Serum concentration of polychlorinated biphenyls and the risk of type 2 diabetes: a 10-year follow-up historical cohort study.

This study investigated the association between serum concentrations of Polychlorinated Biphenyls (PCBs) and the risk of type 2 diabetes within the general population. A ten-year follow-up historical cohort study was conducted during 2009-2019 as part of the Bushehr MONICA cohort study in Iran. Of 893 non-diabetes participants at base line, 181 individuals were included in the study. The concentration of nine PCB congeners was measured in individuals' serum samples at baseline, and the risk of type 2 diabetes was determined based on fasting blood sugar at the end of follow-up. Multiple logistic regression models were used to assess the study outcomes after adjusting for covariates. This study included 59 diabetes individuals (32.6%; mean [SD] age: 58.64 [8.05]) and 122 non-diabetes individuals (67.4%; mean [SD] age: 52.75 [8.68]). Multivariable analysis revealed that a one-tertile increase (increasing from 33rd centile to 67th centile) in Σ non-dioxin-like-PCBs (OR 2.749, 95% CI 1.066-7.089), Σ dioxin-like-PCBs (OR 4.842, 95% CI 1.911-12.269), and Σ PCBs (OR 2.887, 95% CI 1.120-7.441) significantly associated with an increased risk of type 2 diabetes. The strongest association was obtained for dioxin-like PCBs. The results highlight a significant correlation between PCB exposure and an increased risk of type 2 diabetes. The evidence suggests that additional epidemiological studies are necessary to clarify the link between PCBs and diabetes.

In Silico and In Vitro multiple analysis approach for screening naturally derived ligands for red seabream aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AHR) is a key ligand-dependent transcription factor that mediates the toxic effects of compounds such as dioxin. Recently, natural ligands of AHR, including flavonoids, have been attracting physiological and toxicological attention as they have been reported to regulate major biological functions such as inflammation and anti-cancer by reducing the toxic effects of dioxin. Additionally, it is known that natural AHR ligands can accumulate in wildlife tissues, such as fish. However, studies in fish have investigated only a few ligands in experimental fish species, and the AHR response of marine fish to natural AHR ligands of various other structures has not been thoroughly investigated. To explore various natural AHR ligands in marine fish, which make up the most fish, it is necessary to develop new screening methods that consider the specificity of marine fish. In this study, we investigated the response of natural ligands by constructing in vitro and in silico experimental systems using red seabream as a model species. We attempted to develop a new predictive model to screen potential ligands that can induce transcriptional activation of red seabream AHR1 and AHR2 (rsAHR1 and rsAHR2). This was achieved through multiple analyses using in silico/ in vitro data and Tox21 big data. First, we constructed an in vitro reporter gene assay of rsAHR1 and rsAHR2 and measured the response of 10 representatives natural AHR ligands in COS-7 cells. The results showed that FICZ, Genistein, Daidzein, I3C, DIM, Quercetin and Baicalin induced the transcriptional activity of rsAHR1 and rsAHR2, while Resveratrol and Retinol did not induce the transcriptional activity of rsAHR isoforms. Comparing the EC50 values of the respective compounds in rsAHR1 and rsAHR2, FICZ, Genistein, and Daidzein exhibited similar isoform responses, but I3C, Baicalin, DIM and Quercetin show the isoform-specific responses. These results suggest that natural AHR ligands have specific profiling and transcriptional activity for each rsAHR isoform. In silico analysis, we constructed homology models of the ligand binding domains (LBDs) of rsAHR1 and rsAHR2 and calculated the docking energies (U_dock values) of natural ligands with measured in vitro transcriptional activity and dioxins reported in previous studies. The results showed a significant correlation (R2=0.74(rsAHR1), R2=0.83(rsAHR2)) between docking energy and transcriptional activity (EC50) value, suggesting that the homology model of rsAHR1 and rsAHR2 can be utilized to predict the potential transactivation of ligands. To broaden the applicability of the homology model to diverse compound structures and validate the correlation with transcriptional activity, we conducted additional analyses utilizing Tox21 big data. We calculated the docking energy values for 1860 chemicals in both rsAHR1 and rsAHR2, which were tested for transcriptional activation in Tox21 data against human AHR. By comparing the U_dock energy values between 775 active compounds and 1085 inactive compounds, a significant difference (p<0.001) was observed between the U_dock energy values in the two groups, suggesting that the U_dock value can be applied to distinguish the activation of compounds. Furthermore, we observed a significant correlation (R2=0.45) between the AC50 of Tox21 database and U_dock values of human AHR model. In conclusion, we calculated equations to translate the results of an in silico prediction model for ligand screening of rsAHR1 and rsAHR2 transactivation. This ligand screening model can be a powerful tool to quantitatively estimate AHR transactivation of major marine agents to which red seabream may be exposed. The study introduces a new screening approach for potential natural AHR ligands in marine fish, based on homology model-docking energy values of rsAHR1 and rsAHR2, with implications for future agonist development and applications bridging in silico and in vitro data.

Level of polychlorinated biphenyls in tumor and blood serum of breast cancer patients and control subjects from Punjab, Pakistan.

The current study examined the level of Polychlorinated biphenyls (PCBs) in tumor and blood serum of female breast cancer patients and control individuals recruited from Punjab, Pakistan. Breast tumor and blood serum from 40 patients and only blood serum from ten control subjects were obtained and concentration of 32 PCB congeners was analyzed through Gas chromatography coupled with Mass spectrophotometry. Sociodemographic variables of the patients along with essential clinical and haematological parameters were taken as covariates. Tumor reflects the highest median (min-max) concentration (ng g-1 lw) of Æ©PCBs at 115.94 (0.05-17.75) followed by 16.53 (0.09-2.94) and 5.24 (0.01-0.59) in blood serum of cancer patients and control group respectively. Median concentrations (ng g-1 lw) of non-dioxine like Æ©PCBs were considerably higher at 83.04, 32.89 and 4.27 compared to 13.03 and 3.50 and 0.97 for dioxin like Æ©PCBs in tumor, serum of breast cancer patients and control subjects respectively. PCB-87 was most dominant congeners in tumor followed by PCB-170 and -82 whereas PCB-28 and -52 reflected greatest contribution in serum of breast cancer patients. Blood haemoglobin, potassium and chloride ions showed significant positive whereas body mass index reflect inverse relationship when regressed with Æ©PCBs in tumor. This pioneer study depicts elevated concentrations of PCBs in patients compared to control, reflecting potential positive association of PCBs with breast cancer which need further confirmation. We concluded that chronic exposure to PCBs might be associated with an increasing number of breast cancer incidences in developing countries like Pakistan, which should be further elucidated through detail in vitro and in vivo studies.

Potential AhR-independent mechanisms of 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibition of human glioblastoma A172 cells migration.

The toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is generally believed to be mediated by aryl hydrocarbon receptor (AhR), but some evidence suggests that the effects of TCDD can also be produced through AhR-independent mechanisms. In previous experiments, we found that mainly AhR-dependent mechanism was involved in the migration inhibition of glioblastoma U87 cells by TCDD. Due to the heterogeneity of glioblastomas, not all tumor cells have significant AhR expression. The effects and mechanisms of TCDD on the migration of glioblastomas with low AhR expression are still unclear. We employed a glioblastoma cell line A172 with low AhR expression as a model, using wound healing and Transwell® assay to detect the effect of TCDD on cell migration. We found that TCDD can inhibit the migration of A172 cells without activating AhR signaling pathway. Further, after being pre-treated with AhR antagonist CH223191, the inhibition of TCDD on A172 cells migration was not changed, indicating that the effect of TCDD on A172 cells is not dependent on AhR activation. By transcriptome sequencing analysis, we propose dysregulation of the expression of certain migration-related genes, such as IL6, IL1B, CXCL8, FOS, SYK, and PTGS2 involved in cytokines, MAPK, NF-κB, and IL-17 signaling pathways, as potential AhR-independent mechanisms that mediate the inhibition of TCDD migration in A172 cells.

Health assessment of emerging persistent organic pollutants (POPs) in PM2.5 in northern and central Taiwan.

Over the last two decades, Taiwan has effectively diminished atmospheric concentrations of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) through the adept utilization of advanced technologies and the implementation of air pollution control devices. Despite this success, there exists a dearth of data regarding the levels of other PM2.5-bound organic pollutants and their associated health risks. To address this gap, our study comprehensively investigates the spatial and seasonal variations, potential sources, and health risks of PCDD/Fs, Polychlorinated biphenyls (PCBs), and Polychlorinated naphthalene (PCNs) in Northern and Central Taiwan. Sampling collections were conducted at three specific locations, including six municipal waste incinerators in Northern Taiwan, as well as a traffic and an industrial site in Central Taiwan. As a result, the highest mean values of PM2.5 (20.3-39.6 µg/m3) were observed at traffic sites, followed by industrial sites (14.4-39.3 µg/m3), and the vicinity of the municipal waste incinerator (12.4-29.4 µg/m3). Additionally, PCDD/Fs and PCBs exhibited discernible seasonal fluctuations, displaying higher concentrations in winter (7.53-11.9 and 0.09-0.12 fg I-TEQWHO/m3) and spring (7.02-13.7 and 0.11-0.16 fg I-TEQWHO/m3) compared to summer and autumn. Conversely, PCNs displayed no significant seasonal variations, with peak values observed in winter (0.05-0.10 fg I-TEQWHO/m3) and spring (0.03-0.08 fg I-TEQWHO/m3). Utilizing a Positive Matrix Factorization (PMF) model, sintering plants emerged as the predominant contributors to PCDD/Fs, constituting 77.9% of emissions. Woodchip boilers (68.3%) and municipal waste incinerators (21.0%) were identified as primary contributors to PCBs, while municipal waste incinerators (64.6%) along with a secondary copper and a copper sludge smelter (22.1%) were the principal sources of PCNs. Moreover, the study specified that individuals aged 19-70 in Northern Taiwan and those under the age of 12 years in Central Taiwan were found to have a significantly higher cancer risk, with values ranging from 9.26 x 10-9-1.12 x 10-7 and from 2.50 x 10-8-2.08 x 10-7respectively.

Presence of carbazole and polyhalogenated carbazoles in human urine.

Exposure to carbazole (CZ) and polyhalogenated carbazoles (PHCZs) may pose a threat to human health, owing to their potential dioxin-like toxicity. Until now, the presence of these chemicals in the human urine from the general population is still unclear. Human urine samples (n = 210) were taken from the general population in Quzhou, China in this study, and were analyzed for CZ and 14 PHCZs. CZ and nine PHCZs were detected in collected human urine. CZ (detection frequency 100 %), 3-chlorocarbazole (3-CCZ; 88 %), 3,6-dichlorocarbzole (36-CCZ; 84 %), and 3-bromocarbazole (3-BCZ; 80 %) were more frequently detected. Among detected PHCZs, 3-CCZ (mean 0.49 ng/mL, < LOD-4.3 ng/mL) had comparatively higher urinary levels, followed by 3-BCZ (0.30 ng/L, < LOD-1.9 ng/mL) and 36-CCZ (0.20 ng/L, < LOD-1.4 ng/mL). Urinary concentrations of CZ in male participants (1.3 ± 0.26 ng/mL) were significantly (p < 0.05) higher than that in female participants (0.92 ± 0.24 ng/mL). No obvious trend in urinary concentrations with the age of participants was found for CZ and detected PHCZs. The mean daily excretion was found highest for CZ (31 ng/kg bw/day), followed by 3-CCZ (19 ng/kg bw/day) and 3-BCZ (8.5 ng/kg bw/day). This study provides the first data, to our knowledge, on the presence and levels of CZ and PHCZs in human urine, which is necessary for conducting the human exposure risk assessment.

Prediction of Base-Catalyzed Hydrolysis Kinetics of Polychlorinated Dibenzo-p-Dioxins by Density Functional Theory Calculations.

Polychlorinated dibenzo-p-dioxins (PCDDs), comprising 75 congeners, have gained considerable attention from the general public and the scientific community owing to their high toxic potential. The base-catalyzed hydrolysis of PCDDs is crucial for the assessment of their environmental persistence. Nonetheless, owing to the substantial number of congeners and low hydrolysis rates of PCDDs, conducting hydrolysis experiments proves to be exceedingly time-consuming and financially burdensome. Herein, density functional theory and transition state theory were employed to predict the base-catalyzed hydrolysis of PCDDs in aquatic environments. Findings reveal that PCDDs undergo base-catalyzed hydrolysis in aquatic environments with two competing pathways: prevailing dioxin ring-opening and reduced reactivity in the hydrolytic dechlorination pathway. The resultant minor products include hydroxylated PCDDs, which exhibit thermodynamic stability surpassing that of the principal product, chlorinated hydroxydiphenyl ethers. The half-lives (ranging from 17.10 to 1.33 × 1010 h at pH = 8) associated with the base-catalyzed hydrolysis of PCDDs dissolved in water were shorter compared to those within the water-sediment environmental system. This observation implies that hydroxide ions can protect aquatic environments from PCDD contamination. Notably, this study represents the first attempt to predict the base-catalyzed hydrolysis of PCDDs by using quantum chemical methods.

Short- and medium-chain chlorinated paraffins in breast milk in Shanghai, China: Occurrence, characteristics, and risk assessment.

As novel contaminants, short-chain chlorinated paraffins (SCCPs) and medium-chain chlorinated paraffins (MCCPs) have been of great concern in the past several years. Shanghai was one of the provinces with the largest chlorinated paraffins (CPs) emission in China; nevertheless, there is currently little information on the human exposure to SCCPs and MCCPs, particularly MCCPs. In this study, 25 breast milk samples were collected in Shanghai from 2016 to 2017. The concentrations of SCCPs and MCCPs were determined using two-dimensional gas chromatography coupled with orbitrap high-resolution mass spectrometry (GC × GC-orbitrap-HRMS) to investigate their characteristics and assess the associated health risks for breast-fed infants. Compared with the previous studies in other areas, the current study presented the higher CPs concentrations, with median concentrations of SCCPs and MCCPs up to 771 and 125 ng/g lipid weight (lw), respectively. The exposure profiles of the CPs were characterized by C10 and Cl6-7 as the predominant congeners of SCCPs, while C14 and Cl7-9 were identified as the dominant groups of MCCPs. CP-42 and CP-52 were identified as potential sources of CPs found in breast milk samples collected in Shanghai. The concentrations of MCCPs exhibited a positive correlation (p value < 0.05) with the dietary consumption of meat and poultry. No significant positive correlations were observed for SCCPs and MCCPs with polychlorinated dibenzodioxins/furans (PCDD/Fs) congeners. A preliminary exposure assessment showed that SCCPs in breast milk potentially posed high risks to the breast-fed infants in Shanghai.

Probabilistic human health risk assessment of PCDD/Fs near municipal solid-waste incinerator using Monte Carlo analysis coupled with triangular fuzzy numbers.

PCDD/Fs are dioxins produced by waste incineration and pose risks to human health. We aimed to detail the health risks of airborne and soil PCDD/Fs near a municipal solid-waste incinerator (MSWI) for the surrounding population and develop a new model that improves upon existing methods. Thus, we conducted field sampling and then investigated a MSWI in the Pearl River Delta (2016-2018). Our results showed that the carcinogenic and non-carcinogenic risk values of PCDD/Fs exposed to residents in nearby areas were acceptable, with hazard index (HI) values lower than 1.0 and a total carcinogenic risk lower than 1.0E-6. Notably, the results raised concerns regarding higher non-carcinogenic risks in children than in adults. Comparative analysis of the frequency accumulation diagram, accumulated probability risk, and the absolute value of error (δ) between the 95% confidence interval (CI) and the 90% CI of the Monte Carlo stochastic simulation-triangular fuzzy number (MCSS-TFN) and the MCSS model, respectively, demonstrated that the MCSS-TFN exhibited less uncertainty than the MCSS model, regardless of the health risk value of PCDD/Fs in ambient air or in soil. This observation underscores the superiority of the MCSS-TFN model over other models in assessing the health risks associated with PCDD/Fs in situations with limited data. Our new method overcomes the limited dataset size and high uncertainty in assessing the health risks of dioxin substances, providing a more comprehensive understanding of their associated health risks than MCSS models.

Formation of Pre-PCTA/DT Intermediates from 2-Chlorothiophenol on Silica Clusters: A Quantum Mechanical Study.

Silica (SiO2), accounting for the main component of fly ash, plays a vital role in the heterogeneous formation of polychlorinated thianthrenes/dibenzothiophenes (PCTA/DTs) in high-temperature industrial processes. Silica clusters, as the basic units of silica, provide reasonable models to understand the general trends of complex surface reactions. Chlorothiophenols (CTPs) are the most crucial precursors for PCTA/DT formation. By employing density functional theory, this study examined the formation of 2-chlorothiophenolate from 2-CTP adsorbed on the dehydrated silica cluster ((SiO2)3) and the hydroxylated silica cluster ((SiO2)3O2H4). Additionally, this study investigated the formation of pre-PCTA/DTs, the crucial intermediates involved in PCTA/DT formation, from the coupling of two adsorbed 2-chlorothiophenolates via the Langmuir-Hinshelwood (L-H) mechanism and the coupling of adsorbed 2-chlorothiophenolate with gas-phase 2-CTP via the Eley-Rideal (E-R) mechanism on silica clusters. Moreover, the rate constants for the main elementary steps were calculated over the temperature range of 600-1200 K. Our study demonstrates that the 2-CTP is more likely to adsorb on the termination of the dehydrated silica cluster, which exhibits more effective catalysis in the formation of 2-chlorothiophenolate compared with the hydroxylated silica cluster. Moreover, the E-R mechanism mainly contributes to the formation of pre-PCTAs, whereas the L-H mechanism is prone to the formation of pre-PCDTs on dehydrated and hydroxylated silica clusters. Silica can act as a relatively mild catalyst in facilitating the heterogeneous formation of pre-PCTA/DTs from 2-CTP. This research provides new insights into the surface-mediated generation of PCTA/DTs, further providing theoretical foundations to reduce dioxin emission and establish dioxin control strategies.

2,3,7,8-Tetrachlorodibenzo-p-dioxin and kynurenine induce Parkin expression in neuroblastoma cells through different signaling pathways mediated by the aryl hydrocarbon receptor.

Parkin regulates protein degradation and mitophagy in dopaminergic neurons. Deficiencies in Parkin expression or function lead to cellular stress, cell degeneration, and the death of dopaminergic neurons, which promotes Parkinson's disease. In contrast, Parkin overexpression promotes neuronal survival. Therefore, the mechanisms of Parkin upregulation are crucial to understand. We describe here the molecular mechanism of AHR-mediated Parkin regulation in human SH-SY5Y neuroblastoma cells. Specifically, we report that the human Parkin gene (PRKN) is transcriptionally upregulated by the aryl hydrocarbon receptor (AHR) through two different selective ligand-dependent pathways. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a stress-inducing AHR ligand, indirectly promotes PRKN transcription by inducing ATF4 expression via TCDD-mediated endoplasmic reticulum (ER) stress. In contrast, kynurenine, a nontoxic AHR agonist, induces PRKN transcription by promoting AHR binding to the PRKN promoter without activating ER stress. Our results demonstrate that AHR activation may be a potential pharmacological pathway to induce human Parkin, but such a strategy must carefully consider the choice of AHR ligand to avoid neurotoxic side effects.

Exposure estimation and neurotoxicity inhibition of dioxins in sensitive populations near domestic waste incineration plant through adverse outcome pathway.

The neurotoxicity induced by dioxins has been recognized as a serious concern to sensitive population living near waste incineration plants. However, investigating the intracellular neurotoxicity of dioxin in humans and the corresponding mitigation strategies has been barely studied. Thus, a domestic waste incineration plant was selected in this study to characterize the neurotoxicity risks of sensitive populations by estimating the ratio of dioxin in human cells using membrane structure dynamics simulation; and constructing a complete dioxin neurotoxicity adverse outcome pathway considering the binding process of AhR/ARNT dimer protein and dioxin response element (DRE). Six dioxins with high neurotoxicity risk were identified. According to the composite neurotoxicity risk analysis, the highest composite neurotoxicity risk appeared when the six dioxins were jointly exposed. Dietary schemes were designed using 1/2 partial factor experimental design to mitigate the composite neurotoxicity risk of six dioxins and No. 16 was screened as the optimum combination which can effectively alleviate the composite neurotoxicity risk by 29.52%. Mechanism analysis shows that the interaction between AhR/ARNT dimer protein and DRE was inhibited under the optimal dietary scheme. This study provides theoretical feasibility and reference significance for assessing composite toxicity risks of pollutants and safety mitigation measures for toxic effects.

Human biomonitoring of dioxins, furans, and non-ortho dioxin-like polychlorinated biphenyls (PCBs) in blood plasma from Old Crow, Yukon, Canada (2019).

Dioxins, furans, and dioxin-like polychlorinated biphenyls (PCBs) are a group of persistent and toxic chemicals that are known to have human health effects at low levels. These chemicals have been produced for commercial use (PCBs) or unintentionally as by-products of industry or natural processes (PCBs, dioxins, and furans). Additionally, dioxin-like PCBs were formerly used in electrical applications before being banned internationally (2004). These chemicals are widely dispersed in the environment as they can contaminate air and travel hundreds to thousands of kilometers before depositing on land or water, thereafter, potentially entering food chains. Community concerns surrounding the safety of traditional foods prompted a human biomonitoring project in Old Crow, Yukon Territory (YT), Canada (2019). Through collaborative community engagement, dioxins and like compounds were identified as a priority for exposure assessment from biobanked samples. In 2022, biobanked plasma samples (n = 54) collected in Old Crow were used to measure exposures to seven dioxins, ten furans, and four dioxin-like PCBs. 1,2,3,6,7,8-HxCDD, 1,2,3,7,8,9-HxCDD, 1,2,3,4,6,7,8-HpCDD, OCDD, 2,3,4,7,8-PeCDF, 1,2,3,6,7,8-HxCDF, PCB 126, and PCB 169 were detected in at least 50 % of samples. Among these analytes, the only congener at elevated levels was PCB 169, which was approximately ∼2-fold higher than the general population of Canada. No significant sex-based or body mass index (BMI) differences in biomarker concentrations were observed. Generally, the concentrations of the detected congeners increased with age, except for 1,2,3,4,6,7,8-HpCDD. For the first time, this research measures dioxin and like-compound exposures in Old Crow, advancing the information available on chemical exposures in the Arctic. Further research could be directed towards the investigation of PCB 169 exposure sources and temporal monitoring of exposures and determinants.

Results of an international interlaboratory study on dioxin-like activities in drinking-, river surface- and wastewater using DR CALUX bioassay.

Aquatic animals and consumers of aquatic animals are exposed to increasingly complex mixtures of known and as-yet-unknown chemicals with dioxin-like toxicities in the water cycle. Effect- and cell-based bioanalysis can cover known and yet unknown dioxin and dioxin-like compounds as well as complex mixtures thereof but need to be standardized and integrated into international guidelines for environmental testing. In an international laboratory testing (ILT) following ISO/CD 24295 as standard procedure for rat cell-based DR CALUX un-spiked and spiked extracts of drinking-, surface-, and wastewater were validated to generate precision data for the development of the full ISO-standard. We found acceptable repeatability and reproducibility ranges below 36 % by DR CALUX bioassay for the tested un-spiked and spiked water of different origins. The presence of 17 PCDD/Fs and 12 dioxin-like PCBs was also confirmed by congener-specific GC-HRMS analysis. We compared the sum of dioxin-like activity levels measured by DR CALUX bioassay (expressed in 2,3,7,8-TCDD Bioanalytical Equivalents, BEQ; ISO 23196, 2022) with the obtained GC-HRMS chemical analysis results converted to toxic equivalents (TEQ; van den Berg et al., 2013).

Distributions of PCDD/Fs, PCBs, and PCNs in coastal sediments collected from major industrial bays in South Korea.

Polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), polychlorinated biphenyls (PCBs), and polychlorinated naphthalenes (PCNs) were assessed in coastal sediments from industrial bays in South Korea to evaluate the pollution levels and their environmental impact. The mean sediment concentrations of Σ17 PCDD/Fs, Σ18 PCBs, and Σ15 PCNs were 198 ± 140, 3427 ± 7037, and 85 ± 336 pg/g dw, respectively. Generally, pollutant concentrations in the inner bay were higher than those in the outer bay, indicating the influence of industrial emissions and harbor activities. The primary sources were identified as steel manufacturing and wastewater treatment plants for PCDD/Fs, harbor and shipbuilding activities for PCBs, and combustion-related sources for PCNs. Notably, PCDD/F concentrations exceeded sediment guideline values. The combined effects of PCDD/Fs and PCBs demonstrated adverse impacts on aquatic organisms. Hence, the release of toxic pollutants into the marine environment could have potential biological effects due to the combined impact of these various compounds.

Polychlorinated dibenzodioxins/furans and dioxin-like polychlorinated biphenyls in fish and crustaceans of a recreationally fished estuary, following targeted remediation.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) are a suite of harmful chemicals (hereafter collectively referred to as 'dioxins'), and their emission into aquatic habitats leads to persistent contamination of sediments, aquatic food-webs, and seafoods. Quantifying contaminant levels in seafood species is important for the ongoing management of exposure risk by fishers, particularly after any remediation actions. We present dioxin concentrations in four seafood species (Yellowfin Bream Acanthopagrus australis, Sea Mullet Mugil cephalus, Eastern School Prawn Metapenaeus macleayi, and Eastern King Prawn Penaeus plebejus) in a recreationally fished estuary, in relation to a contaminated site that has undergone a remediation process, partially removing contaminated sediments (Homebush Bay, Port Jackson, New South Wales, Australia). Dioxin concentrations in these species were measured before (2005/6) and after (2015/16) remediation at a range of locations in and around the remediated site. Dioxin concentrations and congener profiles differed substantially among taxa, and concentrations were frequently higher than Australian screening criteria. The two prawn species showed evidence of a decline in dioxin concentrations after remediation, but the fish species only showed a declining dioxin concentration with distance from the contaminated site (not between periods). There were some minor changes in the congener profile for some species following remediation. While there was evidence for greatly reduced dioxin concentrations in prawn species following remediation, the complex patterns for fish were likely affected by environmental changes, species-specific and temporal changes in lipid content, and animal movement patterns. Future monitoring may aid interpretation of the patterns and modelling of exposure risk associated with seafood consumption into the future.

Toxicogenomics of the C-C chemokine receptor type 5 (CCR5): Exploring the potential impacts of chemical-CCR5 interactions on inflammation and human health.

This article explores the impact of environmental chemicals on CCR5 expression and related inflammatory responses based on curated data from the Comparative Toxicogenomics Database (CTD). A total of 143 CCR5-interacting chemicals was found, with 229 chemical interactions. Of note, 67 (29.3%) out of 229 interactions resulted in "increased expression" of CCR5 mRNA or CCR5 protein, and 42 (18.3%) chemical interactions resulted in "decreased expression". The top-5 CCR5-interacting chemicals were "Tetrachlorodibenzodioxin", "Lipopolysaccharides", "Benzo(a)pyrene", "Drugs, Chinese Herbal", and "Ethinyl Estradiol". Based on the number of interactions and importance as environmental contaminant, we then focused our analysis on Tetrachlorodibenzodioxin and Benzo(a)pyrene. There is some consistency in the data supporting an increase in CCR5 expression triggered by Tetrachlorodibenzodioxin; although data concerning CCR5-Benzo(a)pyrene interactions is limited. Considering the high linkage disequilibrium between CCR5 and CCR2 genes, we also search for chemicals that interact with both genes, which resulted in 72 interacting chemicals, representing 50.3% of the 143 CCR5-interacting chemicals and 37.5% of the 192 CCR2-interacting chemicals. In conclusion, CTD data showed that environmental contaminants indeed affect CCR5 expression, with a tendency towards increased expression. The interaction of environmental contaminants with other chemokine receptor genes may potentialize their toxic effects on the chemokine system, favoring inflammation.

TCDD and CH223191 Alter T Cell Balance but Fail to Induce Anti-Inflammatory Response in Adult Lupus Mice.

Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.

The aryl hydrocarbon receptor in ß-cells mediates the effects of TCDD on glucose homeostasis in mice.

OBJECTIVE: Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 µg/kg) in vivo reduced fasted and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant. Whether these effects are driven by AhR activation in ß-cells requires investigation. METHODS: We exposed female and male ß-cell specific Ahr knockout (ßAhrKO) mice and littermate Ins1-Cre genotype controls (ßAhrWT) to a single high dose of 20 µg/kg TCDD and tracked the mice for 6 weeks. RESULTS: Under baseline conditions, deleting AhR from ß-cells caused hypoglycemia in female mice, increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure impaired glucose homeostasis and ß-cell function in ßAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed ßAhrKO mice. CONCLUSION: Our study demonstrates that AhR signaling in ß-cells is important for regulating baseline ß-cell function in female mice and energy homeostasis in male mice. We also show that ß-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on ß-cell function and health are driving metabolic phenotypes in peripheral tissues.

Polychlorinated naphthalenes in freshwater fish from Beijing markets: Species-specific differences, effects of cooking, and health risk assessment.

Fish are an important source of human dietary exposure to polychlorinated naphthalenes (PCNs). The occurrence and sources of PCNs in different species of freshwater fish are unknown, and few studies have assessed human exposure risks to PCNs through freshwater fish. In this study, 140 freshwater fish samples from 10 species were collected from Beijing markets, China. The Σ75CNs concentration range in the fish was 20.7-1310 pg/g wet weight (ww). The highest median Σ75PCNs concentration (80.4 pg/g ww) was found in mandarin fish (Siniperca chuatsi), and the lowest (29.6 pg/g ww) in snakehead (Channa argus). Di- and tri-CNs were the dominant PCN homologues with contributions of 35.3 % and 30.8 %, respectively. Unintentionally produced PCNs from metal smelting might be the source of PCN contamination in freshwater fish. The cooking temperature and time did not significantly affect the PCN concentrations in fish or the PCN homologue profiles. The highest toxic equivalent (TEQ) value was observed in sturgeon (Acipenser sinensis), followed by mandarin fish. Hexa-CNs were the most abundant homologue for the PCN TEQs. A risk assessment indicated that the dietary exposure risks for local residents to PCNs through freshwater fish were low. However, the relatively high concentrations of PCNs in the samples deserve attention to avoid PCNs exposure risks for groups with high fish consumption rates. Furthermore, freshwater fish likely contain a mixture of contaminants including dioxin and furans which also display a similar mode of toxicity as the PCNs and could enhance the risk to fish consumers.