Immune cell profiles associated with human exposure to perfluorinated compounds (PFAS) suggest changes in natural killer, T helper, and T cytotoxic cell subpopulations.

Per- and polyfluoroalkyl substances (PFAS) constitutes a group of highly persistent man-made substances. Recent evidence indicates that PFAS negatively impact the immune system. However, it remains unclear how different PFAS are associated with alterations in circulating leukocyte subpopulations. More detailed knowledge of such potential associations can provide better understanding into mechanisms of PFAS immunotoxicity in humans. In this exploratory study, associations of serum levels of common PFAS (perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS)) and immune cell profiles of peripheral blood mononuclear cells, both with and without immunostimulation, were investigated. High-dimensional single cell analysis by mass cytometry was done on blood leukocytes from fifty participants in the Norwegian human biomonitoring EuroMix study. Different PFAS were associated with changes in various subpopulations of natural killer (NK), T helper (Th), and cytotoxic T (Tc) cells. Broadly, PFAS concentrations were related to increased frequencies of NK cells and activated subpopulations of NK cells. Additionally, increased levels of activated T helper memory cell subpopulations point to Th2/Th17 and Treg-like skewed profiles. Finally, PFAS concentrations were associated with decreased frequencies of T cytotoxic cell subpopulations with CXCR3+ effector memory (EM) phenotypes. Several of these observations point to biologically plausible mechanisms that may contribute to explaining the epidemiological reports of immunosuppression by PFAS. Our results suggest that PFAS exposures even at relatively low levels are associated with changes in immune cell subpopulations, a finding which should be explored more thoroughly in a larger cohort. Additionally, causal relationships should be confirmed in experimental studies. Overall, this study demonstrates the strength of profiling by mass cytometry in revealing detailed changes in immune cells at a single cell level.

Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health.

Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.

Transcriptional analysis in peripheral blood cells of individuals with elevated phthalate exposure - Results of the EuroMix study.

Exposure to phthalates is widespread in Europe. Phthalates are considered endocrine disrupting compounds and are classified as toxic for reproduction. However how phthalates affect the transcriptome in humans remains largely unknown. To investigate the effects of phthalate exposure on the transcriptomic profile we conducted RNA sequencing on peripheral blood samples from the Norwegian EuroMix cohort. We compared gene expression changes between participants with high, medium, and low exposure of six phthalates and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Comparing high and low exposure groups, DINCH was the compound that showed the highest number of differentially expressed genes (126 genes) followed by mono-n-butyl phthalate (MnBP; 89 genes) and mono-iso-nonyl phthalate (MiBP; 70 genes). Distributions between up- or down-regulated genes were similar across the different phthalates and DINCH. All phthalates including DINCH shared common differentially expressed genes ranging from 3 to 37 overlaps. Enriched Gene Ontology (GO) and biological pathway analysis revealed that most of the differentially expressed genes were associated with general cellular metabolism GO terms. MnBP and DINCH, particularly, showed a marked enrichment in various immunological function pathways including neutrophil degranulation, adaptive immune system and signaling by interleukins. Furthermore, the association between genes involved in the peroxisome proliferator activated receptor (PPAR) signaling pathway and phthalates, including DINCH, was evaluated. In total, 15 genes showed positive or negative associations across 5 phthalates and DINCH. MnBP and MiBP were the phthalate metabolites with the highest number of associations: 8 and 4 PPAR signaling pathway genes, respectively. Overall, we have performed an association study between phthalate exposure levels and modulation of transcriptomic profiles in human peripheral blood cells. DINCH, which is often mentioned as a substitute for phthalates, had comparable effects on differential gene expression in peripheral blood cells as phthalates.

Exposure to persistent organic pollutants alters the serum metabolome in non-obese diabetic mice.

INTRODUCTION: Autoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized. OBJECTIVES: Here we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfluoroalkyl substances (PFAS). METHODS: Analysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS. RESULTS: Experimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins. CONCLUSION: Taken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunity.

Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health.

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system's components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

Reduced polyfunctional T cells and increased cellular activation markers in adult allergy patients reporting adverse reactions to food.

BACKGROUND: The underlying cellular mechanisms causing adverse reactions to food are complex and still not fully understood. Therefore, in this study we aimed to identify functional and/or phenotypical immune cell signatures characteristic for adult patients reporting adverse reactions to food. By mass cytometry, we performed high-dimensional profiling of peripheral blood mononuclear cells (PBMC) from adult patients reporting adverse reactions to food and healthy controls. The patients were grouped according to sIgE-positive or sIgE-negative serology to common food and inhalant allergens. Two broad antibody panels were used, allowing determination of major immune cell populations in PBMC, as well as activation status, proliferation status, and cytokine expression patterns after PMA/ionomycin-stimulation on a single cell level. RESULTS: By use of data-driven algorithms, several cell populations were identified showing significantly different marker expression between the groups. Most striking was an impaired frequency and function of polyfunctional CD4+ and CD8+ T cells in patients reporting adverse reactions to food compared to the controls. Further, subpopulations of monocytes, T cells, and B cells had increased expression of functional markers such as CD371, CD69, CD25, CD28, and/or HLA-DR as well as decreased expression of CD23 in the patients. Most of the differing cell subpopulations were similarly altered in the two subgroups of patients. CONCLUSION: Our results suggest common immune cell features for both patient subgroups reporting adverse reactions to food, and provide a basis for further studies on mechanistic and diagnostic biomarker studies in food allergy.

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System.

Titanium dioxide (TiO2) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO2 and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO2 warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO2, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO2 and nano-sized TiO2 in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO2.

Early life exposure to air pollution particulate matter (PM) as risk factor for attention deficit/hyperactivity disorder (ADHD): Need for novel strategies for mechanisms and causalities.

Epidemiological studies have demonstrated that air pollution particulate matter (PM) and adsorbed toxicants (organic compounds and trace metals) may affect child development already in utero. Recent studies have also indicated that PM may be a risk factor for neurodevelopmental disorders (NDDs). A pattern of increasing prevalence of attention deficit/hyperactivity disorder (ADHD) has been suggested to partly be linked to environmental pollutants exposure, including PM. Epidemiological studies suggest associations between pre- or postnatal exposure to air pollution components and ADHD symptoms. However, many studies are cross-sectional without possibility to reveal causality. Cohort studies are often small with poor exposure characterization, and confounded by traffic noise and socioeconomic factors, possibly overestimating the study associations. Furthermore, the mechanistic knowledge how exposure to PM during early brain development may contribute to increased risk of ADHD symptoms or cognitive deficits is limited. The closure of this knowledge gap requires the combined use of well-designed longitudinal cohort studies, supported by mechanistic in vitro studies. As ADHD has profound consequences for the children affected and their families, the identification of preventable risk factors such as air pollution exposure should be of high priority.

Allergen Immunization Induces Major Changes in Microbiota Composition and Short-Chain Fatty Acid Production in Different Gut Segments in a Mouse Model of Lupine Food Allergy.

BACKGROUND: The incidence of food allergies in western countries has increased in recent decades. OBJECTIVES: To study the association between gut bacterial microbiota composition, short-chain fatty acids (SCFAs) and food allergy in a mouse model. METHODS: After oral immunizations with the human food allergen lupine with the adjuvant cholera toxin (CT) (or buffer in controls), sensitization and anaphylactic responses were determined. Gastrointestinal content was collected from the distal ileum, cecum, colon, and fecal pellets, and the bacterial diversity and composition was determined by deep sequencing of the 16S rRNA gene. SCFAs in gastrointestinal content supernatants were determined by gas chromatography. RESULTS: The microbiota signatures were profoundly affected by allergen immunization. Ten operational taxonomic units (OTUs) were significantly different between immunized and control animals for at least one of the intestinal segments; eight of these OTUs belonged to the Clostridia class. Although consistent across all four gut segments, the colon showed the highest number of OTUs significantly associated with allergic immunization. SCFA levels in the cecum were also altered by immunization. CONCLUSIONS: Allergen immunization with CT in the present food allergy model induced profound changes in the microbiome composition and SCFA production. The result suggests that the colon may be the most sensitive gut segment for investigating changes in the gut microbiome.

Microbial Community Composition of Tap Water and Biofilms Treated with or without Copper-Silver Ionization.

Copper-silver ionization (CSI) is an in-house water disinfection method primarily installed to eradicate Legionella bacteria from drinking water distribution systems (DWDS). Its effect on the abundance of culturable Legionella and Legionella infections has been documented in several studies. However, the effect of CSI on other bacteria in DWDS is largely unknown. To investigate these effects, we characterized drinking water and biofilm communities in a hospital using CSI, in a neighboring building without CSI, and in treated drinking water at the local water treatment plant. We used 16S rDNA amplicon sequencing and Legionella culturing. The sequencing results revealed three distinct water groups: (1) cold-water samples (no CSI), (2) warm-water samples at the research institute (no CSI), and (3) warm-water samples at the hospital (after CSI; ANOSIM, p < 0.001). Differences between the biofilm communities exposed and not exposed to CSI were less clear (ANOSIM, p = 0.022). No Legionella were cultured, but limited numbers of Legionella sequences were recovered from all 25 water samples (0.2-1.4% relative abundance). The clustering pattern indicated local selection of Legionella types (Kruskal-Wallis, p < 0.001). Furthermore, one unclassified Betaproteobacteria OTU was highly enriched in CSI-treated warm water samples at the hospital (Kruskal-Wallis, p < 0.001).

A primer on systematic reviews in toxicology.

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

Accessible methods and tools to estimate chemical exposure in humans to support risk assessment: A systematic scoping review.

Exposure assessment is a crucial component of environmental health research, providing essential information on the potential risks associated with various chemicals. A systematic scoping review was conducted to acquire an overview of accessible human exposure assessment methods and computational tools to support and ultimately improve risk assessment. The systematic scoping review was performed in Sysrev, a web platform that introduces machine learning techniques into the review process aiming for increased accuracy and efficiency. Included publications were restricted to a publication date after the year 2000, where exposure methods were properly described. Exposure assessments methods were found to be used for a broad range of environmental chemicals including pesticides, metals, persistent chemicals, volatile organic compounds, and other chemical classes. Our results show that after the year 2000, for all the types of exposure routes, probabilistic analysis, and computational methods to calculate human exposure have increased. Sixty-three mathematical models and toolboxes were identified that have been developed in Europe, North America, and globally. However, only twelve occur frequently and their usefulness were associated with exposure route, chemical classes and input parameters used to estimate exposure. The outcome of the combined associations can function as a basis and/or guide for decision making for the selection of most appropriate method and tool to be used for environmental chemical human exposure assessments in Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment (ONTOX) project and elsewhere. Finally, the choice of input parameters used in each mathematical model and toolbox shown by our analysis can contribute to the harmonization process of the exposure models and tools increasing the prospect for comparison between studies and consistency in the regulatory process in the future.

Novel clinical phenotypes, drug categorization, and outcome prediction in drug-induced cholestasis: Analysis of a database of 432 patients developed by literature review and machine learning support.

BACKGROUND: Serum transaminases, alkaline phosphatase and bilirubin are common parameters used for DILI diagnosis, classification, and prognosis. However, the relevance of clinical examination, histopathology and drug chemical properties have not been fully investigated. As cholestasis is a frequent and complex DILI manifestation, our goal was to investigate the relevance of clinical features and drug properties to stratify drug-induced cholestasis (DIC) patients, and to develop a prognosis model to identify patients at risk and high-concern drugs. METHODS: DIC-related articles were searched by keywords and Boolean operators in seven databases. Relevant articles were uploaded onto Sysrev, a machine-learning based platform for article review and data extraction. Demographic, clinical, biochemical, and liver histopathological data were collected. Drug properties were obtained from databases or QSAR modelling. Statistical analyses and logistic regressions were performed. RESULTS: Data from 432 DIC patients associated with 52 drugs were collected. Fibrosis strongly associated with fatality, whereas canalicular paucity and ALP associated with chronicity. Drugs causing cholestasis clustered in three major groups. The pure cholestatic pattern divided into two subphenotypes with differences in prognosis, canalicular paucity, fibrosis, ALP and bilirubin. A predictive model of DIC outcome based on non-invasive parameters and drug properties was developed. Results demonstrate that physicochemical (pKa-a) and pharmacokinetic (bioavailability, CYP2C9) attributes impinged on the DIC phenotype and allowed the identification of high-concern drugs. CONCLUSIONS: We identified novel associations among DIC manifestations and disclosed novel DIC subphenotypes with specific clinical and chemical traits. The developed predictive DIC outcome model could facilitate DIC prognosis in clinical practice and drug categorization.

Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment.

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments. Using combinations of human relevant in vitro models, chemical analysis and computational (in silico) approaches bring advantages compared to animal studies. These include a greater focus on the human species and on molecular mechanisms and kinetics, identification of Adverse Outcome Pathways and downstream Key Events as well as the possibility of addressing susceptible populations and additional endpoints. Much of the advancement and progress made in the Next Generation Risk Assessment (NGRA) have been primarily focused on new approach methodologies (NAMs) and physiologically based kinetic (PBK) modelling without incorporating human biomonitoring (HBM). The integration of toxicokinetics (TK) and PBK modelling is an essential component of NGRA. PBK models are essential for describing in quantitative terms the TK processes with a focus on the effective dose at the expected target site. Furthermore, the need for PBK models is amplified by the increasing scientific and regulatory interest in aggregate and cumulative exposure as well as interactions of chemicals in mixtures. Since incorporating HBM data strengthens approaches and reduces uncertainties in risk assessment, here we elaborate on the integrated use of TK, PBK modelling and HBM in chemical risk assessment highlighting opportunities as well as challenges and limitations. Examples are provided where HBM and TK/PBK modelling can be used in both exposure assessment and hazard characterization shifting from external exposure and animal dose/response assays to animal-free, internal exposure-based NGRA.

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project.

In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.

Dietary intake of acrylamide in the Norwegian EuroMix biomonitoring study: Comparing probabilistic dietary estimates with haemoglobin adduct measurements.

Acrylamide is a probable human carcinogen with widespread exposure via food. The present study compared acrylamide intake measurements obtained from haemoglobin adduct levels and self-registered dietary consumption data in a group of 144 Norwegian healthy adults. Acrylamide adducts to N-terminal valine in haemoglobin were measured and used to estimate the intake via the internal dose approach which showed a median (interquartile range) of 0.24 (0.19-0.30) µg/kg bw/day. Data from weighed food records and food frequency questionnaires from the same individuals were used for probabilistic modelling of the intake of acrylamide. The median acrylamide intake was calculated to be 0.26 (0.16-0.39) and 0.30 (0.23-0.39) µg/kg bw/day, respectively from the two sources of self-registered dietary consumption data. Overall, a relatively good agreement was observed between the methods in pairwise comparison in Bland-Altman plots, with the methods disagreeing with 7% or less of the values. The intake estimates obtained with the two dietary consumption methods and one biomarker method are in line with earlier dietary estimates in the Norwegian population. The Margin of Exposure indicate a possible health risk concern from dietary acrylamide. This is the first study with a comparison in the same individuals of acrylamide intake estimates obtained with these methods.

Suspected gut barrier disruptors and development of food allergy: Adjuvant effects and early immune responses.

Food allergy is an increasing public health challenge worldwide. It has recently been hypothesized that the increase in exposure to intestinal epithelial barrier-damaging biological and chemical agents contribute to this development. In animal models, exposure to adjuvants with a food allergen has been shown to promote sensitization and development of food allergy, and barrier disrupting capacities have been suggested to be one mechanism of adjuvant action. Here, we investigated how gut barrier disrupting compounds affected food allergy development in a mouse model of peanut allergy. Sensitization and clinical peanut allergy in C3H/HEOuJ mice were assessed after repeated oral exposure to peanut extract together with cholera toxin (CT; positive control), the mycotoxin deoxynivalenol (DON), house dust mite (HDM) or the pesticide glyphosate (GLY). In addition, we investigated early effects 4 to 48 h after a single exposure to the compounds by assessing markers of intestinal barrier permeability, alarmin production, intestinal epithelial responses, and local immune responses. CT and DON exerted adjuvant effects on peanut allergy development assessed as clinical anaphylaxis in mice. Early markers were affected only by DON, observed as increased IL-33 (interleukin 33) and thymic stromal lymphopoietin (TSLP) alarmin production in intestines and IL-33 receptor ST2 in serum. DON also induced an inflammatory immune response in lymph node cells stimulated with lipopolysaccharide (LPS). HDM and GLY did not clearly promote clinical food allergy and affected few of the early markers at the doses tested. In conclusion, oral exposure to CT and DON promoted development of clinical anaphylaxis in the peanut allergy mouse model. DON, but not CT, affected the early markers measured in this study, indicating that DON and CT have different modes of action at the early stages of peanut sensitization.

Lipoprotein profiles associated with exposure to poly- and perfluoroalkyl substances (PFASs) in the EuroMix human biomonitoring study.

Exposure to per- and polyfluoroalkyl substances (PFASs) is associated with increased blood cholesterol. Although elevated cholesterol is a well-established risk factor for cardiovascular diseases (CVD), it is not clear whether PFASs affect this risk. Lipoprotein subclasses are emerging biomarkers for disease risk and lipoprotein profiling may provide an insight to physiological implications of PFAS exposure. We explored the association between serum PFAS concentrations and lipoprotein subclasses in a cross-sectional study. We determined the concentrations and lipid composition of the major subclasses of lipoproteins in plasma samples from 127 adult participants of the EuroMix human biomonitoring study by nuclear magnetic resonance (NMR). Serum concentrations of 17 PFASs showed a detection frequency between 30 and 100% and were included in further analyses. We examined the associations between PFAS concentrations and lipoprotein subclasses by linear mixed-effect regression models, adjusted for confounders. In the adjusted models, positive associations were found between several PFASs and cholesterol concentrations in large to medium sized HDL and medium sized LDL particles. We found a 4-12% increase in HDL cholesterol per interquartile range (IQR) increase for several PFASs. In women the associations with PFNA, PFUnDA, PFDoDA and PFOS were significant after adjustment for multiple comparisons. Similar magnitude of change was observed between longer chained PFASs and LDL cholesterol, and a few of these associations reached significance for cholesterol in large to medium LDL particle sizes in women. No significant associations with plasma triglycerides were observed. However, most PFASs tended to be associated with reduction in VLDL (very low-density lipoproteins) particle number and VLDL triglyceride. Findings from this exploratory study, suggest that background PFAS exposures influence particle size distributions and lipid composition of plasma lipoprotein subclasses, and that these effects may be more prominent in women. A two-points lipoprofiling for all subjects indicated both low intra-individual variability and good analytical reproducibility.

Diurnal Variation in Biomarkers of Exposure to Endocrine-Disrupting Chemicals and Their Association with Oxidative Damage in Norwegian Adults: The EuroMix Study.

Much evidence on the adverse health effects of endocrine-disrupting chemicals (EDCs) has accumulated during recent decades. EDCs are commonly found in various foods and personal care products (PCP). Data documenting a diurnally varying EDC metabolism in humans is scarce. This study examined (i) the time-of-day effect on the diurnal magnitude and variance of urinary biomarkers of exposure to EDCs, and (ii) the association between EDC exposures and oxidative damage in a Norwegian adult subpopulation. This was a cross-sectional panel study using biobanked samples from the EuroMix project. During a typical weekday, participants were asked to collect all day's urine voids and record dietary and PCP habitual uses in a diary. Collected time stamps of urine voids were classified into three distinct periods in the day (morning 6 a.m.−12 p.m., mid-day 12 p.m.−6 p.m., evening 6 p.m.−6 a.m.). Questionnaires regarding demographic characteristics, personal care product usage, and dietary habits were completed. Urinary levels of EDCs (phthalates, parabens, and bisphenols) were measured using mass spectrometry and adjusted for urinary volume using specific gravity. Urinary 4-hydroxynonenal (4HNE), a lipid peroxidation marker, was measured using an immunoassay kit. Linear mixed-effect models identified EDCs under the influence of a diurnal variation effect that was adjusted for dietary habits and PCP use and examined associations between EDC and 4HNE. p-values were FDR-adjusted. Most phthalates appeared to be diurnally varying with higher urinary levels towards the evening (q < 0.001) than those measured during mid-day; this strong diurnal variation effect was not present for parabens and bisphenols. Significant (q < 0.001) positive associations were observed between all phthalates, parabens, and bisphenols (except bisphenol S) and 4HNE. This study's findings highlighted the diurnal variation of excretion for certain EDC, but not for others, in real-life conditions. The degree of EDC chronotoxicity in distinct diurnal windows of the day warrants further investigation with longitudinal human studies.