A (BPA), a common endocrine disruptor, has attracted significant attention due to its widespread use and associated health risks. This study examined the effects of maternal BPA exposure on fetal heart development in a murine model. The findings indicated that high-dose BPA exposure resulted in fetal growth restriction, myocardial wall thinning, and ventricular septal defects. Transcriptomic analysis revealed downregulation of genes associated with mitochondrial energy synthesis and cardiomyocyte development following high-dose BPA exposure. Functional assays demonstrated that high-dose BPA exposure impaired mitochondrial respiration reduced ATP production, disrupted mitochondrial membrane potential, and increased intracellular reactive oxygen species levels in fetal cardiomyocytes. These results elucidate the detrimental effects of BPA on fetal heart development and mitochondrial function, providing insights into potential mechanisms linking environmental chemical exposure to CHD.

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury.

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice. Wild-type orthotopic breast tumor-bearing mice receiving 20-Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.

Repeated high-dose esketamine in early postnatal rats leads to behavioural deficits with long-term modifications in white matter microstructural integrity

Esketamine is commonly used for sedation or general anaesthesia in infants and young children. However, repeated esketamine administration during periods of rapid brain growth and development may result in various pathophysiological and cognitive changes. Therefore, this study aimed to investigate the influence of recurrent esketamine exposure on long-term behavioural and white matter consequences. Seven-day-old (P7) male rats were allocated to control, high-, and low-dose groups. Behavioural paradigm assessment was conducted at P25-29. Diffusion tensor imaging revealed long-term effects on water diffusivity in the splenium and cingulum white matter of the corpus callosum at P30. Subsequent two-dimensional structure-tensor analysis of brain tissue sections stained with Luxol fast blue (LFB) showed marked changes in the white matter microstructure in rats after multiple exposures to varying esketamine doses. High-dose esketamine significantly reduced activity time and total distance in the open-field experiment. High-dose esketamine exposure might lead to impaired short-term memory in rats. Additionally, the high-dose group showed prolonged immobility time during the forced swimming test. On the balance beam, the high-dose group displayed more right turns and right-foot slips and lower time spent on the rotating bar, indicating motor defects, than did the other groups. Diffusion tensor imaging demonstrated a decreased water molecule diffusion ability in the corpus callosum in the high-dose group. LFB staining indicated microstructural differences in the white matter of animals in the high-dose group. These findings suggest that behavioural deficits in high-dose esketamine-treated rats are at least partially attributed to changes in the white matter microstructure.

Integrative multiomics analysis of metabolic dysregulation induced by occupational benzene exposure in mice.

Type 2 Diabetes Mellitus (T2DM) is a significant public health burden. Emerging evidence links volatile organic compounds (VOCs), such as benzene to endocrine disruption and metabolic dysfunction. However, the effects of chronic environmentally relevant VOC exposures on metabolic health are still emerging. Building on our previous findings that benzene exposure at smoking levels (50 ppm) induces metabolic impairments in male mice, we investigated the effects of occupationally relevant, below OSHA approved, benzene exposure on metabolic health. Adult male C57BL/6 mice were exposed to 0.9ppm benzene 8 hours a day for 9 weeks. We assessed measures of metabolic homeostasis and conducted RNA and proteome sequencing on insulin-sensitive organs (liver, skeletal muscle, adipose tissue). This low-dose exposure caused significant metabolic disruptions, including hyperglycemia, hyperinsulinemia, and insulin resistance. Transcriptomic analysis of liver, skeletal muscle, and adipose tissue identified key changes in metabolic and immune pathways especially in liver. Proteomic analysis of the liver revealed mitochondrial dysfunction as a shared feature, with disruptions in oxidative phosphorylation, mitophagy, and immune activation. Comparative analysis with high-dose (50 ppm) exposure showed both conserved and dose-specific transcriptomic changes in liver, particularly in metabolic and immune responses. Our study is the first to comprehensively assess the impacts of occupational benzene exposure on metabolic health, highlighting mitochondrial dysfunction as a central mechanism and the dose-dependent molecular pathways in insulin-sensitive organs driving benzene-induced metabolic imbalance. Our data indicate that current OSHA occupational exposure limits for benzene are insufficient, as they could result in adverse metabolic health in exposed workers, particularly men, following chronic exposure.

16S rRNA Sequencing Analysis Uncovers Dose-Dependent Cupric Chloride Effects on Silkworm Gut Microbiome Composition and Diversity.

Copper-based pesticides are extensively used in agriculture, yet their impacts on beneficial insects remain poorly understood. Here, we investigate how cupric chloride exposure affects the gut microbiome of Bombyx mori, a model organism crucial for silk production. Using 16S rRNA sequencing, we analyzed the gut bacterial communities of fifth-instar silkworm larvae exposed to different concentrations of cupric chloride (0, 4, and 8 g/kg) in an artificial diet. The high-dose exposure dramatically altered the microbial diversity and community structure, where the Bacteroidota abundance decreased from 50.43% to 23.50%, while Firmicutes increased from 0.93% to 18.92%. A network analysis revealed complex interactions between the bacterial genera, with Proteobacteria and Firmicutes emerging as key players in the community response to copper stress. The functional prediction indicated significant shifts in metabolic pathways and genetic information processing in the high-dose group. Notably, the low-dose treatment induced minimal changes in both the taxonomic composition and predicted functions, suggesting a threshold effect in the microbiome response to copper exposure. Our findings provide novel insights into how agricultural chemicals influence insect gut microbiota and highlight potential implications for silkworm health and silk production. This work contributes to understanding the ecological impacts of copper-based pesticides and may inform evidence-based policies for their use in sericulture regions.

Long-term exposure to bisphenol-A causes oxidative stress-related alterations at the genetic and cellular levels in the mature ovary of adult zebrafish.

Bisphenol-A (BPA) is categorized as a major endocrine-disrupting chemical (EDC) used to manufacture many plastic products. BPA affects reproductive performance and promotes infertility by causing hormonal imbalance, mitochondrial dysfunction, and altered gene expression. The present investigation aimed to evaluate the effects of BPA exposure for 28days on the activity or level of antioxidant response elements (AREs), mRNA expressions of antioxidant genes, and histomorphological changes in the ovary of adult zebrafish. The adult female zebrafish were randomly divided into four experimental groups, viz. control, vehicle (0.01% ethanol), low dose (BPA: 350µg/L), and high dose (BPA: 700µg/L) exposure groups. After BPA exposure in both groups, superoxide dismutase (SOD) activity and total antioxidant capacity (TAC) level were significantly (p<0.05) decreased in the zebrafish ovary. Whereas, catalase (CAT) activity and malondialdehyde (MDA) level were significantly (p<0.05) increased in both treatment groups. The sod mRNA expression was significantly (p<0.05) down-regulated in the high-dose BPA-exposed group. Whereas, cat and nuclear factor erythroid 2-related factor 2 (nrf2) mRNA expressions were significantly (p<0.05) up-regulated in both BPA-treated groups. Noticeable histomorphological alterations were recorded in the ovary of zebrafish exposed to low and high doses of BPA. The alterations in the activity of ARE, mRNA expressions of antioxidant genes, and histopathological changes suggest that exposure to BPA can cause endocrine disruption and damage to the ovary of adult zebrafish caused by oxidative stress.

A five-day-old victim of chemical terrorism was exposed to sulfur mustard

Sulfur mustard (SM) is a blistering chemical warfare agent and it has cytotoxic effects on ocular, respiratory, cutaneous, and hematological systems. We presented acute hematological effects of high-dose SM exposure on a five-day-old victim who was exposed to SM in Syria in 2015, during a chemical attack. Following onset of typical ocular, respiratory, and cutaneous symptoms of SM, the patient was evacuated to Türkiye on 18th hour after the exposure with an initial diagnosis of second-degree chemical burn. The patient died on 14th day after the exposure. Severe thrombocytopenia, reactive leucocytosis followed by mild leukopenia, isolated lymphopenia, and anaemia were observed after SM exposure. Besides symptomatic treatment, granulocyte-colony stimulating factor (G-CSF), packed red blood cells transfusions, and platelet transfusions were administered for the treatment of hematological complications. Monitoring hematological indices daily, advanced medical interventions including G-GSF treatment for SM-induced neutropenia, and aggressive resuscitation with multiple blood transfusions could reduce the impact of myelosuppression in victims of SM.

Dual effects of GABA A R agonist anesthetics in neurodevelopment and vulnerable brains: from neurotoxic to therapeutic effects.

Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years. A consensus has been reached that prolonged, repeated, high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function, while single exposure has a relatively minor effect on long-term neurological function. In this review, we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists, a representative group of sedatives, on developing brains or central nervous system diseases. Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways. However, recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period. These findings are incomprehensible for the general "dose-effect" principles of pharmacological research, which has attracted researchers' interest and led to the following questions: What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain? To what extent can their protective effects be maximized? What are the underlying mechanisms involved in these effects? Consequently, this issue has essentially become a "mathematical problem." After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases, we believe that all such anesthetics exhibit specific threshold effects unique to each drug. These effects range from neuroprotection to neurotoxicity, depending on different brain functional states. However, the exact values of the specific thresholds for different drugs in various brain states, as well as the underlying mechanisms explaining why these thresholds exist, remain unclear. Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis.

A clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications. To assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation. The search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024. Two independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts. AE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up). A hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively. A total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD. In this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public.

The role of manganese over‐exposure in glutamate dysregulation and EEG outcomes in a mouse model of Alzheimer’s disease

AbstractBackgroundManganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating the glutamate/glutamine cycle and other oxidative stress pathways. Typically, Mn is acquired through the diet, however, Mn overexposure can arise through drinking inadequately treated well water or inhalation of Mn‐containing industrial byproducts. Mn toxicity disrupts dopaminergic neurotransmission resulting in a Parkinsonian disorder referred to as manganism. More recently, increased focus has been given to the role Mn toxicity in the progression of other neurodegenerative diseases including Alzheimer’s Disease (AD). Excess Mn may contribute to dysregulation of astrocytic glutamatergic transport, leading to elevated extracellular glutamate, excitotoxicity, and ultimately cell death, which are all key features of early AD pathology. We hypothesized that Mn toxicity drives glutamatergic signaling dysfunction to exacerbate pathology seen in AD including excitotoxicity and epileptiform activity.MethodAPPswe/PSEN1dE9 mice, a mouse model of AD, and wild‐type littermates of both sexes were exposed to 50mg/kg MnCl2·4H2O or the vehicle subcutaneously three times over the course of a week as an acute high dose exposure of Mn. Increased seizure susceptibility in response to manganese and kainic acid (kainate receptor agonist) exposure was analyzed through surface cortical electroencephalogram recordings. Changes in glutamate reuptake transporter protein and mRNA expression from cortical and hippocampal tissue were quantified using western blot and qPCR.ResultAPPswe/PSEN1dE9 mice have more cortical spiking activity over the course of exposure compared to WT mice. Effects of kainic acid were quantified over four hours and we found that Mn‐exposed mice have significantly decreased spiking over the first hour compared to vehicle treated mice. However, spiking activity increased over time in Mn‐treated mice, while spiking activity decreased in vehicle treated mice resulting in a significant reaction between treatment and time. There was no difference in spiking at the end of the four‐hour observation period.ConclusionDynamic responses to kainic acid and changes in glutamate reuptake transporter expression are consistent with glutamatergic changes that can contribute to excitotoxicity. Taken together, these findings support the hypothesis that manganese acutely interferes with glutamate functioning and could exacerbate phenotypes observed in AD.

Protective Effect of Resveratrol on Kidney Disease and Hypertension Against Microplastics Exposure in Male Juvenile Rats.

Global pollution stems from the degradation of plastic waste, leading to the generation of microplastics (MPs). While environmental pollutants increase the risk of developing hypertension and kidney disease, the effects of MP exposure on these conditions in children remain unclear. Resveratrol, a phenolic compound known for its antihypertensive and renoprotective properties, has gained attention as a potential nutraceutical. This study investigates the effects of resveratrol on kidney disease and hypertension induced by MP exposure in a juvenile rat model. Three-week-old male Sprague--Dawley (SD) rats were randomly allocated into four groups (n = 8 per group): a control group, a low-dose MP group (1 mg/L), a high-dose MP group (10 mg/L), and a high-dose MP group receiving resveratrol (50 mg/L). By 9 weeks of age, MP exposure resulted in elevated blood pressure and increased creatinine levels, both of which were mitigated by resveratrol treatment. The hypertension and kidney damage induced by high-dose MP exposure were linked to oxidative stress, which resveratrol effectively prevented. Additionally, resveratrol's protective effects against hypertension and kidney damage were associated with increased acetic acid levels, reduced renal expression of Olfr78, and decreased expression of various components of the renin-angiotensin system (RAS). Low- and high-dose MP exposure, as well as resveratrol treatment, differentially influence gut microbiota composition. Our findings suggest that targeting oxidative stress, gut microbiota, and the RAS through resveratrol holds therapeutic potential for preventing kidney disease and hypertension associated with MP exposure. However, further research is needed to translate these results into clinical applications.

Organ-specific renal tissue damage manifested by single-walled carbon-nanotubes and single-walled carbon-nanotubes-silver-titania nanocomposite: Cellular toxicity at high doses

Single-walled (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) can pose risks in biological systems leading to harmful effects, such as, reactive oxygen species (ROS) formation, DNA damage, mitochondrial dysfunction, and ultimately, the cell death through apoptosis. The study assessed the nephrotoxicity of the SWCNTs and SWCNTs-Ag-TiO2 nanocomposites through in vitro and in vivo experiments, assessing oxidative stress, genotoxicity, and safety for biomedical applications. In vitro, HK-2 cell lines were utilized to evaluate the effects of nanomaterials on cellular activity, apoptosis, ROS generation, and micronuclei formations. In the in vivo study, twenty male mice were divided into five groups: the first received a control injection of phosphate-buffer saline (PBS), while the second, and third groups received daily intraperitoneal injections of SWCNTs at doses of 50 mg/kg, and 100 mg/kg, respectively, for ten days. The fourth and fifth groups received the SWCNTs-Ag-TiO2 at 50 mg/kg and 100 mg/kg, respectively, for ten days in sequence. SWCNTs and SWCNTs-Ag-TiO2 significantly promoted the micronuclei formations in HK-2 cells, with rates of 48 % and 79 %, respectively, as compared to the 12.67 % of the control group. The analysis of renal tissues revealed increased levels of ROS, DNA-protein crosslinks (DPC), glutathione (GSH), malondialdehyde (MDA), creatinine, and 8-hydroxy-2'-deoxyguanosine, while the GSH levels decreased. These findings indicated renal tissue injury, and oxidative damages. The study demonstrated the cellular toxicity of these nanomaterials, highlighting the need for caution regarding their widespread use, particularly the use of carbon nanotubes and their metallic composites at higher exposure doses in occupational, environmental, or therapeutic contexts.

High-dose folic acid use and cancer risk in women who have given birth: A register-based cohort study.

This study was undertaken to study whether high-dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High-dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy. We identified women with their first pregnancy in Denmark (1997-2017), Norway (2005-2017), and Sweden (2006-2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high-dose folic acid, considered time-varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high-dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6-month time lag was applied, as cancer is unlikely to develop immediately. With up to 21 years of follow-up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high-dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person-years, 95% CI = 193.8-223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person-years, 95% CI = 161.5-166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1-1.2). This risk was attenuated after the 6-month lag analysis (adjusted HR = 1.1, 95% CI = 1.04-1.2). The risk for non-Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3-2.9). The association between high-dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0-1.8). High-dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non-Hodgkin lymphoma, including those with epilepsy, regardless of ASM use.

Attempt to re-estimate organ doses of victims in non-homogeneous exposure accident by means of the state-of-the-art Mesh-type Reference Computational Phantom-a case study of an IR-192 source accident.

An attempt was made to estimate organ doses of a victim in a high-dose non-homogeneous exposure accident caused by a sealed 192Ir gamma-ray source. The Gilan accident was selected as a case study. Organ doses including testis, red bone marrow and so on were properly estimated by applying the Monte Carlo calculation with the state-of-the-art adult male Mesh type Reference Computational Phantom. By introducing a complicated exposure scenario, the dose distribution on the right chest of the victim in the Gilan accident could be reproduced to a certain extent.

Tire wear particle leachate exhibits trophic and multi-generational amplification: Potential threat to population viability

The toxic additives leached from tire wear particles (TWPs) in road runoff can directly poison aquatic organism through high-dose exposure in sporadic hotspots. Given the ubiquity of road runoff carrying TWPs, it is necessary to assess whether there are lagging effects from low-dose exposure, as the toxicity of TWPs leachate can be transferred and amplified across multi-generations and different trophic levels: microalgae, zooplankton and larval fish. In this study, Chlorella pyrenoidesa exposed to different concentrations of TWPs leachate were fed to rotifer Brachionus calyciflorus, which were subsequently used as the initial feeding for fry of Cyprinus carpio. Below 1000mg/L, the growth of microalgae was not influenced by TWPs leachate. Rotifer fed with contaminated microalgae for a single generation exhibited hormesis in their reproduction. After multigenerational feeding, the microalgae from 500mg/L treatment were sufficient to suppress reproduction of rotifer since the third generation. For the secondary consumer carp fry, survival, growth, and feeding rate were significantly inhibited at first generation when consuming the rotifers fed with microalgae exposed to 250mg/L TWPs leachate. So, evidence was presented for the generational and trophic amplification of toxicity in TWPs leachate within the food chain. A seemingly innocuous low dose can exhibit evident ecotoxicity after trophic and generational transfer, which could decline population viability of the aquatic organisms in the future.

Solar ultraviolet radiation exposure of trail runners in an ultraendurance competition at high altitude

Solar ultraviolet radiation exposure of trail runners in an ultraendurance competition at high altitude

Application of FISH based G2-PCC assay for the cytogenetic assessment of high radiation dose exposures: Potential implications for rapid triage biodosimetry.

The main goal of this study is to test the utility of calyculin A induced G2-PCC assay as a biodosimetry triage tool for assessing a wide range of low and acute high radiation dose exposures of photons. Towards this initiative, chromosome aberrations induced by low and high doses of x-rays were evaluated and characterized in G2-prematurely condensed chromosomes (G2-PCCs) by fluorescence in situ hybridization (FISH) using human centromere and telomere specific PNA (peptide nucleic acid) probes. A dose dependent increase in the frequency of dicentric chromosomes was observed in the G2-PCCs up to 20 Gy of x-rays. The combined yields of dicentrics and rings in the G2-PCCs showed a clear dose dependency up to 20 Gy from 0.02/cell for 0.1 Gy to 14.98/cell for 20 Gy. Centric rings were observed more frequently than acentric ring chromosomes in the G2-PCCs at all the radiation doses from 1 Gy to 20 Gy. A head-to-head comparison was also performed by FISH on the yields of chromosome aberrations induced by different doses of x-rays (0 Gy -7.5 Gy) in colcemid arrested metaphase chromosomes and calyculin A induced G2-PCCs. In general, the frequencies of dicentrics, rings and acentric fragments were slightly higher in G2-PCCs than in colcemid arrested metaphase chromosomes at all the radiation doses, but the differences were not statistically significant. To reduce the turnaround time for absorbed radiation dose estimation, attempt was made to obtain G2-PCCs by reducing the culture time to 36 hrs. The absorbed doses estimated in x-rays irradiated (0,1,2 and 4 Gy) G2-PCCs after 36 hrs of culture were grossly like that of G2-PCCs and colcemid arrested metaphase chromosomes prepared after 48 hrs of culture. Our study indicates that the shortened version of calyculin A induced G2-PCC assay coupled with the FISH staining technique can serve as an effective triage biodosimetry tool for large-scale radiological/nuclear incidents.

Lower-dose vs high-dose oral bisphenol S action of lipid metabolism in liver of male SD rat via mediating different SREBP isoforms

Bisphenol S (BPS) is commonly used for the industrial production of thermal paper, polycarbonate plastics, epoxy resins and other materials. Studies have reported that BPS can lead to triglyceride (TAG) or/and cholesterol (CHO) accumulation in the liver in zebrafish and mice, but the reasons for the different types of lipids that accumulate in the liver following BPS exposure are unclear. Here, the influences of lower-dose (10mg/kg body weight/day) and high-dose (50mg/kg body weight/day) BPS exposure to male SD rats on the accumulation of different lipids in the liver were explored. The results indicated that BPS treatment increased the levels of acetyl-CoA and glycogen in the liver. A lower dose of BPS upregulated the mRNA and protein expression levels of sterol regulatory element-binding protein 1 (srebp1), which is involved in the de novo synthesis of TAG in the liver, thus promoting the synthesis of glycerides (diacetylglyceride and TAG). However, a higher dose of BPS induced CHO accumulation, but inhibited the mRNA expression of genes (i.e., srebp2, hmgcr and hmgcs) involved in the de novo synthesis of CHO in the liver. Excessive accumulation of glycerides and CHO led to destruction of the physiological structure of rat liver, causing disorders in liver function. Our data provide new insight into the different mechanisms by which glyceride and CHO accumulate in the liver after BPS exposure.