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On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research (WFSR) analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are screened first with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of structurally diverse chemicals, including halogenated aromatic hydrocarbons. In this work, we investigate the effects of the binding of the AhR prototypical ligand, TCDD, on the stability of the AhR:ARNT complex, as well as the mechanisms by which ligand-induced perturbations propagate to the DNA recognition site responsible for gene transcription. To this aim, a reliable structural model of the overall quaternary structure of the AhR:ARNT:DRE complex is proposed, based on homology modelling. The model shows very good agreement with a previous one and is supported by experimental evidence. Moreover, molecular dynamics simulations are performed to compare the dynamic behaviour of the AhR:ARNT heterodimer in the presence or absence of the TCDD. Analysis of the simulations, performed by an unsupervised machine learning method, shows that TCDD binding to the AhR PASB domain influences the stability of several inter-domain interactions, in particular at the PASA-PASB interface. The inter-domain communication network suggests a mechanism by which TCDD binding allosterically stabilizes the interactions at the DNA recognition site. These findings may have implications for the comprehension of the different toxic outcomes of AhR ligands and drug design.

Bayesian Network was applied to estimate probability of contamination occurrence. Linear programming was used to optimize monitoring based on estimated probabilities.

White-rot fungi produce extracellular lignin-modifying enzymes (LME) that degrade lignin, a class of complex organic polymers, for fungal nutrition and growing. Laccase is the most well-characterized enzyme in the group of LME. Besides, because of their broad substrate specificity, laccase is also capable of degradation of many hazardous pollutants such as herbicides, pesticides, PAHs, dyes, pharmaceutical chemicals, polychlorinated biphenyls, etcetera. The working hypothesis of this study was that ligninolytic fungi and LME can degrade 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) the most toxic congener of the group of dioxins. In order to collect scientific evidence supporting the hypothesis and achieving the main aim of the thesis, which is the investigation into the 2,3,7,8-TCDD biodegradation potential of ligninolytic fungi and lignin-modifying enzymes, the experiments were conducted using white-rot fungi collected from Vietnamese forests and 2,3,7,8-TCDD as subjects and object of the research respectively. In chapter 2, the isolation and screening process for LME producing fungi were described as well as the selection of 2,3,7,8-TCDD degrading fungi. From the 76 fungal isolates collected from Vietnamese forests, 70 isolates showed LME activity based on colorimetric screening using oxidized guaiacol as an indicator. TRigidoporus sp. FMD21 (FMD21) was the only strain that showed a 2,3,7,8-TCDD degradation ability. This strain produced 238 800 U/L of laccase after ten days while MnP activity showed the highest activity of approximately 40 U/L at day 4 in the PDSRb medium consisting of potato dextrose powder, soy meal, and rice bran. In chapter 3 and chapter 4 the enzymatic degradation of 2,3,7,8-TCDD was characterized, while the degradation of 2,3,7,8-TCDD was determined using the DR-CALUX® bioassay. FMD21 ExE, which mainly consisted of laccase, degraded 77.4% of 2,3,7,8-TCDD within 36 days, while starting with an initial concentration of 0.5 pgTEQ/mL. Thre

Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPAR and C/EBP); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

White-rot fungi produce extracellular lignin-modifying enzymes (LME) that degrade lignin, a class of complex organic polymers, for fungal nutrition and growing. Laccase is the most well-characterized enzyme in the group of LME. Besides, because of their broad substrate specificity, laccase is also capable of degradation of many hazardous pollutants such as herbicides, pesticides, PAHs, dyes, pharmaceutical chemicals, polychlorinated biphenyls, etcetera. The working hypothesis of this study was that ligninolytic fungi and LME can degrade 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) the most toxic congener of the group of dioxins. In order to collect scientific evidence supporting the hypothesis and achieving the main aim of the thesis, which is the investigation into the 2,3,7,8-TCDD biodegradation potential of ligninolytic fungi and lignin-modifying enzymes, the experiments were conducted using white-rot fungi collected from Vietnamese forests and 2,3,7,8-TCDD as subjects and object of the research respectively. In chapter 2, the isolation and screening process for LME producing fungi were described as well as the selection of 2,3,7,8-TCDD degrading fungi. From the 76 fungal isolates collected from Vietnamese forests, 70 isolates showed LME activity based on colorimetric screening using oxidized guaiacol as an indicator. TRigidoporus sp. FMD21 (FMD21) was the only strain that showed a 2,3,7,8-TCDD degradation ability. This strain produced 238 800 U/L of laccase after ten days while MnP activity showed the highest activity of approximately 40 U/L at day 4 in the PDSRb medium consisting of potato dextrose powder, soy meal, and rice bran. In chapter 3 and chapter 4 the enzymatic degradation of 2,3,7,8-TCDD was characterized, while the degradation of 2,3,7,8-TCDD was determined using the DR-CALUX® bioassay. FMD21 ExE, which mainly consisted of laccase, degraded 77.4% of 2,3,7,8-TCDD within 36 days, while starting with an initial concentration of 0.5 pgTEQ/mL. Thre

Clothes may contain a large range of chemical additives and other toxic substances, which may eventually pose a significant risk to human health. Since they are associated with pigments, polychlorinated biphenyls (PCBs) may be especially relevant. On the other hand, infants are very sensitive to chemical exposure and they may wear some contact and colored textiles for a prolonged time. Consequently, a specific human health risk assessment is required. This preliminary study was aimed at analyzing the concentrations of PCBs in ten bodysuits purchased in on-line stores and local retailers. The concentrations of 12 dioxin-like and 8 non-dioxin-like PCB congeners were determined by gas chromatography coupled to high resolution mass spectrometry, with detection limits ranging between 0.01 and 0.13 pg/g. The dermal absorption to PCBs of children at different ages (6 months, 1 year and 3 years old) was estimated, and the non-cancer and cancer risks were evaluated. Total levels of PCBs ranged from 74.2 to 412 pg/g, with a mean TEQ concentration of 13.4 pg WHO-TEQ/kg. Bodysuits made of organic cotton presented a total mean PCB concentration substantially lower than clothes made of regular cotton (11.0 vs. 15.8 pg WHO-TEQ/kg). The dermal absorption to PCBs for infants was calculated in around 3.10(-5) pg WHO-TEQ/kg.day, regardless the age. This value is > 10,000-fold lower than the dietary intake of PCBs, either through breastfeeding or food consumption. Furthermore, this exposure value would not pose any health risks for the infants wearing those bodysuits. Anyhow, as it is a very preliminary study, this should be confirmed by analyzing larger sets of textile samples. Further investigations should be also focused on the co-occurrence of PCBs and other toxic chemicals (i.e., form

UNEP/GMP2 project

UNEP/GMP2 project

Study questionIs there an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and fecundability and infertility among Seveso women and their daughters?Summary answerTCDD exposure is associated with a decrease in fecundability and increased risk of infertility in women, as well as their daughters.What is known alreadyIn animal studies, maternal exposure to TCDD is associated with decreased fertility in offspring. Effects of TCDD are mediated by activation of the aryl hydrocarbon receptor (AHR) pathway.Study design, size, durationThe Seveso Women's Health Study (SWHS) has followed 981 women exposed to TCDD in a 1976 accident since 1996. In 2014, we initiated the Seveso Second Generation Study to follow-up their children.Participants/materials, setting, methodsWe obtained information on pregnancy history including time of trying to conceive from SWHS women and their daughters who were 18 years or older. We considered TCDD exposure as initial 1976 serum TCDD concentration and estimated TCDD at pregnancy. We examined relationships of TCDD exposure with time to pregnancy (TTP, the monthly probability of conception within the first 12 months of trying) and infertility (≥12 months of trying to conceive). We also assessed contributions of polymorphisms in the AHR pathway via genetic risk score.Main results and the role of chanceAmong SWHS women (n = 446), median TTP was 3 months and 18% reported taking ≥12 months to conceive. Initial 1976 TCDD (log10) was associated with longer TTP (adjusted fecundability odds ratio = 0.82; 95% CI 0.68-0.98) and increased risk of infertility (adjusted relative risk = 1.35; 95% CI 1.01-1.79). TCDD at pregnancy yielded similar associations. Among SWHS daughters (n = 66), median TTP was 2 months and 11% reported taking ≥12 months to conceive. Daughters showed similar, but non-significant, associations with maternal TCDD exposure.Limitations, reasons for cautionA limitation of this study is time to pregnancy was reported retr

Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.

STUDY QUESTION: Is there an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and fecundability and infertility among Seveso women and their daughters? SUMMARY ANSWER: TCDD exposure is associated with a decrease in fecundability and increased risk of infertility in women, as well as their daughters. WHAT IS KNOWN ALREADY: In animal studies, maternal exposure to TCDD is associated with decreased fertility in offspring. Effects of TCDD are mediated by activation of the aryl hydrocarbon receptor (AHR) pathway. STUDY DESIGN, SIZE, DURATION: The Seveso Women's Health Study (SWHS) has followed 981 women exposed to TCDD in a 1976 accident since 1996. In 2014, we initiated the Seveso Second Generation Study to follow-up their children. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained information on pregnancy history including time of trying to conceive from SWHS women and their daughters who were 18 years or older. We considered TCDD exposure as initial 1976 serum TCDD concentration and estimated TCDD at pregnancy. We examined relationships of TCDD exposure with time to pregnancy (TTP, the monthly probability of conception within the first 12 months of trying) and infertility (≥12 months of trying to conceive). We also assessed contributions of polymorphisms in the AHR pathway via genetic risk score. MAIN RESULTS AND THE ROLE OF CHANCE: Among SWHS women (n = 446), median TTP was 3 months and 18% reported taking ≥12 months to conceive. Initial 1976 TCDD (log10) was associated with longer TTP (adjusted fecundability odds ratio = 0.82; 95% CI 0.68-0.98) and increased risk of infertility (adjusted relative risk = 1.35; 95% CI 1.01-1.79). TCDD at pregnancy yielded similar associations. Among SWHS daughters (n = 66), median TTP was 2 months and 11% reported taking ≥12 months to conceive. Daughters showed similar, but non-significant, associations with maternal TCDD exposure. LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is time to pregnan

UNEP/GMP2 project

UNEP/GMP2 project

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish)

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

On behalf of the Ministry of Agriculture, Nature and Food Quality (LNV), Wageningen Food Safety Research analyses samples of agricultural products of animal origin for dioxins, PCBs, brominated flame retardants (BFRs) and poly- and perfluorinated alkyl substances (PFASs). This includes meat, milk, eggs and fish. The samples are taken at the primary production or processing stage (e.g. in slaughterhouses or raw milk collection services). For dioxin-like compounds, 350 samples are first screened with the DR CALUX® method. Samples giving a signal indicating a level above the lowest action level are regarded as suspected. These samples are further examined using GC/HRMS as confirmatory method. Concerning fish, shellfish and crustaceans, approx. 25 samples are collected at sea by research vessels, at the fish auction, or from whole-sale traders (farmed fish).

Dioxins and aflatoxins contamination along the dairy supply chain. We used a mixed integer nonlinear programming approach to maximize the performance of the sampling in terms of reducing the risk of the potential disability adjusted life years (DALYs) in the population. Decision variables are the number of samples collected and analyzed at each stage of the food chain (feed mills, dairy farms, milk trucks, and dairy processing plants) for each chemical, given a predefined budget. The model was applied to the case of monitoring for aflatoxin B1/M1(AFB1/M1) and dioxins in a hypothetical Dutch dairy supply chain, and results were calculated for various contamination scenarios defined in terms of contamination fraction and concentrations.

UNEP/GMP2 project

UNEP/GMP2 project

Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR. (Figure presented.). © 2020 International Society for Neurochemistry

Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR. (Figure presented.). © 2020 International Society for Neurochemistry

Halter av många ”klassiska” föroreningar minskar i miljön. Alltjämt förekommer dock förhöjda halter av dioxiner och PCB i feta fiskarter från Östersjön, Vänern och Vättern. I detta projekt har en kartläggning och utvärdering av dioxinlika ämnen i sik, strömming, lax och öring utförts. Fisken har samlats in mellan 2014 och 2019, huvudsakligen av yrkesfiskare under ordinarie verksamhet vilket betyder att uppmäta halter genom analys av cirka 500 fiskprover väl speglar vad de produkter som når svenska konsumenter innehåller. Resultaten visar på förhållandevis stora variationer mellan olika fångstområden. Exempelvis är halterna av dioxinlika ämnen i sik från Vänern betydligt högre än de som uppmäts i sik från Vättern eller Östersjön. En starkt bidragande faktor till skillnader i halter av dioxinlika ämnen mellan olika områden är skillnader i fetthalt. Ju fetare fisken är desto högre blir föroreningshalterna. En annan faktor som visade sig betydelsefull är så kallad bioackumulation. Ju äldre och större en fisk är desto högre blir föroreningshalterna. Detta samband var mest tydligt i strömming. I lax konstaterades en avtagande trend i halter av dioxinlika ämnen sett över hela undersökningsperioden. Projektet har utförts inom ramen för IVL:s samfinansierade forskningsprogram med medfinansiering från Svenska Insjöfiskarnas Centralförbund och Norrlands kustfiskare., Förekomsten av dioxiner i fet fisk är en begränsande faktor för det svenska småskaliga kust- och insjöfisket. I detta projekt har under sex år halter av dioxiner och PCB i yrkesmässigt fångad sik, strömming, lax och öring från Östersjön, Vänern och Vättern kartlagts. Det huvudsakliga syfte har varit att ta fram underlag till fiskerinäringen över vilka arter, platser, bestånd, storleksklasser, årstider och beredningsmetoder som lämpar sig bäst att använda för att minimera dioxininnehållet i de produkter som når konsumenter.

Intresset för hållbart producerade livsmedel ökar i samhället. Braxen, en allmänt förekommande fiskart i insjö- och kustvatten, är i dagsläget en outnyttjad resurs som i liten grad används för mänsklig konsumtion. Flera initiativ har emellertid tagits för att återintroducera braxen på fiskmarknaden. IVL har mot bakgrund av detta analyserat förekomsten av potentiellt hälsofarliga ämnen i braxen från några kust-och insjölokaler.

Förekomsten av dioxiner och PCB:er i strömming från Östersjön har under flera decennier varit en uppmärksammad miljöfråga och rönt mycket intresse från såväl myndigheter, forskare, yrkesfiskare som från allmänheten. Än finns kunskapsluckor att fylla. Baserat på provtagningar från senare år redovisas i denna rapport närmare hur situationen ser ut i strömming från Svealandskusten. Särskilt har geografiska och säsongsmässiga haltvariationer undersökts.

Background: Maternal exposure to polychlorinated biphenyls (PCBs) is associated with increased proportions of spontaneous abortion and stillbirth in animal studies. In Japan in 1968, accidental human exposure to rice oil contaminated with PCBs and other dioxin-related compounds, such as polychlorinated dibenzofurans (PCDFs), led to the development of what was later referred to as Yusho oil disease. Objective: The aim of this study was to investigated the association of maternal PCB and dioxin exposure with adverse pregnancy outcomes in Yusho women. Methods: In 2004, we interviewed 214 Yusho women (512 pregnancies) about their pregnancy outcomes over the past 36 years. Pregnancy outcomes included induced abortion, spontaneous abortion, preterm delivery, and pregnancy loss. Results: In pregnancy years 1968-1977 (within the first 10 years after exposure), the proportions of induced abortion [adds ration adjusted for age at delivery (ORadj) = 5.93; 95% confidence interval (CI), 2.21-15.91; two-tailed p < 0.001) and preterm delivery (ORadj = 5.70; 95% CI, 1.17-27.79; p = 0.03) were significantly increased compared with the proportions in pregnancy years 1958-1967 (10 years before the incident). Spontaneous abortion (ORadj = 2.09; 95% CI, 0.84-5.18), and pregnancy loss (ORadj = 2.11; 95% CI, 0.92-4.87) were more frequent (OR = 2.18; 95% CI, 1.02-4.66), but these were not significant (p = 0.11 and p = 0.08, respectively) in pregnancy years 1968-1977. We found no significant increases in the proportions of these adverse pregnancy outcomes in pregnancies occurring during 1978-1987 or 1988-2003 compared with those in pregnancies before 1968. Conclusion: High levels of PCB/PCDF exposure had some adverse effects on pregnancy outcome in Yusho women., identifier:Environmental Health Perspectives, 116(5), pp.626-630; 2008

BackgroundDioxins are persistent organic pollutants generated from industrial combustion processes such as waste incineration. To date, results from epidemiologic studies of dioxin exposure and breast cancer risk have been mixed.ObjectivesTo prospectively examine the association between ambient dioxin exposure using a nationwide spatial database of industrial dioxin-emitting facilities and invasive breast cancer risk in the Nurses' Health Study II (NHSII).MethodsNHSII includes female registered nurses in the US who have completed self-administered biennial questionnaires since 1989. Incident invasive breast cancer diagnoses were self-reported and confirmed by medical record review. Dioxin exposure was estimated based on residential proximity, duration of residence, and emissions from facilities located within 3, 5, and 10 km around geocoded residential addresses updated throughout follow-up. Cox regression models adjusted for breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsFrom 1989 to 2013, 3840 invasive breast cancer cases occurred among 112,397 participants. There was no association between residential proximity to any dioxin facilities (all facilities combined) and breast cancer risk overall. However, women who resided within 10 km of any municipal solid waste incinerator (MSWI) compared to none had increased breast cancer risk (adjusted HR = 1.15, 95% CI: 1.03, 1.28), with stronger associations noted for women who lived within 5 km (adjusted HR = 1.25, 95% CI: 1.04, 1.52). Positive associations were also observed for longer duration of residence and higher dioxin emissions from MSWIs within 3, 5, and 10 km. There were no clear differences in patterns of association for ER + vs. ER-breast cancer or by menopausal status.DiscussionResults from this study support positive associations between dioxin exposure from MSWIs and invasive breast cancer risk.

In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with delayed pubertal development in animal studies. No epidemiologic study has investigated this association. We examined the relationship of in utero exposure to TCDD with reported age at onset of menarche in female children born to a unique cohort of TCDD-exposed women resulting from an explosion in Seveso, Italy, on 10 July 1976.MethodsIn 2014, nearly 40 years after the explosion, we enrolled postexplosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. Age at onset of menarche (years) was collected for 316 daughters by maternal report or self-report at interview. In utero TCDD exposure was defined by maternal TCDD serum concentrations extrapolated to the pregnancy.ResultsAt interview, 287 daughters were postmenarche and reported age at menarche averaged 12.1 years (±1.3 years). Overall, we found no change in risk of menarche onset with a 10-fold increase in in utero TCDD exposure (hazard ratio [HR] = 0.86; 95% confidence interval [CI] = 0.71, 1.04). When we considered maternal menarche status in 1976 as a potentially sensitive developmental exposure window, in utero TCDD (log10) was associated with later age at menarche among daughters whose mothers were premenarche (HR = 0.71; 95% CI = 0.52, 0.97) but not postmenarche (HR = 0.89; 95% CI = 0.71, 1.12) at the time of the explosion (P int = 0.24).ConclusionsThese results suggest that in utero TCDD exposure may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

Halter av många ”klassiska” föroreningar minskar i miljön. Alltjämt förekommer dock förhöjda halter av dioxiner och PCB i feta fiskarter från Östersjön, Vänern och Vättern. I detta projekt har en kartläggning och utvärdering av dioxinlika ämnen i sik, strömming, lax och öring utförts. Fisken har samlats in mellan 2014 och 2019, huvudsakligen av yrkesfiskare under ordinarie verksamhet vilket betyder att uppmäta halter genom analys av cirka 500 fiskprover väl speglar vad de produkter som når svenska konsumenter innehåller. Resultaten visar på förhållandevis stora variationer mellan olika fångstområden. Exempelvis är halterna av dioxinlika ämnen i sik från Vänern betydligt högre än de som uppmäts i sik från Vättern eller Östersjön. En starkt bidragande faktor till skillnader i halter av dioxinlika ämnen mellan olika områden är skillnader i fetthalt. Ju fetare fisken är desto högre blir föroreningshalterna. En annan faktor som visade sig betydelsefull är så kallad bioackumulation. Ju äldre och större en fisk är desto högre blir föroreningshalterna. Detta samband var mest tydligt i strömming. I lax konstaterades en avtagande trend i halter av dioxinlika ämnen sett över hela undersökningsperioden. Projektet har utförts inom ramen för IVL:s samfinansierade forskningsprogram med medfinansiering från Svenska Insjöfiskarnas Centralförbund och Norrlands kustfiskare., Förekomsten av dioxiner i fet fisk är en begränsande faktor för det svenska småskaliga kust- och insjöfisket. I detta projekt har under sex år halter av dioxiner och PCB i yrkesmässigt fångad sik, strömming, lax och öring från Östersjön, Vänern och Vättern kartlagts. Det huvudsakliga syfte har varit att ta fram underlag till fiskerinäringen över vilka arter, platser, bestånd, storleksklasser, årstider och beredningsmetoder som lämpar sig bäst att använda för att minimera dioxininnehållet i de produkter som når konsumenter.

Förekomsten av dioxiner och PCB:er i strömming från Östersjön har under flera decennier varit en uppmärksammad miljöfråga och rönt mycket intresse från såväl myndigheter, forskare, yrkesfiskare som från allmänheten. Än finns kunskapsluckor att fylla. Baserat på provtagningar från senare år redovisas i denna rapport närmare hur situationen ser ut i strömming från Svealandskusten. Särskilt har geografiska och säsongsmässiga haltvariationer undersökts.

Intresset för hållbart producerade livsmedel ökar i samhället. Braxen, en allmänt förekommande fiskart i insjö- och kustvatten, är i dagsläget en outnyttjad resurs som i liten grad används för mänsklig konsumtion. Flera initiativ har emellertid tagits för att återintroducera braxen på fiskmarknaden. IVL har mot bakgrund av detta analyserat förekomsten av potentiellt hälsofarliga ämnen i braxen från några kust-och insjölokaler.

Acetylcholinesterase (AChE, EC 3.1.1.7) plays important roles in cholinergic neurotransmission and has been widely recognized as a biomarker for monitoring pollution by organophosphate (OP) and carbamate pesticides. Dioxin is an emerging environmental AChE disruptor and is a typical persistent organic pollutant with multiple toxic effects on the nervous system. Growing evidence has shown that there is a significant link between dioxin exposure and neurodegenerative diseases and neurodevelopmental disorders, most of which involve AChE and cholinergic dysfunctions. Therefore, an in-depth understanding of the effects of dioxin on AChE and the related mechanisms of action might help to shed light on the molecular bases of dioxin impacts on the nervous system. In the past decade, the effects of dioxins on AChE have been revealed in cultured cells of different origins and in rodent animal models. Unlike OP and carbamate pesticides, dioxin-induced AChE disturbance is not due to direct inhibition of enzymatic activity; instead, dioxin causes alterations of AChE expression in certain models. As a widely accepted mechanism for most dioxin effects, the aryl hydrocarbon receptor (AhR)-dependent pathway has become a research focus in studies on the mechanism of action of dioxin-induced AChE dysregulation. In this mini-review, the effects of dioxin on AChE and the diverse roles of the AhR pathway in AChE regulation are summarized. Additionally, the involvement of AhR in AChE regulation during different neurodevelopmental processes is discussed. These AhR-related findings might also provide new insight into AChE regulation triggered by diverse xenobiotics capable of interacting with AhR. (Figure presented.). © 2020 International Society for Neurochemistry

open, Toxicology in the broadest sense is the study of the adverse effects of drugs or chemicals on living systems. The questions posed by this discipline include what compounds are toxic, how and why toxicity is manifested, and how might toxicity be predicted, treated, or prevented. Some of the toxicity effects are receptor-mediated, i.e. the toxic chemical binds to a receptor that initiates a cellular response. Ligand-induced modifications of the physicochemical properties or conformational changes of the receptor can trigger transcription processes or signal-transduction cascades. Computational toxicology aims to use rules, models and algorithms based on prior data for specific endpoints, to enable the prediction of whether a molecule is or is not toxic. Computational molecular modeling methods are at the core of mechanistic toxicology, allowing to understand the mechanisms through which a given chemical induces an adverse outcome pathway. We can say that the first step of the detoxification mechanism is the xenobiotic detection by the receptors, which include: Aryl hydrocarbon Receptor (AhR) and Pregnane X Receptor (PXR). Both receptors act as transcription factor activated by ligands. The functional domain responsible for ligand recognition is the Ligand Binding Domain (LBD). Xenobiotic receptors are highly promiscuous, because they have to bind a large variety of chemicals in order to eliminate toxic compounds, which can be very diverse. Promiscuity is often achieved increasing protein flexibility and plasticity. In case of AhR, we modeled the LBD by homology modeling and managed to include flexibility during both the docking step, and the post-docking step, by a short MD simulation. This new protocol allowed the identification of three groups of ligands, each binding in a specific site inside the cavity. The differences observed in the ligand-protein interactions could result in differential effects downstream in the AhR signaling pathway, thus these findings could, La tossicologia in senso ampio è lo studio degli effetti collaterali di farmaci o altri composti sui sistemi viventi. Le domande che questa disciplina si pone includono quali composti sono tossici, come e perché manifestano tossicità, e come questa tossicità possa essere predetta, trattata e prevenuta. Alcuni effetti di tossicità sono mediati da recettori, ossia il tossico lega un recettore che scatena una risposta cellulare. Le modificazioni, indotte dal ligando, delle proprietà chimico-fisiche o conformazionali del recettore possono innescare processi trascrizionali o cascate di trasduzione del segnale. La tossicologia computazionale mira a usare regole, modelli e algoritmi basati su dati con scopi specifici, per consentire il discernimento tra molecole tossiche e non tossiche. I metodi di modellistica molecolare sono al cuore della tossicologia meccanicistica, ossia che permette di comprendere il meccanismo attraverso il quale un composto espleta la sua tossicità. Possiamo dire che il primo passo del meccanismo di detossificazione è l’individuazione del tossico da parte dei recettori, questi recettori sono: Aryl hydrocarbon Receptor (AhR) e Pregnane X Receptor (PXR). Entrambi agiscono come fattori trascrizionali attivati da ligandi. Il dominio funzionale responsabile per il riconoscimento dei ligandi è il Ligand Binding Domain (LBD). I recettori degli xenobiotici sono molto promiscui, perché devono legare una vasta gamma di composti per poter eliminare quelli tossici, essi possono essere molto diversi. La promiscuità è ottenuta spesso aumentando la flessibilità e la plasticità della proteina. Nel caso di AhR, abbiamo modellato il LBD tramite homology modeling e incluso la flessibilità sia durante la fase di docking, sia durante il post-docking, grazie ad una breve simulazione di dinamica molecolare. Abbiamo identificato tre gruppi di ligandi, ciascuno che occupa un sito diverso all’interno della cavità di legame. Le differenze osservate nelle interazioni ligando, No, embargoed_20200219, GIANI TAGLIABUE, S

Marine debris (MDs) produces a wide variety of negative environmental, economic, safety, health and cultural impacts, thus further research should focus on these kinds of waste. The present work has three main purposes: First, characterization of the MDs has been carried out in terms of their plastic composition, and their pollutant content (PAHs, ClBzs, ClPhs, BrPhs, PCDD/Fs and PCBs). Thermogravimetry has been used to identify the main constituents of the debris, using kinetic modelling to fit the proportion of each plastic. The decomposition of MDs is compared with that of their neat constituents, i.e. polyethylene (PE), polystyrene (PS), polypropylene (PP), nylon and polyethylen-tereftalate (PET). Furthermore, the analysis of pollutants in the samples reveal that MDs is not a highly contaminated waste. In addition, thermal decomposition of MD materials has been studied in a thermobalance at different atmospheres and heating rates. Second, a method for reusing the MDs is presented, consisting on the hydrothermal carbonization (HTC) of the wastes and the seawater where they are found. The plastics, once removed from the sea, cannot usually be recycled or reused. This debris has high net calorific value (NCV) what makes them suitable as a fuel. For this reason, a mixture of plastic materials was treated by HTC using seawater as a solvent, to examine the characteristics of the final products obtained and to test the feasibility of converting marine plastic debris to fuel. Results showed that an increase in the temperature of the process reduces the content of the inorganic anions and increases the NCV of the hydrochar (HTC char). The content of inorganic compounds in the HTC-liquor was measured, which increases as the process temperature rises. Organic compounds were also analyzed, being amides, alcohols and alkanes the major compounds in all cases. Finally, worried about the way in which these plastics reach the human being, microplastics where measured in sea prod

BackgroundExposure to endocrine-disrupting chemicals (EDCs) during sensitive developmental windows, such as in utero, may influence disease later in life but direct measurement of fetal hormones is not feasible. The ratio of the length of the second finger digit to the fourth digit (2D:4D), a sexually dimorphic trait, is a biomarker of androgen levels and the androgen/estrogen balance in utero. However, it is unclear whether in utero EDC exposure might alter 2D:4D ratio.AimsWe examined 2D:4D ratio in Seveso children in relation to in utero exposure to a potent EDC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using linear regression.Study designThe Seveso Women's Health Study (SWHS) is a historical cohort study, following the health of women exposed to TCDD during a 1976 explosion in Seveso, Italy. Individual-level TCDD was measured for SWHS in serum collected soon after the accident. In 2014, the SWHS children born after the explosion were enrolled in the Seveso Second Generation Study.Subjects594 SWHS children born post-explosion to 397 mothers.Outcome measuresRight hand 2D:4D ratio.ResultsOn average, 2D:4D ratio for males was significantly lower than for females (p < 0.05). Overall, in utero TCDD exposure, either as maternal initial serum TCDD concentration or as TCDD extrapolated to pregnancy was not significantly associated with 2D:4D ratio in Seveso children. Results from all adjusted sensitivity analyses remained non-significant.ConclusionsOur results suggest in utero exposure to TCDD is not associated with alteration in 2D:4D ratio.

Marine debris (MDs) produces a wide variety of negative environmental, economic, safety, health and cultural impacts, thus further research should focus on these kinds of waste. The present work has three main purposes: First, characterization of the MDs has been carried out in terms of their plastic composition, and their pollutant content (PAHs, ClBzs, ClPhs, BrPhs, PCDD/Fs and PCBs). Thermogravimetry has been used to identify the main constituents of the debris, using kinetic modelling to fit the proportion of each plastic. The decomposition of MDs is compared with that of their neat constituents, i.e. polyethylene (PE), polystyrene (PS), polypropylene (PP), nylon and polyethylen-tereftalate (PET). Furthermore, the analysis of pollutants in the samples reveal that MDs is not a highly contaminated waste. In addition, thermal decomposition of MD materials has been studied in a thermobalance at different atmospheres and heating rates. Second, a method for reusing the MDs is presented, consisting on the hydrothermal carbonization (HTC) of the wastes and the seawater where they are found. The plastics, once removed from the sea, cannot usually be recycled or reused. This debris has high net calorific value (NCV) what makes them suitable as a fuel. For this reason, a mixture of plastic materials was treated by HTC using seawater as a solvent, to examine the characteristics of the final products obtained and to test the feasibility of converting marine plastic debris to fuel. Results showed that an increase in the temperature of the process reduces the content of the inorganic anions and increases the NCV of the hydrochar (HTC char). The content of inorganic compounds in the HTC-liquor was measured, which increases as the process temperature rises. Organic compounds were also analyzed, being amides, alcohols and alkanes the major compounds in all cases. Finally, worried about the way in which these plastics reach the human being, microplastics where measured in sea prod

La tossicologia in senso ampio è lo studio degli effetti collaterali di farmaci o altri composti sui sistemi viventi. Le domande che questa disciplina si pone includono quali composti sono tossici, come e perché manifestano tossicità, e come questa tossicità possa essere predetta, trattata e prevenuta. Alcuni effetti di tossicità sono mediati da recettori, ossia il tossico lega un recettore che scatena una risposta cellulare. Le modificazioni, indotte dal ligando, delle proprietà chimico-fisiche o conformazionali del recettore possono innescare processi trascrizionali o cascate di trasduzione del segnale. La tossicologia computazionale mira a usare regole, modelli e algoritmi basati su dati con scopi specifici, per consentire il discernimento tra molecole tossiche e non tossiche. I metodi di modellistica molecolare sono al cuore della tossicologia meccanicistica, ossia che permette di comprendere il meccanismo attraverso il quale un composto espleta la sua tossicità. Possiamo dire che il primo passo del meccanismo di detossificazione è l’individuazione del tossico da parte dei recettori, questi recettori sono: Aryl hydrocarbon Receptor (AhR) e Pregnane X Receptor (PXR). Entrambi agiscono come fattori trascrizionali attivati da ligandi. Il dominio funzionale responsabile per il riconoscimento dei ligandi è il Ligand Binding Domain (LBD). I recettori degli xenobiotici sono molto promiscui, perché devono legare una vasta gamma di composti per poter eliminare quelli tossici, essi possono essere molto diversi. La promiscuità è ottenuta spesso aumentando la flessibilità e la plasticità della proteina. Nel caso di AhR, abbiamo modellato il LBD tramite homology modeling e incluso la flessibilità sia durante la fase di docking, sia durante il post-docking, grazie ad una breve simulazione di dinamica molecolare. Abbiamo identificato tre gruppi di ligandi, ciascuno che occupa un sito diverso all’interno della cavità di legame. Le differenze osservate nelle inte, Toxicology in the broadest sense is the study of the adverse effects of drugs or chemicals on living systems. The questions posed by this discipline include what compounds are toxic, how and why toxicity is manifested, and how might toxicity be predicted, treated, or prevented. Some of the toxicity effects are receptor-mediated, i.e. the toxic chemical binds to a receptor that initiates a cellular response. Ligand-induced modifications of the physicochemical properties or conformational changes of the receptor can trigger transcription processes or signal-transduction cascades. Computational toxicology aims to use rules, models and algorithms based on prior data for specific endpoints, to enable the prediction of whether a molecule is or is not toxic. Computational molecular modeling methods are at the core of mechanistic toxicology, allowing to understand the mechanisms through which a given chemical induces an adverse outcome pathway. We can say that the first step of the detoxification mechanism is the xenobiotic detection by the receptors, which include: Aryl hydrocarbon Receptor (AhR) and Pregnane X Receptor (PXR). Both receptors act as transcription factor activated by ligands. The functional domain responsible for ligand recognition is the Ligand Binding Domain (LBD). Xenobiotic receptors are highly promiscuous, because they have to bind a large variety of chemicals in order to eliminate toxic compounds, which can be very diverse. Promiscuity is often achieved increasing protein flexibility and plasticity. In case of AhR, we modeled the LBD by homology modeling and managed to include flexibility during both the docking step, and the post-docking step, by a short MD simulation. This new protocol allowed the identification of three groups of ligands, each binding in a specific site inside the cavity. The differences observed in the ligand-protein interactions could result in differential effects downstream in the AhR signaling pathway, thus these findings could

Background: Exposure to endocrine-disrupting chemicals (EDCs) during sensitive developmental windows, such as in utero, may influence disease later in life but direct measurement of fetal hormones is not feasible. The ratio of the length of the second finger digit to the fourth digit (2D:4D), a sexually dimorphic trait, is a biomarker of androgen levels and the androgen/estrogen balance in utero. However, it is unclear whether in utero EDC exposure might alter 2D:4D ratio. Aims: We examined 2D:4D ratio in Seveso children in relation to in utero exposure to a potent EDC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using linear regression. Study design: The Seveso Women's Health Study (SWHS) is a historical cohort study, following the health of women exposed to TCDD during a 1976 explosion in Seveso, Italy. Individual-level TCDD was measured for SWHS in serum collected soon after the accident. In 2014, the SWHS children born after the explosion were enrolled in the Seveso Second Generation Study. Subjects: 594 SWHS children born post-explosion to 397 mothers. Outcome measures: Right hand 2D:4D ratio. Results: On average, 2D:4D ratio for males was significantly lower than for females (p < 0.05). Overall, in utero TCDD exposure, either as maternal initial serum TCDD concentration or as TCDD extrapolated to pregnancy was not significantly associated with 2D:4D ratio in Seveso children. Results from all adjusted sensitivity analyses remained non-significant. Conclusions: Our results suggest in utero exposure to TCDD is not associated with alteration in 2D:4D ratio

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, is a persistent and ubiquitous environmental contaminant. Although the immunotoxic effects of TCDD have been reported, the mechanisms underlying these effects are still unclear. In this study, we have determined the toxic effects of TCDD on thymocytes and splenic T cells with in vitro cell culture systems. Magnetically isolated mouse splenic Th cells, Treg cells and the mixed spleen lymphocytes (SLC) were cultured and treated with TCDD and the differentiation of CD4 Th cells was determined by flow cytometery. Our results showed that different concentrations of TCDD caused immunotoxic effects through different toxicological mechanisms in both the purified mouse splenic Th cells and the mixed SLC. The low dose exposure to TCDD triggered regulatory effects in the immune system, while the high dose TCDD exposure resulted in severe immune toxicity. Notably, a decline of Treg subset was observed, suggesting an imbalanced immune regulation by TCDD treatment, as well as a possible decrease of TCDD's indirect effects on bystander immune cells. Our CD4 Th subset co-culture experiments showed that TCDD-induced pathobiology depended on immune cell balance, suggesting that cytokine-induced micro-environments further modulated toxic effects associated with TCDD exposure.

Fetal exposure to polychlorinated biphenyls (PCBs), polychlorinated-p-dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have been associated with a number of adverse health outcomes. Although the placenta acts as a barrier between the mother and the fetus, these contaminants transfer through the placenta exposing the fetus. Several studies have investigated placental transfer, but few have assessed the co-variation among these contaminants. Maternal blood, cord blood, and cord tissue were collected from 41 Japanese mother-infant pairs and analyzed for dioxin-like PCBs and PCDD/Fs. Hierarchical cluster analysis followed by principal component analysis were used to assess the co-variation. Two stable clusters of dioxin-like PCBs were found in maternal and cord blood. One cluster of low/medium chlorinated dioxin-like PCBs was present in all three matrices with 2,3',4,4',5-PeCB(#118) and 3,3',4,4',5-PeCB(#126) explaining the majority of the clusters' variances. Medium/high chlorinated dioxin-like PCBs clustered in maternal blood and cord blood but not in cord tissue. 2,3,4,4',5-PeCB(#114) and 2,3,3',4,4',5,5'-HpCB(#189) explained the majority of the clusters' variances. There was a substantial correlation between the sum of dioxin-like PCBs and total PCDD/F in all three matrices. The sum of the four suggested PCBs plus 3,3',4,4'-TeCB(#77) correlated well with total PCDD/F in all three matrices. Apart from the dioxin-like PCBs, little co-variation existed among the studied contaminants. The five PCBs can be used as fetal exposure markers for dioxin and dioxin-like PCBs in maternal and cord blood respectively. In cord tissue, more higher chlorinated dioxin-like PCBs need to be measured as well.

Fetal exposure to polychlorinated biphenyls (PCBs), polychlorinated-p-dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have been associated with a number of adverse health outcomes. Although the placenta acts as a barrier between the mother and the fetus, these contaminants transfer through the placenta exposing the fetus. Several studies have investigated placental transfer, but few have assessed the co-variation among these contaminants. Maternal blood, cord blood, and cord tissue were collected from 41 Japanese mother-infant pairs and analyzed for dioxin-like PCBs and PCDD/Fs. Hierarchical cluster analysis followed by principal component analysis were used to assess the co-variation. Two stable clusters of dioxin-like PCBs were found in maternal and cord blood. One cluster of low/medium chlorinated dioxin-like PCBs was present in all three matrices with 2,3',4,4',5-PeCB(#118) and 3,3',4,4',5-PeCB(#126) explaining the majority of the clusters' variances. Medium/high chlorinated dioxin-like PCBs clustered in maternal blood and cord blood but not in cord tissue. 2,3,4,4',5-PeCB(#114) and 2,3,3',4,4',5,5'-HpCB(#189) explained the majority of the clusters' variances. There was a substantial correlation between the sum of dioxin-like PCBs and total PCDD/F in all three matrices. The sum of the four suggested PCBs plus 3,3',4,4'-TeCB(#77) correlated well with total PCDD/F in all three matrices. Apart from the dioxin-like PCBs, little co-variation existed among the studied contaminants. The five PCBs can be used as fetal exposure markers for dioxin and dioxin-like PCBs in maternal and cord blood respectively. In cord tissue, more higher chlorinated dioxin-like PCBs need to be measured as well.

Fetal exposure to polychlorinated biphenyls (PCBs), polychlorinated-p-dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have been associated with a number of adverse health outcomes. Although the placenta acts as a barrier between the mother and the fetus, these contaminants transfer through the placenta exposing the fetus. Several studies have investigated placental transfer, but few have assessed the co-variation among these contaminants. Maternal blood, cord blood, and cord tissue were collected from 41 Japanese mother-infant pairs and analyzed for dioxin-like PCBs and PCDD/Fs. Hierarchical cluster analysis followed by principal component analysis were used to assess the co-variation. Two stable clusters of dioxin-like PCBs were found in maternal and cord blood. One cluster of low/medium chlorinated dioxin-like PCBs was present in all three matrices with 2,3',4,4',5-PeCB(#118) and 3,3',4,4',5-PeCB(#126) explaining the majority of the clusters' variances. Medium/high chlorinated dioxin-like PCBs clustered in maternal blood and cord blood but not in cord tissue. 2,3,4,4',5-PeCB(#114) and 2,3,3',4,4',5,5'-HpCB(#189) explained the majority of the clusters' variances. There was a substantial correlation between the sum of dioxin-like PCBs and total PCDD/F in all three matrices. The sum of the four suggested PCBs plus 3,3',4,4'-TeCB(#77) correlated well with total PCDD/F in all three matrices. Apart from the dioxin-like PCBs, little co-variation existed among the studied contaminants. The five PCBs can be used as fetal exposure markers for dioxin and dioxin-like PCBs in maternal and cord blood respectively. In cord tissue, more higher chlorinated dioxin-like PCBs need to be measured as well.