Comprehensive metabolic profiling of dioxin-like compounds exposure in laying hens: Implications for toxicity assessment.

The evaluation of toxicity related to polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) is crucial for a comprehensive risk assessment in real-world exposure scenarios. This study employed a controlled feeding experiment to investigate the metabolic effects of dioxin-like compounds (DLCs) on laying hens via feed exposure. Diets enriched with two concentrations (1.17 and 5.13 pg toxic equivalents (TEQ)/g dry weight (dw)) were administered over 14 days, followed by 28 days of clean feed. Metabolomics analyses of blood samples revealed significant metabolic variations between PCDD/Fs and DL-PCBs exposed groups and controls, reflecting the induced metabolic disruption. Distinct changes were observed in sphingosine, palmitoleic acid, linoleate, linolenic acid, taurocholic acid, indole acrylic acid, and dibutyl phthalate levels, implying possible connections between PCDD/Fs and DL-PCBs toxic effects and energy-neuronal imbalances, along with lipid accumulation and anomalous amino acid metabolism, impacting taurine metabolism. Moreover, we identified three differential endogenous metabolites-L-tryptophan, indole-3-acetaldehyde, and indole acrylic acid-as potential ligands for the aryl hydrocarbon receptor (AhR), suggesting their role in mediating PCDD/Fs and DL-PCBs toxicity. This comprehensive investigation provides novel insights into the metabolic alterations induced by PCDD/Fs and DL-PCBs in laying hens, thereby enhancing our ability to assess risks associated with their exposure in human populations.

Levels of PCDD/Fs, PCBs, metals and rare earth elements in eggs and vegetables from areas with different environmental contamination impacts in the Campania region (Southern Italy).

Studying the links between environmental pollution and the levels of contamination in food is an important challenge to ensure human health. Matched samples of eggs from free-range hens and vegetables were analysed to investigate the bioaccumulation of PCDD/Fs, PCBs, metals and rare earth elements. Only two egg samples resulted above the limit fixed for PCDD/Fs and the action level set for DL-PCBs. The highest concentrations were found in the eggs from an area situated in a big city affected by strong urbanisation. Although eggs and vegetables were subjected to the same environmental pollution, the PCDD/F and PCB bioaccumulation that occurred in the eggs was much higher than those in vegetables (p < 0.01). In vegetables, the highest PCDD/F and PCB concentrations were found in lettuce and potatoes grown on contaminated soil. Higher bioaccumulation of Fe and Zn occurred in eggs compared to vegetables; La, Pr, Nd, Sm and Eu were found only in lettuce samples. The results of this study may provide important data useful in the risk assessment of human exposure through diet in accidents involving dangerous chemicals. Furthermore, the estimated weekly intakes calculated for PCDD/Fs and PCBs highlighted that, although vegetables accumulate very low concentrations of these contaminants, they contribute more than eggs to human exposure.

Temporal variations in airborne PCDD/F and dl-PCB concentrations surrounding the dioxin-remediated areas in Da Nang, Vietnam, and health risk assessments.

The air pollution levels from polychlorodibenzo-p-dioxins/polychlorodibenzofurans (PCDD/Fs) and dioxin-like polychlorobiphenyls (dl-PCBs) in three residential areas located north, west, and south of the Da Nang airport were determined by using passive air samplers containing polyurethane foam (PUF) discs with 3-month sampling intervals from 2017 to 2020. The total toxic equivalents (∑TEQs) of the PCDD/Fs and dl-PCBs, using WHO2005-TEFs, were highest north of the airport (134 to 10610 fg WHO-TEQ/PUF day, with an average of 1108 fg WHO-TEQ/PUF day). The ∑TEQs were lower west of the airport, between 159 and 381 fg WHO-TEQ/PUF day and averaged 230 fg WHO-TEQ/PUF day. The lowest ∑TEQs occurred south of the airport, with ranges of 76 and 331 fg WHO-TEQ/PUF day and an average of 152 fg WHO-TEQ/PUF day. Construction activities, including excavation and transportation of dioxin-contaminated soil north of the airport, have increased airborne PCDD/F and dl-PCB contamination and health risks. The average daily doses of PCDD/Fs and dl-PCBs through inhalation (ADDA) for residents located north of the airport were the highest (10.9 to 3434 fg WHO-TEQ/kg BW/day and average: 597 fg WHO-TEQ/kg BW/day). Residents located west of the airport faced lower health risks (13-123 fg WHO-TEQ/kg BW/day and average: 39 fg WHO-TEQ/kg BW/day). Residents south of the airport were exposed to a minimum of 6.2-107 fg WHO-TEQ/kg BW/day, with an average of 28 fg WHO-TEQ/kg BW/day. The maximum and average ADDA values for residents north of the airport exceeded 10% of the tolerable daily intake (TDI) recommended by the WHO (100-400 fg WHO-TEQ/kg BW/day). In comparison, all the ADDA values for residents located west and south of the airport were less than and within 10% of the TDI.

Temporal trends (1972-2017) and spatial differences of persistent halogenated aromatic hydrocarbons in osprey eggs in Finland.

Time trends and regional differences of polychlorinated dibenzo-p-dioxins and -furans (PCDD/Fs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), DDTs, polybrominated biphenyls (PBBs) and polybrominated diphenylethers (BDEs) were studied in unhatched osprey eggs collected by bird ringers in 1972-2017 from four areas in Finland. Two study areas were from Baltic Sea, Northern Quark and Finnish Archipelago Sea, while the two others were inland lake areas, eutrophicated Lake Vanajanselkä affected by industrial emissions, and Pristine SW Lake Area. The highest concentrations of most compound groups were in Lake Vanajanselkä consistent with high emissions, the predominance of bream as a prey, and higher concentrations in bream compared to other prey fish. Concentrations of all chlorinated compounds decreased significantly in all study areas. Average annual decreases were ∑PCDD/F 2.3-4.9%, ∑PCB 2.2-4.2%, ∑PCN 2.6-7.0% and ∑DDT 7.1-9.5%, primarily in line with decreased levels in prey fish. From 1972 PBBs and BDEs increased significantly until 1990s declining rapidly thereafter. PCDD/F congener profile was dominated by 2,3,4,7,8-PeCDF, except in Lake Vanajanselkä by 1,2,3,6,7,8-HxCDD. PCB congener profile was dominated by PCB 153 in all study areas, followed by PCB 180 and PCB 138. Among dioxin-like compounds PCBs contributed 82%, PCDDs 14% and PCDFs 4% to toxic equivalent quantity (∑TEQ). PCB 126 contributed most to ∑TEQ, followed by 1,2,3,7,8-PeCDD. BDE 47 being the dominant BDE congener, followed by BDE 100. ∑DDT concentrations were relatively similar across all study areas, with DDE contributing about 90%. Productivity of chicks per active nest was significantly decreased in Lake Vanajanselkä, and the likely explanation is embryotoxicity of dioxin-like compounds. It is plausible that dioxin-like compounds influenced embryonic survival among highly exposed ospreys prior to 2010, especially in Lake Vanajanselkä and Northern Quark. However, decreased survival due to DDE-induced eggshell thinning seems unlikely after 1985, and BDE levels were below those potentially causing adverse effects.

Temporal, spatial, and seasonal variations in airborne PCDD/F and dl-PCB concentrations around Bien Hoa hot spot, Vietnam, and health risk assessments.

Passive air samplers were used to monitor polychlorodibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorobiphenyls (dl-PCBs) between 2020 and 2022 in four residential areas around Bien Hoa hot spot (BHS) including Trung Dung (TD), Tan Phong (TP), Quang Vinh (QV), and Buu Long (BL). The total toxic equivalents of PCDD/Fs and dl-PCBs (∑TEQs) were highest in the TD area, from 284 to 642 fg TEQ/PUF day. Next was the QV area, where ∑TEQs ranged from 229 to 569 fg TEQ/PUF day. Then, ∑TEQs varied from 205 to 503 fg TEQ/PUF day in the TP area. The lowest ∑TEQs were between 179 and 385 fg TEQ/PUF day in the BL area. The temporal, spatial, and seasonal variations in concentrations of PCDD/Fs and dl-PCBs were related to the prevailing wind direction and the distance from each area to the dioxin hot spot. The average ∑TEQs for all four areas surrounding BHS in the dry season (423 fg TEQ/PUF day) were 1.4 times higher than in the rainy season (303 fg TEQ/PUF day). Health risk assessments from airborne dioxin exposure were estimated using the average daily doses through inhalation (ADDI). The ADDI for residents surrounding BHS ranged from 14.6 to 208 fg TEQ/kg BW/day. The ADDI values by areas were as follows: 23.2-208 fg TEQ/kg BW/day in the TD, 18.7-184 fg TEQ/kg BW/day in the QV, 16.7-163 fg TEQ/kg BW/day in the TP, and 14.6-125 fg TEQ/kg BW/day in the BL. These ADDI values remained within and below the 10% threshold of the WHO-recommended tolerable daily intake (100-400 fg TEQ/kg BW/day). It is necessary to control the excavation activities inside the BHS and cover the temporary storage sites of dioxin-contaminated materials to minimize the emissions of PCDD/Fs and dl-PCB into the ambient air.

Predictive toxicology of chemical mixtures using proteome-wide thermal profiling and protein target properties.

Our capability to predict the impact of exposure to chemical mixtures on environmental and human health is limited in comparison to the advances on the chemical characterization of the exposome. Current approaches, such as new approach methodologies, rely on the characterization of the chemicals and the available toxicological knowledge of individual compounds. In this study, we show a new methodological approach for the assessment of chemical mixtures based on a proteome-wide identification of the protein targets and revealing the relevance of new targets based on their role in the cellular function. We applied a proteome integral solubility alteration assay to identify 24 protein targets from a chemical mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin, alpha-endosulfan, and bisphenol A among the HepG2 soluble proteome, and validated the chemical mixture-target interaction orthogonally. To define the range of interactive capability of the new targets, the data from intrinsic properties of the targets were retrieved. Introducing the target properties as criteria for a multi-criteria decision-making analysis called the analytical hierarchy process, the prioritization of targets was based on their involvement in multiple pathways. This methodological approach that we present here opens a more realistic and achievable scenario to address the impact of complex and uncharacterized chemical mixtures in biological systems.

In Silico Exploration of AHR-HIF Pathway Interplay: Implications for Therapeutic Targeting in ccRCC.

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel-Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1ß, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein-protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions.

Modulation of Ceramide-Induced Apoptosis in Enteric Neurons by Aryl Hydrocarbon Receptor Signaling: Unveiling a New Pathway beyond ER Stress.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant and a potent aryl hydrocarbon receptor (AHR) ligand, causes delayed intestinal motility and affects the survival of enteric neurons. In this study, we investigated the specific signaling pathways and molecular targets involved in TCDD-induced enteric neurotoxicity. Immortalized fetal enteric neuronal (IM-FEN) cells treated with 10 nM TCDD exhibited cytotoxicity and caspase 3/7 activation, indicating apoptosis. Increased cleaved caspase-3 expression with TCDD treatment, as assessed by immunostaining in enteric neuronal cells isolated from WT mice but not in neural crest cell-specific Ahr deletion mutant mice (Wnt1Cre+/-/Ahrb(fl/fl)), emphasized the pivotal role of AHR in this process. Importantly, the apoptosis in IM-FEN cells treated with TCDD was mediated through a ceramide-dependent pathway, independent of endoplasmic reticulum stress, as evidenced by increased ceramide synthesis and the reversal of cytotoxic effects with myriocin, a potent inhibitor of ceramide biosynthesis. We identified Sptlc2 and Smpd2 as potential gene targets of AHR in ceramide regulation by a chromatin immunoprecipitation (ChIP) assay in IM-FEN cells. Additionally, TCDD downregulated phosphorylated Akt and phosphorylated Ser9-GSK-3ß levels, implicating the PI3 kinase/AKT pathway in TCDD-induced neurotoxicity. Overall, this study provides important insights into the mechanisms underlying TCDD-induced enteric neurotoxicity and identifies potential targets for the development of therapeutic interventions.

Cell-specific AHR-driven differential gene expression in the mouse liver cell following acute TCDD exposure.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that disrupts hepatic function leading to steatotic liver disease (SLD)-like pathologies, such as steatosis, steatohepatitis, and fibrosis. These effects are mediated by the aryl hydrocarbon receptor following changes in gene expression. Although diverse cell types are involved, initial cell-specific changes in gene expression have not been reported. In this study, differential gene expression in hepatic cell types was examined in male C57BL/6 mice gavaged with 30 µg/kg of TCDD using single-nuclei RNA-sequencing. Ten liver cell types were identified with the proportions of most cell types remaining unchanged, except for neutrophils which increased at 72 h. Gene expression suggests TCDD induced genes related to oxidative stress in hepatocytes as early as 2 h. Lipid homeostasis was disrupted in hepatocytes, macrophages, B cells, and T cells, characterized by the induction of genes associated with lipid transport, steroid hormone biosynthesis, and the suppression of ß-oxidation, while linoleic acid metabolism was altered in hepatic stellate cells (HSCs), B cells, portal fibroblasts, and plasmacytoid dendritic cells. Pro-fibrogenic processes were also enriched, including the induction retinol metabolism genes in HSCs and the early induction of anti-fibrolysis genes in hepatocytes, endothelial cells, HSCs, and macrophages. Hepatocytes also had gene expression changes consistent with hepatocellular carcinoma. Collectively, these findings underscore the effects of TCDD in initiating SLD-like phenotypes and identified cell-specific gene expression changes related to oxidative stress, steatosis, fibrosis, cell proliferation and the development of HCC.

A Natural Chalcone Cardamonin Inhibited Transformation of Aryl Hydrocarbon Receptor Through Binding to the Receptor Competitively.

SCOPE: Chalcones are widely present in most plants and have various health beneficial functions. This study investigates the suppressive effect of 13 natural and synthetic chalcones on transformation of aryl hydrocarbon receptor (AhR) induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC) in a cell-free system, Hepa-1c1c7 cells, and liver of ICR mice. METHODS AND RESULTS: In the cell-free system, cardamonin dose-dependently inhibits AhR transformation. Chalcones with substitution on 2' and/or 6' position is important for the suppressive effect, while the substitution on 4' position is negatively for the effect. Moreover, cardamonin and 2'-hydroxychalcone competitively inhibit the binding of [3H]-3-MC to the AhR. In Hepa-1c1c7 cells, cardamonin inhibits AhR transformation and expression of cytochrome P4501A1 (CYP1A1) in a dose-dependent manner through suppressing TCDD-induced phosphorylation of both AhR and AhR nuclear translocator, heterodimerization of them, and nuclear translocation of AhR. In the liver of mice, oral administered cardamonin also inhibits 3-MC-induced AhR translocation and expression of CYP1A1. CONCLUSION: Among used chalcones, a natural chalcone cardamonin competitively binds to AhR and suppresses its transformation. Thus, cardamonin is an effective food factor for suppression of the dioxin-caused biochemical alterations and toxicities.

Regulatory compliance of PCDD/F emissions by a municipal solid waste incinerator. A case study in Sant Adrià de Besòs, Catalonia, Spain.

Despite incineration is an important emission source of toxic pollutants, such as heavy metals and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), it is still one of the most widely used methods for the management of municipal solid waste. The current paper summarizes the results of a 20-year follow-up study of the emissions of PCDD/Fs by a municipal solid waste incinerator (MSWI) in Sant Adrià de Besòs (Catalonia, Spain). Samples of ambient air, soils and herbage were periodically collected near the facility and the content of PCDD/Fs was analyzed. In the last (2017) survey, mean levels in soil were 3.60 ng WHO-TEQ/kg (range: 0.40-10.6), being considerably higher than the mean concentrations of PCDD/Fs in soil samples collected near other MSWIs in Catalonia. Moreover, air PCDD/F concentrations were even higher than those found in a previous (2014) survey, as they increased from 0.026 to 0.044 pg WHO-TEQ/m3. Ultimately, the PCDD/F exposure would be associated to a cancer risk (2.5 × 10-6) for the population living in the surrounding area. Globally, this information indicates that the MSWI of Sant Adrià de Besòs could have had a negative impact on the environment and potentially on public health, being an example of a possible inappropriate management for years. The application of Best Available Techniques to minimize the emission of PCDD/Fs and other chemicals is critical.

Serum metabolism distribution in individuals exposed to dioxins: A case study of residents near the municipal solid waste incinerators in China.

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) have attracted considerable attention owing to their environmental persistence, bioaccumulation, and high toxicity. This study aimed to investigate changes in serum metabolites following exposure to PCDD/Fs and to reveal a novel pathogenesis of PCDD/Fs. Serum samples were collected from 75 residents living near a municipal solid waste incinerator in China to analyse the relationship between PCDD/Fs and serum metabolic components. The serum level in the low-exposure group [19.07 (13.44-23.89) pg-TEQ/L] was significantly lower than that in the high-exposure group [115.60 (52.28-592.65) pg-TEQ/L]. Non-targeted metabolomic studies based on liquid chromatography-high resolution mass spectrometry have been applied to the metabolomic analysis of serum. Thirty-seven metabolites with significant differences among the different groups were identified as biomarkers. Pathway analysis revealed that high dioxin exposure perturbed various biological processes, including glycerol phospholipid metabolism and the interconversion of pentose and glucuronate. The results of a population health survey showed that the serum dioxin concentration in patients with diabetes was significantly higher than that in the control population. These findings suggest that dioxin exposure is associated with several potential adverse health risks, including inflammation, diabetes, and cardiovascular disease, through metabolic changes.

Statistical comparison for assessing agreement between two mass spectrometric methods for the analysis of polychlorinated dibenzo-p-dioxins and furans (PCDDs/Fs) in contaminated soils.

A gas chromatography coupled to high-resolution mass spectrometry (GC-HR/MS) has been used as the standard method for the quantification of polychlorinated dibenzo-p-dioxins and furans (PCDDs/Fs), which are regulated at screening and action levels in the environment. However, several alternative methods have been attempted due to the disadvantage of its high cost. Although a gas chromatography with triple quadrupole mass spectrometry (GC-QqQ-MS/MS) has been used in a wide variety of sample matrices, showing that they are interchangeable, there has been a lack of comprehensive studies on statistical agreement with GC-HR/MS. In this study, a pairwise comparison of the total concentrations of PCDDs/Fs in 90 soil field samples obtained by two mass spectrometric methods was performed using the Passing-Bablok (P&B) regression and Bland-Altman (B&A) analysis for the method comparison. According to the result of the B&A analysis, the concentration range of PCDDs/Fs was between 98.2 and 1760 pg/g showed good agreement between two methods at the 95 % confidence level (CL). Although there was a large discrepancy between the two methods in the low concentrations (<16.5 pg/g of PCDDs/Fs), this result was similar to the P&B regression analysis. As the verification results by B&A and P&B regression analysis, the interchangeable concentration range between the two methods was confirmed to be adequate for the monitoring of PCDDs/Fs regulating levels in soils.

Urban air PCDD/Fs: Dry deposition fluxes and mass transfer coefficients determined using a water surface sampler.

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) cause significant environmental concerns. Atmospheric PCDD/Fs permeate water bodies and other ecosystems through wet and dry deposition. In an urban site, dry deposition flux samples of gaseous phase PCDD/Fs were collected by a water surface sampler (WSS) operated between June 2022 and June 2023. There is a conspicuous absence of literature on the direct measurement of dry deposition flux levels in the gaseous phase of PCDD/Fs. In the study, PCDD/Fs in the gas phase reaching the WSS dissolved in the water according to Henry's Law. The PCDD/Fs in the water were transferred to an XAD-2 resin column, sorbing the dissolved PCDD/Fs. The average monthly gas phase dry deposition flux was 34.07 ± 9.35 pg/m2-day (7.35 ± 2.16 pg I-TEQ/m2-day). The highest flux was measured in March (49.53 pg/m2-day), and the lowest was in August (18.64 pg/m2-day). These values indicated the direct flux from air to water. The atmospheric concentration of the gas-phase ranged from 68.38 to 126.88 fg/m3 (13.22-25.01 fg I-TEQ/m3). Dry deposition fluxes and concentrations of atmospheric PCDD/Fs were bigger in the colder months than in the warmer months. This was probably due to a significant increase in residential heating during the colder months, decreased photochemical reactions, and lower mixing heights. Regarding congeners in the dry deposition flux and concentration values in I-TEQ units, 2,3,7,8-TCDD compound predominated with the proportions of 31.61 ± 7.76% and 29.09 ± 12.34%, respectively. Concurrently measured dry deposition flux (Fg) and ambient air concentration (Cg) of PCDD/Fs were considered in the determination of mass transfer coefficient (MTC = Fg/Cg) calculation for each PCDD/F congener. The average MTC for targeted 17 PCDD/Fs was 0.45 ± 0.15 cm/s, and it fluctuated between 0.89 ± 0.30 cm/s for 2,3,7,8-TCDF and 0.2 ± 0.16 cm/s for OCDD.

Mortality and cancer incidence in a population exposed to TCDD after the Seveso, Italy, accident (1976-2013).

OBJECTIVES: The Seveso accident (1976) caused the contamination with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in an area north of Milan, Italy. We report the results of the update of mortality and cancer incidence in the exposed population through 2013. METHODS: The study cohort includes subjects living in three contaminated zones with decreasing TCDD soil concentrations (zone A, B and R) and in a surrounding uncontaminated territory (reference). Poisson models stratified/adjusted for gender, age and period were fitted to calculate rate ratios (RRs) and 95% CIs. RESULTS: In zone A in males, we found elevated mortality from circulatory diseases in the first decade after the accident (17 deaths, RR 2.00, 95% CI 1.24 to 3.23). In females, mortality from diabetes mellitus was increased, with a positive trend across zones. Incidence of soft tissue sarcoma was increased in males in zone R in the first decade (6 cases, RR 2.62, 95% CI 1.01 to 6.83). In females in zone B, there was an excess of non-Hodgkin's lymphoma after 30 years (6 cases, RR 2.87, 95% CI 1.14 to 7.23). Multiple myeloma was increased in the second decade in females in zone B (4 cases, RR 5.09, 95% CI 1.82 to 14.2) and in males in zone R (11 cases, RR 2.15, 95% CI 1.08 to 4.26). In males in zone R, there was a leukaemia excess after 30 years (23 cases, RR 2.02, 95% CI 1.04 to 3.93). CONCLUSIONS: Although with different patterns across gender, zone and time, we confirmed previous results of increased cardiovascular diseases, diabetes, soft tissue sarcoma, and lymphatic and haematopoietic cancers.

Timing influences the impact of aryl hydrocarbon receptor activation on the humoral immune response to respiratory viral infection.

Humoral responses to respiratory viruses, such as influenza viruses, develop over time and are central to protection from repeated infection with the same or similar viruses. Epidemiological and experimental studies have linked exposures to environmental contaminants that bind the aryl hydrocarbon receptor (AHR) with modulated antibody responses to pathogenic microorganisms and common vaccinations. Other studies have prompted investigation into the potential therapeutic applications of compounds that activate AHR. Herein, using two different AHR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE), to modulate the duration of AHR activity, we show that the humoral response to viral infection is dependent upon the duration and timing of AHR signaling, and that different cellular elements of the response have different sensitivities. When AHR activation was initiated prior to infection with influenza A virus, there was suppression of all measured elements of the humoral response (i.e., the frequency of T follicular helper cells, germinal center B cells, plasma cells, and circulating virus-specific antibody). However, when the timing of AHR activation was adjusted to either early (days -1 to +5 relative to infection) or later (days +5 onwards), then AHR activation affected different aspects of the overall humoral response. These findings highlight the importance of considering the timing of AHR activation in relation to triggering an immune response, particularly when targeting the AHR to manipulate disease processes.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) prediction model based on limited peat samples using an evolved artificial neural network.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) are involuntary by-products of incomplete combustion and are highly toxic to humans and the environment. The Malaysian peat is often acidic or extremely acidic having high levels of chlorine and/or other organic acids that act as catalysts or precursors in PCDD/Fs formation. This study aims to predict PCDD/Fs emissions in peat soil using an artificial neural network (ANN) approach based on limited emission data and selected physico-chemical properties. The ANN's prediction performance is affected by uncertainties in its initial connection weights. To improve prediction performance, an optimisation algorithm, termed differential evolution (DE), is used to optimise the ANN's initial connection weights and bias. The study adopts several ANNs with fixed architecture to predict PCDD/Fs emissions, each consisting of a multilayer perceptron (MLP) with a backpropagation algorithm. Eight input variables and one output variable were adopted to train and test various neural network architectures using real-world datasets. The model optimisation procedure was conducted to ascertain the network architecture with the best predictive accuracy. The evolved ANN based on 5 hidden neurons, with the assistance of self-adaptive ensemble-based differential evolution with enhanced population sizing (SAEDE-EP), successfully produced the lowest MSEtest (6.1790 × 10-3) and highest R2 (0.97447) based on the mean among the other HNs. An evolutionary-optimised ANN-based methodology is a viable solution to predict PCDD/Fs in peat soil. It is cost-effective for pollution control, environmental monitoring and capable of aiding authorities prevent PCDD/Fs exposure, e.g., during a fire.

Atmospheric concentrations and potential sources of dioxin-like contaminants to Acadia National Park.

Acadia National Park (ANP) is located on Mt. Desert Island, ME on the U.S. Atlantic coast. ANP is routinely a top-ten most popular National Park with over four million visits in 2022. The overall contribution and negative effects of long-range atmospheric transport and local sources of dioxin-like contaminants endangering natural and wildlife resources is unknown. Dioxin-like (DL) contaminants polychlorinated dibenzo-p-dioxins (∑PCDD) and polychlorinated dibenzofurans (∑PCDF), non-ortho coplanar PCBs (∑CP4), and polychlorinated naphthalenes (∑PCNs) were measured at the McFarland Hill air monitoring station (44.37°N, 68.26°W). On a mass/volume basis, total PCNs averaged 90.9 % (788 fg/m3) of DL contaminants measured annually, with 92.9 % of the collected total in the vapor-phase. Alternatively, total dioxin/furans (∑PCDD/Fs) represented 71.6 % of the total toxic equivalence (∑TEQ) (1.018 fg-TEQ/m3), with 69.7 % in the particulate-phase. Maximum concentrations measured for individual sampling events for ∑PCDD/F, ∑CP4, and ∑PCN were 159 (winter), 139 (summer), and 2100 (autumn), fg/m3 respectively. Whereas the maximum ∑TEQ concentrations for individual sampling events for ∑PCDD/F, ∑CP4, and ∑PCN were 2.8 (autumn), 0.38 (summer), and 0.71 (autumn), fg-TEQ/m3 respectively. Pearson correlations were calculated for ∑PCDD/Fs and ∑PCN particulate/vapor-phase air concentrations and PM2.5 wood smoke "indicator" species. The most significant correlations were observed in autumn for particulate-phase ∑PCDD/Fs suggesting a relationship between visitation-generated combustion sources (campfires and/or waste burning) or climate-change mediated forest fires. Significant Clausius-Clapeyron (C-C) correlations observed for particulate-phase ∑PCDDs (r2 = 0.567) as ambient temperatures decreased suggests a connection between localized domestic heating sources or visitor-based burning of wood/trash resources. Alternatively, highly significant C-C vapor-phase ∑CP4-PCBs correlations (r2 = 0.815) implies that the majority of ∑CP4-PCB loading to ANP is from long-range atmospheric transport processes. Based on these findings, Acadia National Park should be classified as a remote site with minor depositional impacts from ∑PCDD/Fs, ∑CP4-PCBs, and ∑PCN atmospheric transport or local diffuse sources.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype.

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD.

Accumulation Rate, Depuration Kinetics, and Tissue Distribution of Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans (PCDD/Fs) in Suckler Ewes (Ovis aries).

Understanding the transfer of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in farm animals is essential for ensuring food safety, but such information for suckler ewes (Ovis aries) has been lacking. This work quantifies the accumulation, tissue distribution, and depuration kinetics of PCDD/Fs in these animals. Six suckler ewes (EXP group) were exposed to PCDD/Fs through contaminated hay (2.3-12.7 ng toxic-equivalent kg-1 dry matter) and then allowed to depurate by switching to noncontaminated hay from 29 days of lactation. Four control ewes were fed continuously with noncontaminated hay. At different time points covering depuration, weaning and slaughter, PCDD/F analysis of milk (three time points), blood and sternal adipose tissue (five time points), Longissimus thoracis muscle, liver, and empty body homogenate at slaughter (188 days of depuration) was performed. A relevant PCDD/F bioaccumulation was observed from oral intake in milk and adipose tissue (biotransfer factors of 1.24 and 1.06 day kg-1 lipids for the sum toxic-equivalent, respectively) in the EXP ewes, especially for penta- and hexa-chlorinated congeners. The EXP ewes' adipose tissue started at 10-fold the EU maximum level (ML) and showed depuration below the ML after 130 days. Specific PCDD/F accumulation in the ewe liver was observed, especially for dibenzofurans. These toxicokinetic data can inform recommendations to ensure the chemical safety of sheep food products.