To 2,3,7,8-tetrachlorodibenzo-p-dioxin Research Articles

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces peripheral blood abnormalities and plasma cell neoplasms resembling multiple myeloma in mice

Although epidemiologic studies have suggested a possible association between occupational exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the risk of development of multiple myeloma, definitive evidence in support of this association is lacking. In the present study, we employed the Vk*Myc mouse model of multiple myeloma to assess the impact of TCDD exposure on multiple myeloma pathogenesis. TCDD induced splenomegaly and multiple peripheral blood abnormalities, including anemia and high serum IgG levels. In addition, TCDD triggered bone lytic lesions, as well as renal tubular casts, a phenomenon associated with human myeloma kidney disease. Even in wild-type C57BL/6 mice, TCDD increased serum IgG levels, induced anemia, and increased plasma cell presence in the spleen and bone marrow, hallmarks of benign monoclonal gammopathy. Lastly, TCDD induced AKT activation and the DNA damage response, key pathogenic events in myeloma pathogenesis, in animal spleen and/or bone marrow. These data indicate that TCDD accelerates monoclonal gammopathy development and promotes progression to multiple myeloma in genetically-predisposed mice. This work offers the first direct experimental evidence establishing TCDD as an environmental risk factor for monoclonal gammopathy of undetermined significance and multiple myeloma.

Identification and characterization of long non-coding RNAs in porcine granulosa cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

BackgroundLong non-coding RNAs (lncRNAs) may regulate gene expression in numerous biological processes including cellular response to xenobiotics. The exposure of living organisms to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, results in reproductive defects in many species including pigs. The aims of the study were to identify and characterize lncRNAs in porcine granulosa cells as well as to examine the effects of TCDD on the lncRNA expression profile in the cells.ResultsOne thousand six hundred sixty-six lncRNAs were identified and characterized in porcine granulosa cells. The identified lncRNAs were found to be shorter than mRNAs. In addition, the number of exons was lower in lncRNAs than in mRNAs and their exons were longer. TCDD affected the expression of 22 lncRNAs (differentially expressed lncRNAs [DELs]; log2 fold change ≥ 1, P-adjusted < 0.05) in the examined cells. Potential functions of DELs were indirectly predicted via searching their target cis- and trans-regulated protein-coding genes. The co-expression analysis revealed that DELs may influence the expression of numerous genes, including those involved in cellular response to xenobiotics, dioxin metabolism, endoplasmic reticulum stress and cell proliferation. Aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1) were found among the trans-regulated genes.ConclusionsThese findings indicate that the identified lncRNAs may constitute a part of the regulatory mechanism of TCDD action in granulosa cells. To our knowledge, this is the first study describing lncRNAs in porcine granulosa cells as well as TCDD effects on the lncRNA expression profile. These results may trigger new research directions leading to better understanding of molecular processes induced by xenobiotics in the ovary.

Cohort study of workers at a New Zealand agrochemical plant to assess the effect of dioxin exposure on mortality

ObjectivesTo describe how the exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) influenced mortality in a cohort of workers who were exposed more recently, and at lower levels, than other cohorts of trichlorophenol process...

In Utero Dioxin Exposure and Age at Menarche in the Seveso Second Generation

Introduction: In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant and potent endocrine disrupting compound, is associated with delayed pubertal development in animal studies. On July 10, 1976, an explosion at a chemical plant near Seveso, Italy exposed nearby residents to high levels of TCDD. The Seveso Women&amp;#8217;s Health Study (SWHS), initiated in 1996, is the only study to date of TCDD&amp;#8217;s health effects in a female population with the unique benefit of individual TCDD measured in blood collected near the time of the explosion. In 2014, we enrolled SWHS offspring (those exposed in utero to TCDD) in the Seveso Second Generation study. We examined the relationship of in utero TCDD exposure with reported age at onset of menarche among SWHS daughters.Methods: Age at onset of menarche (in years) was collected by maternal or self-report at interview in 341 SWHS daughters. We defined in utero TCDD exposure as initial (1976) maternal serum TCDD level and TCDD extrapolated to pregnancy. Data were analyzed using Cox proportional hazards models.Results: At interview, 287 daughters were postmenarche, averaging 25.6 (&amp;#177;8.0) years of age. The mean reported age at menarche was 12.1 (&amp;#177;1.3) years. Overall, we found no change in risk of menarche onset with a 10-fold increase in initial maternal TCDD (Hazard Ratio (HR) &amp;#61; 0.91, 95% CI 0.79, 1.06) or TCDD estimated at pregnancy (HR &amp;#61; 0.86, 95% CI 0.72, 1.03). When we considered maternal menarche status at explosion as a potentially sensitive developmental exposure window, TCDD estimated at pregnancy (log10) was associated with later age at menarche among daughters whose mothers were premenarche at explosion (HR &amp;#61; 0.71, 95% CI 0.50, 1.00) but not postmenarche at explosion (HR &amp;#61; 0.87, 95% CI 0.71, 1.07).Conclusions: These results suggest in utero exposure to TCDD may alter pubertal timing among daughters of women who were prepubescent at the time of the Seveso accident.

The effect of prenatal exposure on disposition of hexachloronaphthalene in female Wistar rats and fetal compartment.

Due to structural and toxicological similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated naphthalenes (PCNs) were included in the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2015. Hexachloronaphthalene (HxCN) is considered to be one of the most toxic congeners of PCNs. The objective of this study was to determine the maternal and fetal tissue concentrations of hexachloronaphthalene after a single administration. Pregnant female Outbred Wistar rats were used for the study. The [14C]-HxCN was administered in a single oral dose of 0.3 mg/rat (150 kBq/rat) on gestational day 17 (GD17), GD18 or GD19. All dams were sacrificed on GD20. The blood and selected tissue samples taken from mothers and fetuses 24 h, 48 h or 72 h after exposure were evaluated for the distribution of HxCN. Maximum concentrations of HxCN in pregnant rats were found in the liver and adipose tissue. Relatively high levels of HxCN were also reported in the spleen, ovaries, adrenal glands and uterus, as well as in the sciatic nerve, brain and kidneys. Hexachloronaphthalene penetrates through the blood-brain barrier (BBB), as evidenced by twice the concentration in the brain compared to the blood concentration, and through the placental barrier, as indicated by the level of maternal-fetal compartment (placenta, amniotic fluid, litter). Among the examined fetal tissues, the highest levels of HxCN were found in the kidneys and in the brain. The concentrations in these organs were higher than that found in the maternal blood. This paper is the first to detail the concentrations of HxCN in the maternal tissues and the transplacental transfer of the tested compound to the fetuses. The exposure of pregnant rats to HxCN results in its accumulation in the maternal liver, fat tissue, reproductive and nervous system, and particularly in the fetal brain. This demonstrates both the effective absorption and significant systemic accumulation which could lead to negative health implications. Int J Occup Med Environ Health 2018;31(5):685-695.

In Utero Dioxin Exposure and Fertility of the Seveso Second Generation

Background/Aim: In animal studies, maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with decreased fertility in offspring. The Seveso Women’s Health Study (SWHS) of women exposed to TCDD in 1976 is unique in that we measured TCDD blood levels near the time of the explosion. In 2014, we initiated the Seveso Second Generation Health Study. We aim to examine the relationship of in utero TCDD exposure with time to pregnancy (TTP) and infertility among SWHS daughters. Methods: We asked SWHS children ≥ 18 years about their pregnancy history, including time to pregnancy and infertility. Of 225 daughters, 80 had attempted pregnancy. Of these, 66 had delivered a livebirth not associated with contraceptive failure and 4 reported still trying unsuccessfully after 12 or more months. We defined in utero TCDD exposure as: 1) initial maternal serum TCDD concentration and 2) TCDD estimated at pregnancy. We examined the relation of in utero TCDD to TTP (parameterized as the monthly probability of conception within the first 12 months of trying) and to infertility (defined as conception after at least 12 months of trying). We modelled fecundability with discrete-time Cox proportional hazards regression and fertility with logistic regression. Results: Women averaged 30.0 (±3.5) years at the time of attempting pregnancy. Median TTP was 2 months and 15.7% reported taking 12 or more months to conceive. A 10-fold increase in initial maternal TCDD was non-significantly associated with longer TTP (adjusted fecundability odds ratio = 0.61; 95%CI: 0.32, 1.18) and increased odds of infertility (adjusted odds ratio= 1.38; 95%CI: 0.36, 5.36). Results for TCDD estimated at pregnancy will be presented. Conclusions: These results are consistent with animal studies and suggest in utero TCDD exposure may alter fertility in female offspring. However, sample size of pregnancies is lower than expected given the age of the female population.

Alterations in DNA methyltransferases and methyl-CpG binding domain proteins during cleft palate formation as induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cleft palate formation in mice. This TCDD treatment, which may be considered an environmental factor in cleft palate formation, is associated with alterations in DNA methylation. However, the underlying molecular mechanisms of DNA methylation produced by TCDD in mouse embryos are poorly understood. DNA methyltransferases (DNMTs) and methyl‑CpG binding domain proteins (MBDs) are thought to be closely associated with the actions of DNA methylation. Therefore, the present study tested the hypothesis that this cleft palate inducing effect of TCDD will alter the expression levels of DNMTs and various MBDs in palate tissue of fetal mice. Pregnant C57BL/6Jmice were treated with either TCDD (64µg/kg) or corn oil (control) at embryonic day10.5 (E10.5) and fetal palates were harvested for structural and molecular analyses at E13.5, E14.5, E15.5 and E17.5. Expression levels of DNMTs and MBDs were assayed using reverse transcription‑quantitative polymerase chain reaction and western blotting. The incidence of cleft palates in the TCDD group was 98.24%, whereas no cases of cleft palate were observed in the control group. Expression levels of DNMTs and MBDs were significantly increased in the TCDD group compared with the control. The results demonstrate clear alterations in DNMTs and MBDs, as induced by TCDD, and suggest that such alterations are important in cleft palate formation in fetal mice.

Modulating effect of selected pharmaceuticals on bone in female rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

This paper discusses the problems connected with the influence of TCDD on the mechanical properties and structure of the bone tissue in female rats treated with the dioxin. Moreover an analysis of the protective role of tocopherol, acetylsalicylic acid, dexamethazone and levamisol was performed. Rat tibiae were assessed by mechanical testing, and histological and trace element analysis. It was proved that TCDD has negative effect on bone mechanical properties, histological microstructure and trace element content. The results indicate that usage of both steroid and non-steroid anti-inflammatory medicaments, along with tocopherol and levamisol, modulating their activity, can reduce the negative effect of dioxin activity on the bone tissue of female rats intoxicated with TCDD.

THE PROTECTIVE EFFECTS OF GREEN TEA AND CURCUMIN AGAINST 2, 3, 7, 8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) INDUCED HEPATOTOXICIY IN ADULT MALE MICE

Exposure to 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) as an environmental pollutant caused hepatotoxicity and tumor promotion. Recently researchers pay an attention to the power of green tea (GT) and curcumin (CUR) as natural antioxidants against cellular damage. The present study was designed to evaluate the protective role of GT and CUR against TCDD-induced hepatotoxicity in mice. Fifty adult male mice were divided into 5 groups as follows: G1; control received vehicles, G2: treated with oral dose of TCDD (1.332 mg/kg bw) and left as positive control, G3, G4 and G5 were treated with GT (0.5 mg/kg bw), CUR (0.5 m /kg bw), and the combination of GT and CUR (1 mg/kg bw) 30 minutes before injection with oral dose of TCDD (1.332 mg/kg bw), respectively. After 30 days of daily treatment with the antioxidants and TCDD mice were killed for collection of liver. Histological studies using light and electron microscopy were done in addition to the estimation of antioxidants parameters; catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH). Microscopically observations showed necrosis, inflammatory reactions, increased collagen, decreased polysaccharides and protein contents, and reduction in the antioxidants in the liver of mice treated with TCDD. However, the liver of mice treated with GT, CUR, and the combination showed improvement in the histological structure of the liver with enhancement in the antioxidants levels with the priority for the GT. In conclusion, TCDD induced histological and biochemical changes in the hepatic tissue and the ability of GT and/or CUR to prevent these changes was due to their activity as powerful antioxidants.

Roles of cytosolic phospholipase A2\u03b1 in reproductive and systemic toxicities in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mice

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a variety of toxicities upon binding of TCDD to aryl hydrocarbon receptor. Although this binding upregulates the synthesis of prostaglandins and their related lipid mediators via cytosolic phospholipase A2α (cPLA2α), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA2α in TCDD toxicities using cPLA2α-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 μg/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA2α-null type was significantly less than that of wild-type in TCDD-exposed litters. TCDD-induced hydronephrosis was more severe in wild-type fetuses than in cPLA2α-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α were increased in a cPLA2α-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 μg/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA2α-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA2α-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA2α is involved in TCDD-induced body weight loss, lipid accumulation in the liver, fetal hydronephrosis, and cytokine gene expression, and that the molecular basis of TCDD toxicity differs considerably between target tissues and life stages.

Morbidity in New Zealand pesticide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

ObjectivesTo conduct a cross-sectional morbidity survey among 245 former employees of a pesticide production plant exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in New Zealand. MethodsDemographic factors and health information were collected in face-to-face interviews. TCDD, lipids, thyroid hormones, glucose and immunoglobulin G (IgG) were determined in non-fasting blood. For 111 participants, a neurological examination was conducted. Associations between health outcomes and working in a TCDD exposed job (prevalence 49%) and serum TCDD concentration≥10pg/g lipid (18%) were assessed using logistic regression whilst controlling for age, gender, smoking, body mass index and ethnicity. ResultsDiabetes was more common in those who had worked in TCDD exposed jobs (OR 4.0, 95%CI 1.0–15.4) and in those with serum TCDD ≥10pg/g (OR 3.1, 95%CI 0.9–10.7). Non-fasting glucose levels >6.6mmol/l were more common in those with TCDD exposed jobs (OR 3.6, 95%CI 1.0–12.9), as were serum free thyroxine 4<12.8pmol/l (OR 4.5, 95%CI 1.4–14.4), triglycerides >1.7mmol/l (OR 2.5, 95%CI 1.1–5.7) and high density lipoprotein cholesterol (HDL) <1mmol/l (OR 4.0, 95%CI 1.2–13.2). IgG was negatively associated with TCDD (linear regression p=0.05). The neurological examination revealed a higher frequency of abnormal reflexes in those with serum TCDD ≥10pg/g (OR 4.8, 95%CI 1.1–21.0). ConclusionsIn this occupationally exposed population, TCDD was associated with an increased risk of diabetes and a range of subclinical responses in multiple systems (peripheral nervous system, immune system, thyroid hormones and lipid metabolism), several decades after last exposure. These results need to be interpreted with caution due to the small study size and the cross-sectional nature of the study.

Aryl Hydrocarbon Receptor Ablation in Cardiomyocytes Protects Male Mice From Heart Dysfunction Induced by NKX2.5 Haploinsufficiency.

Epidemiological studies in humans and research in vertebrates indicates that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous and biopersistent environmental toxicant, is associated with incidence of early congenital heart disease in the embryo and later in the adult. TCDD-mediated toxicity depends on the aryl hydrocarbon receptor (AHR) but the role of the TCDD-activated AHR in cardiac function is not well-defined. To characterize the mechanisms responsible for AHR-mediated disruption of heart function, we generated several mouse strains with cardiomyocyte-specific Ahr gene knockout. Here, we report results on one of these strains in which the Ahr gene was deleted by cre recombinase regulated by the promoter of the cardiomyocyte-specific Nkx2.5 gene. We crossed mice with loxP-targeted Ahrfx/fx alleles with Nkx2.5+/cre mice bearing a "knock-in" cre recombinase gene integrated into one of the Nkx2.5 alleles. In these mice, loss of one Nkx2.5 allele is associated with disrupted cardiac development. In males, Nkx2.5 hemizygosity resulted in cardiac haploinsufficiency characterized by hypertrophy, dilated cardiomyopathy, and impaired ejection fraction. Ahr ablation protected Nkx2.5+/cre haploinsufficient males from cardiac dysfunction while inducing a significant increase in body weight. These effects were absent or largely blunted in females. Starting at 3 months of age, mice were exposed by oral gavage to 1 μg/kg/week of TCDD or control vehicle for an additional 2 months. TCDD exposure restored cardiac physiology in aging males, appearing to compensate for the heart dysfunction caused by Nkx2.5 hemizygosity. Our findings underscore the conclusion that deletion of the Ahr gene in cardiomyocytes protects males from heart dysfunction due to NKX2.5 haploinsufficiency.

Chronic exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces an obesogenic effect in C57BL/6J mice fed a high fat diet

Contaminant involvement in the pathophysiology of obesity is widely recognized. It has been shown that low dose and chronic exposure to endocrine disruptor compounds (EDCs) potentiated diet- induced obesity. High and acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant (POP) and an EDC with anti-estrogenic property, causes wasting syndrome . However at lower doses, the TCDD metabolic effects remain poorly understood. We investigated the obesogenic effect during chronic exposure of TCDD at 1μg/kg body weight (bw)/week in adult C57BL/6J mice fed with a high fat diet (HFD) and exposed from 10 to 42 weeks old to TCDD or equal volume of vehicle by intragastric gavage. Under these conditions, TCDD was obesogenic in adult mice (7% in males and 8% in females), which was linked to fat mass. A sex effect was observed in the fat mass distribution in adipose tissue and in the hepatic triglyceride content evolution. In visceral fat pad weight, we observed a decrease (11%) in males and an increase (14%) in females. The hepatic triglyceride content increase (41%) in females only. TCDD failed to induce any change in plasma parameters regarding glucose and lipid homeostasis. Messenger ribonucleic acid (mRNA) levels involved in adipose tissue and hepatic metabolism, inflammation, xenobiotic metabolism and endocrine disruption were differently regulated between males and females. In conclusion, these results provide new evidence that dioxin, a POP and EDC can be obesogenic for adult mice with multi-organ effects.

Age at Menopause: Do Chemical Exposures Play a Role?

Age at Menopause: Do Chemical Exposures Play a Role?

The aryl hydrocarbon receptor in T cells contributes to sustaining oral tolerance against ovalbumin in a mouse model.

Oral tolerance (OT) towards antigens encountered in the gut is a vital immune function of gut immunity. Experimental models can demonstrate OT efficacy by feeding of a protein followed by peripheral immunization and measuring the specific antibody titer. We had previously shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a xenobiotic high-affinity aryl hydrocarbon receptor (AhR)-ligand, destabilized OT against ovalbumin (OVA) in mice. AhR is involved in the development, differentiation and function of immune cells, and highly expressed in gut epithelial cells and gut immune cells. We here used AhR-deficient mice to study the role of AhR in OT further. We show that complete AhR-deficiency undermines the stability of oral tolerance against OVA upon multiple immunizations, despite no renewed oral encounter with the antigen. This OT destabilization is accompanied by significant changes in IL10 and TGFβ RNA in the gut tissue. Using conditional AhR-deficient mouse lines, we identify T cells as the major responsible immune cell type in this context. Our findings add to knowledge that lack of AhR signaling in the gut impairs important gut immune functions.

The Influence of \u03b1-Tocopherol on Serum Biochemical Markers During Experimentally Induced Pleuritis in Rats Exposed to Dioxin

Toxicity of dioxins is wide ranging. Amongst the organs, the liver is the most susceptible to damage by dioxins. Damage caused to liver cells results in promoting inflammatory processes. The aim of this work was to evaluate whether high doses of tocopherol will change the inflammatory response, monitored by biochemical indicators, by improving liver function in rats exposed to tetrachlorodibenzo-p-dioxin (TCDD). The study was conducted on a population of female Buffalo rats. The animals were divided into the following groups: Control Group A—representing physiological norms for the studied diagnostic indicators; Control Group B—subjects were administered a 1% ceragenin solution to induce pleuritis; Study Group 1—where rats were administered α-tocopherol acetate for 3 weeks, after which pleuritis was induced; Study Group 2—rats were administered a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), while 3 weeks later, pleuritis was induced; and Study Group 3—rats were administered a single dose of TCDD and next, were administered α-tocopherol acetate for 3 weeks, followed by pleuritis induction. The results clearly show that administering tocopherol in the course of inflammation causes changes to the distribution and ratio of in the serum protein fractions, including acute phase proteins. The latter proteins are indicative to the improvement in liver function and linked to protein synthesis and stimulation of the antibody-mediated immunity. Moreover, in the course of inflammation caused by exposure of rats to TCDD, tocopherol significantly affected the acute phase protein concentration.

DNA Product Formation in Female Sprague-Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure.

DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague–Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC–MS/MS: 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGuo); 1,N6-etheno-2′-deoxyadenosine (1,N6-εdAdo); N2,3-ethenoguanine (N2,3-εG); 7-(2-oxoethly)guanine (7-OEG); 1,N2-etheno-2′-deoxyguanosine (1,N2-εdGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2′-deoxyguanosine adducts. Exposure to TCDD (100 ng/kg/day) significantly induced 1,N6-εdAdo at 31 and 53 weeks, while no increase of 8-oxo-dGuo was observed. Significant increases were observed for 8-oxo-dGuo and 1,N6-εdAdo at all time points following exposure to the tertiary mixture (TEQ 100 ng/kg/day). Exposure to TCDD for 53 weeks only significantly increased 1,N6-εdAdo, while increases of N2,3-εG and 7-OEG were only found in the highest dose group (100 ng/kg/day). Exposure to the tertiary mixture for 53 weeks had no effect on N2,3-εG in any exposure group (TEQ 0, 22, 46, or 100 ng/kg/day), while significant increases were observed for 1,N6-εdAdo (all dose groups), 8-oxo-dGuo (46 and 100 ng/kg/day), and 7-OEG (100 ng/kg/day). While no significant increase was observed at 53 weeks for 1,N2-εdGuo, M1dGuo, AcrdGuo, or CrdGuo following exposure to TCDD (100 ng/kg/day), all of them were significantly induced in animals exposed to the tertiary mixture (TEQ 100 ng/kg/day). This oxidation DNA product data suggest that the simple TEF methodology cannot be applied to evaluate the diverse patterns of toxic effects induced by DLCs.

From Sediment to Top Predators: Broad Exposure of Polyhalogenated Carbazoles in San Francisco Bay (U.S.A.).

The present study provides the first comprehensive investigation of polyhalogenated carbazoles (PHCZs) contamination in an aquatic ecosystem. PHCZs have been found in soil and aquatic sediment from several different regions, but knowledge of their bioaccumulation and trophodynamics is extremely scarce. This work investigated a suite of 11 PHCZ congeners in San Francisco Bay (United States) sediment and organisms, including bivalves (n = 6 composites), sport fish (n = 12 composites), harbor seal blubber (n = 18), and bird eggs (n = 8 composites). The most detectable congeners included 3,6-dichlorocarbazole (36-CCZ), 3,6-dibromocarbazole (36-BCZ), 1,3,6-tribromocarbazole (136-BCZ), 1,3,6,8-tetrabromocarbazole (1368-BCZ), and 1,8-dibromo-3,6-dichlorocarbazole (18-B-36-CCZ). The median concentrations of ΣPHCZs were 9.3 ng/g dry weight in sediment and ranged from 33.7 to 164 ng/g lipid weight in various species. Biomagnification was observed from fish to harbor seal and was mainly driven by chlorinated carbazoles, particularly 36-CCZ. Congener compositions of PHCZs differed among species, suggesting that individual congeners may be subject to different bioaccumulation or metabolism in species occupying various trophic levels in the studied aquatic system. Toxic equivalent (TEQ) values of PHCZs were determined on the basis of their relative effect potencies (REP) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The median TEQ was 1.2 pg TEQ/g dry weight in sediment and 4.8-19.5 pg TEQ/g lipid weight in biological tissues. Our study demonstrated the broad exposure of PHCZs in San Francisco Bay and their characteristics of bioaccumulation and biomagnification along with dioxin-like effects. These findings raise the need for additional research to better elucidate their sources, environmental behavior, and fate in global environments.

Sex ratio of the offspring of New Zealand phenoxy herbicide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

ObjectivesExposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inconsistently been associated with a decreased sex ratio of the offspring (number of male births divided by total births). We conducted a study among men...

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis.

We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1β, -2, -4, -6, and -10, as well as TNF-α and IFN-γ, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNA-Seq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.