Inadvertent Exposure Research Articles

Absorptivity Is an Important Determinant in the Toxicity Difference between Aristolochic Acid I and Aristolochic Acid II.

Inadvertent exposure to aristolochic acids (AAs) is causing chronic renal disease worldwide, with aristolochic acid I (AA-I) identified as the primary toxic agent. This study employed chemical methods to investigate the mechanisms underlying the nephrotoxicity and carcinogenicity of AA-I. Aristolochic acid II (AA-II), which has a structure similar to that of AA-I, was investigated with the same methods for comparison. Despite their structural similarities, findings from cultured human cells and gut sac experiments showed that AA-I is absorbed more effectively than AA-II (∼3 times greater for AA-I than for AA-II; p < 0.001). This increased absorption, along with the previously observed higher activity of reductive activation enzymes for AA-I, results in greater DNA damage and oxidative stress, both of which are key factors in AA-related toxicity. The similar patterns of cell mortality (34.4 ± 2.3% vs 9.7 ± 0.1% for AA-I and AA-II at 80 μM; p < 0.0001), DNA adduct formation (∼3 times greater for AA-I than for AA-II; p < 0.001), and oxidative stress levels in relation to the concentrations of AA-I and AA-II indicate that the higher absorption rate of AA-I is a significant contributor to its greater toxicity. The toxicity of AA-I was also found to be further enhanced by its (natural) coexistence with AA-II. Since AA-I and AA-II differ only by a methoxy group, future research on reducing risks associated with AA exposure should focus on strategies to lower the absorption of these compounds.

Usefulness and limitations of ChatGPT in getting information on teratogenic drugs exposed in pregnancy.

There is a growing interest in using artificial intelligence (AI) technology to obtain information on the risk and safety of drugs in pregnancy. Inadvertent drug exposure in pregnant women is inevitable in acute or chronic diseases, especially in unplanned pregnancies. According to the Korean mother safe counselling center database (2010-2023), many Korean pregnant women and their families asked about the teratogenicity of their exposed drugs. The most frequently used drug was topiramate (n=2,018), followed by isotretinoin (n=1,972), dexamethasone (n=1,279), and doxycycline (n=1,119). Unexpectedly, thalidomide, a notorious teratogen that causes phocomelia, was included. It has been withdrawn from general prescriptions since 1961, except for the treatment of multiple myeloma. Her partner used it for the treatment of multiple myeloma. In this study, we evaluated the usefulness of AI Chat generative pretrained transformer (Chat GPT) by comparing information between AI and a literature review on isotretinoin, a well-known teratogen to which Korean pregnant women are frequently exposed. ChatGPT provides general information on teratogenicity for pregnant women and medical providers rather than on their exposure. Thus, AI can induce unnecessary termination of pregnancy due to misinformation and misperception in cases of notorious teratogens such as isotretinoin. Therefore, counseling on the teratogenicity of medication exposure in pregnancy must be performed with ChatGPT, as well as a literature review. Further studies are required to obtain more individualized information using AI in the field of teratology.

Prevalence and etiologies of non-responsive celiac disease: A systematic review and meta-analysis.

Non-responsive celiac disease (NRCD) is defined as ongoing symptoms despite 6-12months of gluten-free diet (GFD), the only known treatment for celiac disease (CeD). There is inconsistency in studies describing the proportion of patients having NRCD and its various causes among patients with CeD. We therefore conducted a systematic review and meta-analysis to determine the prevalence and causes of NRCD. The PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases were searched for original studies reporting the proportion of patients with persistent symptoms after ≥6months of GFD. Studies reporting the etiologies of NRCD were also identified. The systematic review was conducted as per the Meta-analysis of Observational Studies in Epidemiology guidelines. Statistical analysis was performed in STATA. Of 2965 search results, nine studies met the inclusion and exclusion criteria. Five studies (n=4414) reported data on prevalence, and seven studies (n=790) reported the causes of NRCD. The pooled prevalence of NRCD was 22% (95% confidence interval, 11-35%). Among patients with NRCD, inadvertent exposure to gluten was the most common cause (33%), followed by functional gastrointestinal disorders including irritable bowel syndrome in 16%. Refractory CeD type II along with its premalignant and malignant sequelae was observed in 7% of patients with NRCD. One in five patients with CeD may not respond to GFD and would likely be classified as NRCD. Inadvertent gluten exposure was the cause of ongoing symptoms in one-third of patients with NRCD. Improving adherence to GFD along with developing novel therapeutics to mitigate symptoms due to ongoing gluten exposure is critical.

Toxicokinetic model of the pyrethroid pesticide lambda-cyhalothrin, main exposure route and dose reconstruction predictions in agricultural workers.

A toxicokinetic model of the pyrethroid insecticide lambda-cyhalothrin (LCT) was developed to relate absorbed doses to urinary cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) metabolite levels used as a biomarker of exposure. The model then served to reconstruct absorbed doses in agricultural workers and their probability of exceeding the EFSA Acceptable occupational Exposure Level (AOEL). The toxicokinetic model was able to reproduce the temporal profiles of CFMP in the urine of operators spraying pesticides using the optimized model parameters (adjusted to human volunteer data). Modeling also showed that simulation of an inadvertent oral exposure mainly was the exposure scenario giving the best fit to CFMP urinary time-course data in applicators. With the dermal model parameters optimized from data in volunteers, simulation of a dermal exposure in applicators did not allow to reproduce the observed peak excretions and urinary metabolite levels; extremely high applied dermal doses would be required but still simulated dermal penetration rate would remain too slow. Simulation of an inhalation exposure allowed to reproduce the observed time-courses, but with unrealistic air concentrations. For applicators with the highest urinary concentrations, there was a probability of exceeding the AOEL at some points during the biomonitoring period [>50% probability of exceeding for 27% of 24-h samples]; for non-applicator workers the probability of exceeding the AOEL value was very low [corresponding value of 5%]. Furthermore, the median [95% CI] estimates of 10 000 Monte Carlo simulations led to a biological reference value corresponding to the AOEL of 116 [113-119] ng/kg bw/d and 7.5 [7.3-7.7] μg/L. Overall, 7% of applicators and 1% of workers performing weeding and strawberry picking had a probability of exceeding this biological reference value. As a next step, it would be interesting to apply these methods to multiple exposure to various contaminants.

Unravelling the threat of contamination in elite sports: Exploring diverse sources impacting adverse analytical findings and the risk of inadvertent exposure to prohibited substances

In recent years, increasing concerns have emerged regarding athletes being exposed to various sources of contamination that could result in an adverse analytical finding (AAF), which is considered a positive doping test and may lead to the athlete's sanction. This review aims to examine the potential sources of contamination. Firstly, exogenous sources such as food, water, supplements, and medications will be described, along with endogenous sources, primarily arising from the athlete’s physiological condition via the biotransformation of Medications. Finally, other hypothetical contaminations arising from sample collection procedures, poor transport or storage, and laboratory conditions will be discussed. Despite some legislative efforts to regulate the production of food and supplements, contamination remains a significant concern in the context of anti-doping, necessitating athletes to stay vigilant against the risks of inadvertent uptake of illicit products. Increased knowledge of the potential sources of contamination is essential for all parties involved in the fight against doping, including athletes, support personnel, legitimate supplement product manufacturers, and the anti-doping and scientific community. Such insights can contribute to developing the most effective strategy for preventing contamination and, most importantly, reducing the risk of inadvertent AAFs.

Synthetic Microplastics in UK tap and bottled water; Implications for human exposure

There is increasing concern for public health over inadvertent human exposure to MPs due to potential adverse health effects linked to MPs polymeric composition, toxic chemical additives, and/or harmful microorganisms adsorbing onto their surfaces. While numerous studies have reported MPs occurrence and risk in the freshwater aquatic environment and drinking water sources (e.g., rivers, lakes, and reservoirs), the current state-of-knowledge on MPs pollution in drinking water (i.e., tap water and bottled water) remains limited at a global level. This paper provides the first comprehensive study of the occurrence, concentrations, size distribution, shape, and polymer type of MPs in 177 tap water samples from 13 cities in the United Kingdom, as well as 85 samples of bottled water from 17 popular brands, with various packaging materials, on the UK market.MPs were detected in all tap water samples (range 6–100 MP/L) and bottled water samples (range 12–62 MP/L). Average MPs concentration in tap water (40 ± 16 MP/L) was statistically indistinguishable from that in bottled water (37 ± 11 MP/L). However, the average MPs particle size in tap water (32.4 μm) exceeded significantly (p < 0.05) that in bottled water (26.5 μm), indicating the various purification processes applied to bottled water may help remove larger MPs, but raises concern over the potential adverse health effects from exposure to smaller MPs. The most frequently detected polymer types were: polypropylene (PP), polyethylene (PE), and polyvinyl chloride (PVC) in tap water, and PE, PP and polyethylene terephthalate (PET) in bottled water. A strong correlation was observed (r = 0.68, P = 0.049) between the plastic cap material (PE) and the predominant polymer type in the bottled water. In terms of morphology, fragments and fibres were the most abundant MPs, together constituting 92 % and 96 % of MPs detected in tap and bottled water samples, respectively.Using EFSA (European Food Safety Authority) recommended daily water intakes, the corresponding exposures to MPs in different UK age groups were estimated. On a body weight (BW) basis, infants and toddlers were exposed (4 MP/kg BW/day) at a higher level than adults (1 MP/kg BW/day). This raises concern, given the former's incompletely developed immune/nervous systems rendering them at higher risk of adverse health effects from such exposure.

ENHANCING SECURITY IN NIGERIA: THE IMPLICATIONS OF SOCIAL MEDIA-BASED CRIME REPORTING

With the widespread use of social media platforms, individuals have increasingly turned to these platforms to report crimes, creating an evolving landscape for law enforcement and security agencies. Social media-based crime reporting has emerged as a transformative approach to public safety, offering real-time updates, accessibility, and community engagement. This study examines how social media platforms like Facebook and Twitter promote community mobilization and real-time information sharing by applying Information Diffusion Theory (IDT) and Social Network Theory (SNT). Notable examples, such as the Aluu Four lynching, End-SARS movement, Chibok kidnapping and the 2023 presidential elections amongst other events, demonstrate how social media plays a crucial role in increasing public knowledge, coordinating group efforts, and impacting legislative reforms. However, this innovative method of reporting also brings forth several security implications that demand careful consideration. By examining the advantages and challenges of social media for crime reporting, this study aims to provide insights into how such practices can enhance security measures while mitigating potential risks. This study, therefore, explores these security concerns and strategies for enhancing the security implications of social media-based crime reporting. It discusses the potential risks of misinformation, privacy issues, tipping off perpetrators, and the inadvertent exposure of victims and witnesses. The results emphasize the importance of adopting a well-rounded strategy to utilize the capabilities of social media for reporting crimes, while also acknowledging the difficulties it presents. The study highlights the need for collaboration between law enforcement agencies, policymakers, social media platforms, and the public to develop a robust legal framework, promote responsible reporting practices, and protect evidence integrity. The study therefore recommends the use of sophisticated verification technology, the establishment of responsible reporting criteria, collaboration with social media platforms, and the implementation of strong privacy protection measures.

Safety of methotrexate administration in women with pregnancy of unknown location at high risk of ectopic pregnancy.

To evaluate the safety of current guidelines on methotrexate (MTX) administration in women with pregnancy of unknown location (PUL) who are considered to have a high risk of underlying ectopic pregnancy (EP), and to investigate whether implementation of these guidelines would result in inadvertent exposure to MTX of viable intrauterine pregnancies (IUPs). This was a retrospective observational study of consecutive clinically stable women who were classified with PUL at the early pregnancy unit of Nepean Hospital, Sydney, Australia, between 2007 and 2021. PUL was defined as a positive pregnancy test in the absence of signs of IUP or EP on transvaginal ultrasound. Patients with a PUL that behaved biochemically like an EP, but for which the location of pregnancy was not confirmed on ultrasound, were eligible for MTX to minimize the risk of subsequent tubal rupture. Criteria discussed in the guidelines of the American College of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Care Excellence (NICE) were applied to the PUL database. The number of patients eligible to receive MTX and the number with an underlying viable IUP who would be inadvertently prescribed MTX were calculated. A total of 816 women with PUL were reviewed, of whom 724 had complete data and were included in the final analysis. Six patients had persistent PUL and the remaining 718 had a diagnosis of viable IUP, non-viable IUP, EP or failed PUL. According to the ACOG, ASRM, RCOG and NICE guidelines, the rate of MTX administration among patients with PUL would have been 2.76%, 4.56%, 0.41% and 35.36%, respectively. However, no persistent PUL would have received MTX according to the ACOG, ASRM and RCOG protocols (the NICE protocol identified patients with persistent PUL with a sensitivity of 100%), and the majority of MTX treatments were unnecessary because those patients were later classified as having non-viable IUP or failed PUL. Application of ACOG and ASRM guidance could result theoretically in inadvertent MTX administration to women with an underlying viable IUP at a rate of 4.1/1000 (3/724). Current guidelines used to predict high risk of EP in the PUL population lead to inadvertent MTX administration to women with an underlying viable IUP. These guidelines should be used wisely to ensure that no wanted pregnancy is exposed to MTX. Women with PUL should be monitored carefully, and MTX should be used judiciously when the location of pregnancy is yet to be confirmed. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Post-Conceptional Exposure to Clomiphene Citrate and Congenital Malformations: A Cohort Study.

Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies. The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring. A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification. Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern. Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.

Do heavy metals have a role in extrahepatic portal vein obstruction in children: A pilot case-control study

ObjectiveExtrahepatic portal venous obstruction (EHPVO) is a common cause of portal hypertension in Southeast Asia as compared to the western world, where chronic liver disease is the most common cause. Pollution and inadvertent exposure to heavy metals in poor socio-economic status in this part of the world are quite common. Therefore, this study was proposed to determine the association between heavy metal levels and oxidative stress in children with EHPVO. MethodsThis pilot case-control study was conducted in the department of Pediatrics, of a tertiary health care centre from January 2020 to October 2021. Children between 1 and 14 years, diagnosed with EHPVO were included. Controls were the healthy volunteers from OPD and near discharge indoor pediatrics patients. Metal analysis for Copper, Lead, Zinc, and Manganese, & Antioxidant activity for superoxide dismutase (SOD), Glutathione reductase (GR) and Lipid peroxidase (LPO) in form of malondialdehyde (MDA) was measured in both the groups. ResultsA total of 80 subjects were enrolled (40 EHPVO cases and 40 controls) mean age for cases was 8.15 ± 3.53, and for control, was 7.69 ± 3.55 years (p = 0.560). Lead values were found to be significantly higher (p = 0.003) in EHPVO cases (5.39 ± 3.13) in comparison to controls (3.30 ± 2.91). Mean superoxide dismutase (SOD) and Glutathione reductase (GR) values were decreased (p = 0.035- GR) and the malondialdehyde (MDA) value was increased in the EHPVO cases as compared to controls. ConclusionChildren with high blood levels of lead might be at risk of portal vein thrombosis resulting in EHPVO, and lead-induced oxidative stress.

CeO2 nanoparticle dose and exposure modulate soybean development and plant-mediated responses in root-associated bacterial communities

Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg−1. Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops.

The Relationship Between Eye Distance To The Computer And Computer Vision Syndrome (CVS) Complaints

The use of computers is now commonplace among individuals, ranging from students to professionals. Computers offer numerous advantages, leading to a high dependency on them, particularly among office workers, who incorporate computer usage into their daily activities. In general, the occupational setting necessitates prolonged computer usage, thereby leading to inadvertent exposure to the computer screen/monitor and subsequent development of eye-related complaints, including Computer Vision Syndrome (CVS). This study aimed to investigate the correlation between eye distance to the computer and the occurrence of CVS symptoms. This research employs an analytical observational study design with a cross-sectional approach. The study sample consists of employees from the Middle Type Customs and Excise Service Office (KPPBC TMC) in Malang. The sample selection was based on the prolonged duration of computer usage, averaging 6 hours per working day. The study findings indicated a significant correlation between the viewing distance to the computer screen and the occurrence of CVS complaints among the respondents. Among the total of 65 respondents, 66.2% experienced CVS complaints, with the most predominant symptom being tired eyes at 53.8%. A higher proportion of respondents (53.8%) had an eye distance from the computer of less than 50 cm, compared to those with an eye distance of more than 50 cm (46.2%). The majority of respondents in this study were in the age range of 25-29 years, comprising 40% of the sample. Among them, the majority were male, accounting for 57.7% of the respondents.

Implications of environmental nanoparticles on neurodegeneration.

The ubiquity of nanoparticles, sourced from both natural environments and human activities, presents critical challenges for public health. While offering significant potential for innovative biomedical applications-especially in enhancing drug transport across the blood-brain barrier-these particles also introduce possible hazards due to inadvertent exposure. This concise review explores the paradoxical nature of nanoparticles, emphasizing their promising applications in healthcare juxtaposed with their potential neurotoxic consequences. Through a detailed examination, we delineate the pathways through which nanoparticles can reach the brain and the subsequent health implications. There is growing evidence of a disturbing association between nanoparticle exposure and the onset of neurodegenerative conditions, highlighting the imperative for comprehensive research and strategic interventions. Gaining a deep understanding of these mechanisms and enacting protective policies are crucial steps toward reducing the health threats of nanoparticles, thereby maximizing their therapeutic advantages.

HOST SPECIFICITY, INFECTION DYNAMICS, AND ALLERGENICITY IN Anisakis SPP. INFESTATION: A REVIEW

Fish and seafood are important in providing protein to human diets. However, they are susceptible to contamination by various parasites, such as nematodes, cestodes, and trematodes. Among these, Anisakis spp. and other species of trematodes belonging to the Anisakidae family are commonly identified in fish and shellfish, posing a significant health risk. This contamination poses a substantial risk to public health, particularly with the increasing prevalence of these parasites in marine fish. The globalisation of cuisines, including sushi, is one of the factors causing this development. The risk of Anisakis contamination has increased due to the global popularity of sushi, a form of Japanese food that features raw or undercooked fish. Gastric anisakiasis is the primary infection in humans, caused by the penetration of L3 larvae into the gastric wall. However, the indefinite symptoms associated with anisakiasis make precise identification challenging, complicating efforts to effectively treat this health issue. This study reviewed the host specificity, risk factors, infection mechanisms, and infestation areas of Anisakis spp. Various reputable sources, including Google Scholar, PubMed Central, ScienceDirect, Springer Link, and the Wiley Online Library, were used to explore the diverse host preferences and the impact of environmental changes. The larvae of Anisakis spp. exhibit diverse host preferences and environmental changes like global warming make hosts more vulnerable. Inadvertent exposure to these parasites occurs when individuals consume raw or undercooked fish and seafood. An extremely serious threat is posed by allergic anisakiasis, characterised by severe symptoms such as respiratory arrest, shock, and collapse. Research focusing on bioactive substances capable of blocking or neutralising the excretions and secretions of Anisakis sp. should be encouraged. Metalloproteinases (MMPs) and serine proteases, in particular, show promise for minimising adverse effects and reducing dependency on medication in treating allergic anisakiasis. Further research and intervention techniques are essential if health issues associated with Anisakis exist.

Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring

BackgroundAs emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. MethodsIn this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. ResultsOnly 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01–10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. ConclusionsIntentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services

ObjectivesGlucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the...

In silico biomarker analysis of the adverse effects of perfluorooctane sulfonate (PFOS) exposure on the metabolic physiology of embryo-larval zebrafish

Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant in global aquatic ecosystems with increasing concern for its toxicity to aquatic wildlife through inadvertent exposures. To assess the likely adverse effects of PFOS exposure on aquatic wildlife inhabiting polluted ecosystems, there is a need to identify biomarkers of its exposure and toxicity. We used an integrated systems toxicological framework to identify physiologically relevant biomarkers of PFOS toxicity in fish. An in silico stoichiometric metabolism model of zebrafish (Danio rerio) was used to integrate available (published by other authors) metabolomics and transcriptomics datasets from in vivo toxicological studies with 5 days post fertilized embryo-larval life stage of zebrafish. The experimentally derived omics datasets were used as constraints to parameterize an in silico mathematical model of zebrafish metabolism. In silico simulations using flux balance analysis (FBA) and its extensions showed prominent effects of PFOS exposure on the carnitine shuttle and fatty acid oxidation. Further analysis of metabolites comprising the impacted metabolic reactions indicated carnitine to be the most highly represented cofactor metabolite. Flux simulations also showed a near dose-responsive increase in the pools for fatty acids and acyl-CoAs under PFOS exposure. Taken together, our integrative in silico results showed dyslipidemia effects under PFOS exposure and uniquely identified carnitine as a candidate metabolite biomarker. The verification of this prediction was sought in a subsequent in vivo environmental monitoring study by the authors which showed carnitine to be a modal biomarker of PFOS exposure in wild-caught fish and marine mammals sampled from the northern Gulf of Mexico. Therefore, we highlight the efficacy of FBA to study the properties of large-scale metabolic networks and to identify biomarkers of pollutant exposure in aquatic wildlife.

Immobilisation remediation of arsenic-contaminated soils with promising CaAl-layered double hydroxide and bioavailability, bioaccessibility, and speciation-based health risk assessment

Arsenic (As)-contaminated soil poses great health risk to human mostly through inadvertent oral exposure. We investigated CaAl-layered double hydroxide (CaAl-LDH), a promising immobilising agent, for the remediation of As-contaminated Chinese soils. The effects on specific soil properties and As fractionation were analyzed, and changes in the health risk of soil As were accurately assessed by means of advanced in vivo mice model and in vitro PBET-SHIME model. Results showed that the application of CaAl-LDH significantly increased soil pH and concentration of Fe and Al oxides, and effectively converted active As fractions into the most stable residual fraction, guaranteeing long-term remediation stability. Based on in vivo test, As relative bioavailability was significantly reduced by 37.75%. Based on in vitro test, As bioaccessibility in small intestinal and colon phases was significantly reduced by 25.65% and 28.57%, respectively. Furthermore, As metabolism (reduction and methylation) by the gut microbiota inhabiting colon was clearly observed. After immobilisation with CaAl-LDH, the concentration of bioaccessible As(Ⅴ) in the colon fluid was significantly reduced by 61.91%, and organic As (least toxic MMA(V) and DMA(V)) became the main species, which further reduced the health risk of soil As. In summary, CaAl-LDH proved to be a feasible option for immobilisation remediation of As-contaminated soils, and considerable progress was made in relevant health risk assessment.

Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet.

The gluten-free diet (GFD) has limitations, and there is intense research in the development of adjuvant therapies. To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease (AN-PEP) on inadvertent gluten exposure and symptom prevention in adult celiac disease (CeD) patients following their usual GFD. This was an exploratory, double-blind, randomized, placebo-controlled trial that enrolled CeD patients on a long-term GFD. After a 4-wk run-in period, patients were randomized to 4 wk of two AN-PEP capsules (GliadinX; AVI Research, LLC, United States) at each of three meals per day or placebo. Outcome endpoints were: (1) Average weekly stool gluten immunogenic peptides (GIP) between the run-in and end of treatments and between AN-PEP and placebo; (2) celiac symptom index (CSI); (3) CeD-specific serology; and (4) quality of life. Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments. Forty patients were randomized for the intention-to-treat analysis, and three were excluded from the per-protocol assessment. Overall, 628/640 (98.1%) stool samples were collected. GIP was undetectable (< 0.08 μg/g) in 65.6% of samples, and no differences between treatment arms were detected. Only 0.5% of samples had GIP concentrations sufficiently high (> 0.32 μg/g) to potentially cause mucosal damage. Median GIP concentration in the AN-PEP arm was 44.7% lower than in the run-in period. One-third of patients exhibiting GIP > 0.08 μg/g during run-in had lower or undetectable GIP after AN-PEP treatment. Compared with the run- in period, the proportion of symptomatic patients (CSI > 38) in the AN-PEP arm was significantly lower (P < 0.03). AN-PEP did not result in changes in specific serologies. This exploratory study conducted in a real-life setting revealed high adherence to the GFD. The AN-PEP treatment did not significantly reduce the overall GIP stool concentration. However, given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm, further clinical research is warranted.

Integrated mRNA- and miRNA-sequencing analyses unveil the underlying mechanism of tobacco pollutant-induced developmental toxicity in zebrafish embryos

Tobacco pollutants are prevalent in the environment, leading to inadvertent exposure of pregnant females. Studies of these pollutants' toxic effects on embryonic development have not fully elucidated the potential underlying mechanisms. Therefore, in this study, we aimed to investigate the developmental toxicity induced by cigarette smoke extract (CSE) at concentrations of 0.25, 1, and 2.5% using a zebrafish embryo toxicity test and integrated transcriptomic analysis of microRNA (miRNA) and messenger RNA (mRNA). The findings revealed that CSE caused developmental toxicity, including increased mortality and decreased incubation rate, in a dose-dependent manner. Moreover, CSE induced malformations and apoptosis, specifically in the head and heart of zebrafish larvae. We used mRNA and miRNA sequencing analyses to compare changes in the expression of genes and miRNAs in zebrafish larvae. The bioinformatics analysis indicates that the mechanism underlying CSE-induced developmental toxicity was associated with compromised genetic material damage repair, deregulated apoptosis, and disturbed lipid metabolism. The enrichment analysis and RT-qPCR show that the ctsba gene plays a crucial function in embryo developmental apoptosis, and the fads2 gene mainly regulates lipid metabolic toxicity. The results of this study improve the understanding of CSE-induced developmental toxicity in zebrafish embryos and contribute insights into the formulation of novel preventive strategies against tobacco pollutants during early embryonic development.