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

Neurodevelopmental Effects of Perinatal TCDD Exposure Differ from Those of Other PCDD/Fs in Vietnamese Children Living near the Former US Air Base in Da Nang, Vietnam

This study reports that children exposed to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), the major toxin in Agent Orange, from the breast milk of mothers residing near the former Da Nang US air base in Vietnam may have specific alterations in higher brain functions, resulting in social and communication deficits, including autism spectrum disorder (ASD). After the age of 8 years, girls with high TCDD showed increased attention deficit hyperactivity disorder (ADHD)-like behaviors and altered mirror neuron activity, which is often observed in children with ASD. However, no significant relationship between autistic traits and toxic equivalency values of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (TEQ-PCDD/Fs) was found in these children. Notably, boys with high levels of TEQ-PCDD/Fs showed poor language and motor development in the first 3 years of life, although boys with high TCDD levels did not. However, at 8 years of age, boys with high TCDD showed reading learning difficulties, a neurodevelopmental disorder. These findings suggest that perinatal TCDD exposure impacts social-emotional cognitive functions, leading to sex-specific neurodevelopmental disorders-learning difficulty in boys and ADHD in girls. Future studies with a greater number of children exposed to high levels of TCDD are necessary to estimate the threshold values for neurodevelopmental effects.

Comparative Toxicotranscriptomics of Single Cell RNA-Seq and Conventional RNA-Seq in TCDD-Exposed Testicular Tissue.

In this report, we compare the outcomes and limitations of two methods of transcriptomic inquiry on adult zebrafish testes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during sexual differentiation: conventional or bulk RNA-seq (bulk-seq) and single cell RNA sequencing (scRNA-seq) data. scRNA-seq has emerged as a valuable tool for uncovering cell type-specific transcriptome dynamics which exist in heterogeneous tissue. Our lab previously showed the toxicological value of the scRNA-seq pipeline to characterize the sequelae of TCDD exposure in testes, demonstrating that loss of spermatids and spermatozoa, but not other cell types, contributed to the pathology of infertility in adult male zebrafish exposed during sexual differentiation. To investigate the potential for technical artifacts in scRNA-seq such as cell dissociation effects and reduced transcriptome coverage, we compared bulk-sequenced and scRNA-seq-paired samples from control and TCDD-exposed samples to understand what is gained and lost in scRNA-seq vs bulk-seq, both transcriptomically and toxicologically. We hypothesized that the testes may be sensitive to tissue disruption as they contain multiple cell types under constant division and/or maturation, and that TCDD exposure may mediate the extent of sensitivity. Thus, we sought to understand the extent to which this dissociation impacts the toxicological value of data returned from scRNA-seq. We confirm that the required dissociation of individual cells from intact tissue has a significant impact on gene expression, affecting gene pathways with the potential to confound toxicogenomics studies on exposures if findings are not well-controlled and well-situated in context. Additionally, a common scRNA-seq method using cDNA amplified from the 3’ end of mRNA under-detects low-expressing transcripts including transcription factors. We confirm this, and show TCDD-related genes may be overlooked by scRNA-seq, however, this under-detection effect is not mediated by TCDD exposure. Even so, scRNA-seq generally extracted toxicologically relevant information better than the bulk-seq method in the present study. This report aims to inform future experimental design for transcriptomic investigation in the growing field of toxicogenomics by demonstrating the differential information extracted from sequencing cells—despite being from the same tissue and exposure scheme—is influenced by the specific protocol used, with implications for the interpretation of exposure-induced risk.

Activation of the aryl hydrocarbon receptor positively regulates gut migration markers on mouse B cells

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that links diet and environmental factors to intestinal immune function. Activation of the AhR has been shown to enhance migration to the gut by some murine CD4+ T cells with upregulated expression of CCR9. In B cells, AhR activation has been shown to suppress B cell activation and class switch recombination (CSR), but an impact on B cell migration has not been explored. Because AhR activation can enhance fecal over serum IgA levels in mice, we hypothesized that AhR activation increases B cell migration to the gut. To test this hypothesis, we examined the expression of α4β7 and CCR9 on mouse CD19+ spleen cells in vitro. Cells were activated under conditions to stimulate CSR to IgA (poly-IgD-Dextran + LPS + TGF-β), cultured with AhR ligands for 96 hours, and analyzed by flow cytometry. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (50 nM) did not change α4β7 surface expression (mean fluorescence intensity, MFI), but the MFI for CCR9 was significantly increased by 96.7% (P < 0.05) when compared to CH-223191 exposure (AhR antagonist, 100 μM). Similarly, when comparing exposure to TCDD versus CH-223191, TCDD exposure increased the percentage of α4β7+ and CCR9+ cells by 3.8% and 23.3%, respectively (P < 0.05). These results suggest that enhanced migration of B cells to the gut may be positively regulated by AhR activation. Supported by University of Northern Colorado

Effects of perinatal TCDD exposure on colonic microbiota and metabolism in offspring and mother mice

Emerging evidence supports that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impacts the gut microbiota and metabolic pathways. TCDD can be transmitted from mother to child; thus, we hypothesize that maternal exposure to TCDD may affect the gut microbiota in mothers and offspring. To acquire in vivo evidence supporting this hypothesis, female C57BL/6 mice were administered with TCDD (0.1 and 10 μg/kg body weight (bw)) during pregnancy and lactation periods, and then changes of colonic microbiota in offspring and mothers were evaluated. High-throughput sequencing of the V4 regions of the 16S rRNA gene was performed. The composition and structure of the colonic microbiota in offspring and mothers were significantly influenced by 10 μg/kg bw TCDD as demonstrated by upregulation of harmful bacteria and downregulation of beneficial bacteria. Paradoxically, pathogenic bacteria and opportunistic pathogens were conversely decreased in the offspring of the low-dose TCDD treatment group. Tryptophan (Trp) metabolism exhibited a noticeable change caused by the alteration of colonic microbiota in offspring after maternal exposure to 10 μg/kg bw TCDD, which showed a linear dependence, demonstrating that pathogens or opportunistic pathogens may accelerate the dysbiosis of Trp metabolism. Trp metabolism dysregulation caused by the changed colonic microbiota may subsequently impact other intestinal segments or even living organisms. Our study provides new evidence indicating a potential influence of early TCDD exposure on the colonic microbiota and metabolism.

Inflammasome activation in psychosis – Consequence of peripheral dyslipidaemia or reflection of an inflammatory pathogenesis?

Recent studies have shown that the aryl hydrocarbon receptor (AhR) is expressed in the brain’s native immune cells, known as microglia. However, while the impact of exposure to AhR ligands is well studied in the peripheral immune system, the impact of such exposure on immune function in the brain is less well defined. Microglia serve dual roles in providing synaptic and immunological support for neighboring neurons and in mediating responses to environmental stimuli, including exposure to environmental chemicals. Because of their dual roles in regulating physiological and pathological processes, cortical microglia are well positioned to translate toxic stimuli into defects in cortical function via aberrant synaptic and immunological functioning, mediated either through direct microglial AhR activation or in response to AhR activation in neighboring cells. Here, we use gene expression studies, histology, and two-photon in vivo imaging to investigate how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity and persistent AhR agonist, modulates microglial characteristics and function in the intact brain. Whole cortical RT-qPCR analysis and RNA-sequencing of isolated microglia revealed that gestational and lactational TCDD exposure produced subtle, but durable, changes in microglia transcripts. Histological examination and two-photon in vivo imaging revealed that while microglia density, distribution, morphology, and motility were unaffected by TCDD exposure, exposure resulted in microglia that responded more robustly to focal tissue injury. However, this effect was rectified with depletion and repopulation of microglia. These results suggest that gestational and lactational exposure to AhR ligands can result in long-term priming of microglia to produce heightened responses towards tissue injury which can be restored to normal function through microglial repopulation.

Gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin primes cortical microglia to tissue injury

Recent studies have shown that the aryl hydrocarbon receptor (AhR) is expressed in the brain’s native immune cells, known as microglia. However, while the impact of exposure to AhR ligands is well studied in the peripheral immune system, the impact of such exposure on immune function in the brain is less well defined. Microglia serve dual roles in providing synaptic and immunological support for neighboring neurons and in mediating responses to environmental stimuli, including exposure to environmental chemicals. Because of their dual roles in regulating physiological and pathological processes, cortical microglia are well positioned to translate toxic stimuli into defects in cortical function via aberrant synaptic and immunological functioning, mediated either through direct microglial AhR activation or in response to AhR activation in neighboring cells. Here, we use gene expression studies, histology, and two-photon in vivo imaging to investigate how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity and persistent AhR agonist, modulates microglial characteristics and function in the intact brain. Whole cortical RT-qPCR analysis and RNA-sequencing of isolated microglia revealed that gestational and lactational TCDD exposure produced subtle, but durable, changes in microglia transcripts. Histological examination and two-photon in vivo imaging revealed that while microglia density, distribution, morphology, and motility were unaffected by TCDD exposure, exposure resulted in microglia that responded more robustly to focal tissue injury. However, this effect was rectified with depletion and repopulation of microglia. These results suggest that gestational and lactational exposure to AhR ligands can result in long-term priming of microglia to produce heightened responses towards tissue injury which can be restored to normal function through microglial repopulation.

Preventive effects of yogurt fortified with purple roselle extract against cardiotoxicity in rats exposed with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Dioxin is one of the environmental persistent organic pollutants that harm animal and human health. Prolonged exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can disrupt normal organ function including heart. Yogurt is known to have antioxidant properties, and fortification natural plant-based antioxidant purple roselle (Hibiscus sabdariffa L) extract into yogurt can improve the antioxidant potential. The purpose of this study was to determine the preventive effect of yogurt fortified with purple roselle on dioxin exposure rats (Rattus norvegicus) based on the levels of Malondialdehyde (MDA) and histopathological of the heart. This experimental study using a completely randomized design (CRD). A total of 30 male Wistar rats were divided into 5 groups (NC, PC, T1, T2, T3), a dose of 200 ng/kg BW TCDD and 1 mL of roselle yogurt 0.5%, 1.0%, and 1.5% were given orally for 12 days. MDA levels were analyzed using the Thiobarbituric Acid (TBA) assay and histopathology of the heart using the Haematoxylin Eosin (HE) staining method. Statistical analysis using one-way Analysis of Variance (ANOVA). Histopathology changes were analyzed descriptively. The results showed that TCDD exposure induced oxidative stress in heart tissue and yogurt roselle has the potential to prevent an increase of MDA levels significantly (p<0.05). Furthermore, TCDD can cause histopathological alterations such as necrosis and hemorrhage, and yogurt roselle was proven to prevent cardiotoxicity due to TCDD exposure.

Developmental and lifelong dioxin exposure induces measurable changes in cardiac structure and function in adulthood

Congenital heart disease (CHD) is the most common congenital abnormality. A precise etiology for CHD remains elusive, but likely results from interactions between genetic and environmental factors during development, when the heart adapts to physiological and pathophysiological conditions. Further, it has become clearer that early exposure to toxins that do not result in overt CHD may be associated with adverse cardiac outcomes that are not manifested until later life. Previously, interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, was shown to cause structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. Here, we show that continuous exposure to TCDD from fertilization throughout adulthood caused male mice to underperform at exercise tolerance tests compared to their control and female counterparts, confirming previous observations of a sexually dimorphic phenotype. Renin-angiotensin stimulation by angiotensin II (Ang II) caused measurable increases in blood pressure and left ventricle mass, along with decreased end diastolic volume and preserved ejection fraction. Interestingly, TCDD exposure caused measurable reductions in the myocardial hypertrophic effects of Ang II, suggesting that endogenous AHR signaling present in adulthood may play a role in the pathogenesis of hypertrophy. Overall, the findings reported in this pilot study highlight the complex systems underlying TCDD exposure in the development of cardiac dysfunction in later life.

Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring

Although dioxins and related chemicals have been suspected to disrupt child development, their toxic mechanism remains poorly understood. Our previous studies in rat fetuses revealed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, suppresses fetal synthesis of pituitary growth hormone (GH) that is essential for development. This study examined the hypothesis that attenuating GH expression in fetuses triggers developmental disorders. Treating pregnant rats with 1 μg/kg TCDD reduced the circulating level of GH and its downstream factor, insulin-like growth factor-1 (IGF-1), in the offspring only during the fetal and early neonatal stages. Although maternal TCDD exposure resulted in low body weight and length at babyhood and defects in the learning and memory ability at adulthood, GH supplementation in TCDD-exposed fetuses restored or tended to restore the defects including IGF-1 downregulation. Moreover, maternal TCDD exposure decreased the number of GH-positive cells during the fetal/neonatal stage. A microarray analysis showed that TCDD reduced the expression of death-associated protein-like 1 (DAPL1), a cell cycle-dependent proliferation regulator, in the fetal pituitary gland. In addition, TCDD treatment attenuated proliferating cells and cyclin mRNA expression in the fetal pituitary gland. Aryl hydrocarbon receptor (AHR)-knockout fetuses were insensitive to TCDD treatment, indicating that the TCDD-induced reduction in DAPL1 and GH mRNAs expression was due to AHR activation. Finally, DAPL1 knockdown suppressed GH and cyclin D2 expression in fetal pituitary cells. These results provide a novel evidence that dioxin suppresses GH-producing cell proliferation and GH synthesis due to partly targeting DAPL1, thereby impairing offspring development.

2,3,7,8-Tetrachlorodibenzo-p-dioxin prompted differentiation to CD4+CD8−CD25+ and CD4+CD8+CD25+ Tregs and altered expression of immune-related genes in the thymus of chicken embryos

The chicken (Gallus gallus), which has three aryl hydrocarbon receptor (AHR) isoforms (ckAHR1, ckAHR2, and ckAHR1β) and two AHR nuclear translocator (ARNT) isoforms (ckARNT1 and ckARNT2), is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and can serve as an avian model to gain an understanding of the mechanism underlying dioxin toxicity. To elucidate the mechanism of TCDD-induced immunotoxicity in avian species, we treated chicken embryos in ovo with graded concentrations of TCDD (1.5, 2.5, 3.0, 3.3, 3.5, and 4.0 μM). Initially, we measured mRNA expression levels of ckAHR and ckARNT isoforms and analyzed the T cell populations and transcriptome in the thymuses of TCDD-treated chicken embryos. Quantitative polymerase chain reaction analysis revealed that mRNA expressions of ckAHR1 and ckARNT2 were dominant in the thymus. Severe weight loss and thymus atrophy were observed in the TCDD-treated embryos. Immunophenotyping analyses demonstrated significant increases in CD4+CD8-CD25+ and CD4+CD8+CD25+ regulatory T cells (Tregs) populations following TCDD exposure, suggesting that TCDD suppresses T cell-mediated immune responses in chicken embryos. In addition, thymic transcriptome analyses intimated that alteration of the signaling pathways related to erb-b2 receptor tyrosine kinase 4 (ERBB4) and wnt family member 5A (WNT5A), and bone morphogenetic protein (BMP) may be associated with the TCDD-induced thymus atrophy. We also observed significantly altered expression levels of genes including interleukine 13 receptor subunit alpha 2 (IL13RA2), transforming growth factor beta 1 (TGFβ1), collagen type III alpha 1 chain (COL3A1), and collagen type IX alpha 3 chain (COL9A3), implying immunosuppression, fibrosis development, and collagen deposition. Collectively, these findings suggest that TCDD exposure activates the ckAHR1-ckARNT2 signaling pathway and suppresses immune responses through the prompted differentiation to CD4+CD8-CD25+ and CD4+CD8+CD25+ Tregs and altered expressions of immune-related genes in the thymus of chicken embryos.

Age at menarche in Seveso daughters exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

In 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. At 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). These 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.

Dioxin male rat reproductive toxicity mode of action and relative potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran characterized by fetal pituitary and testis transcriptome profiling

Fetal rat exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces epididymal sperm number involving altered pituitary-testicular hormonal signaling as the proposed mode-of-action (MOA). To evaluate this MOA and compare TCDD to 2,3,7,8-tetrachlorodibenzofuran (TCDF), an in utero rat exposure and study was conducted. Endpoints included congener tissue levels and transcriptomes of maternal liver and fetal liver, testis, and pituitary. Decreased gonadotropin subunit mRNAs levels (Lhb and Fshb) and enriched signaling pathways including GNRH Signaling and Calcium Signaling were observed in fetal pituitary after TCDD (but not TCDF) exposure. TCDD (but not TCDF) decreased fetal testis cholesterologenic and steroidogenic pathway genes. TCDD tissue concentrations in dam liver, dam adipose, and whole fetus were approximately 3- to 6-fold higher than TCDF. These results support a MOA for dioxin-induced rat male reproductive toxicity involving key events in both the fetal pituitary (e.g., reduced gonadotropin production) and fetal testis (e.g., reduced Leydig cell cholesterologenesis and steroidogenesis).

Prenatal dioxin exposure and thyroid hormone levels in the Seveso second generation study

BackgroundIn animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited. ObjectivesWe aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy. MethodsWe included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy. ResultsCompared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-β = −0.13, 95%CI -0.26, 0.00; Q3: adj-β = −0.22, 95%CI -0.35, −0.09; Q4: adj-β = −0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-β = 11.4%, 95%CI -25.2, 66.1; Q3: adj-β = 49.0%, 95%CI 3.0, 115.5; Q4: adj-β = 105.5, 95%CI 36.6, 209.2; p-trend < 0.01) but not in those participants with normal antibody status (p-interaction < 0.01). Similar results were found for TCDD estimated at pregnancy. DiscussionOur results suggest prenatal exposure to TCDD, a potent endocrine-disrupting compound, may alter thyroid function later in life. Populations with additional thyroid stress may be particularly susceptible to in utero exposure of thyroid disrupting chemicals.

Gene-Dioxin Interactions and Time to Pregnancy in the Seveso Women’s Health Study

TPS 634: Health effects of pops, voc and other chemicals, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background/Aim: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, has been associated with reduced fertility in multiple animal species. TCDD is proposed to impact fertility via altered activity of the aryl hydrocarbon receptor (AhR) pathway, which regulates diverse biological and developmental processes, including xenobiotic metabolism. The Seveso Women’s Health Study (SWHS) followed up 981 women exposed to TCDD in a chemical factory explosion in 1976. Twenty years later, we reported longer time to pregnancy (TTP) associated with individual 1976 serum TCDD levels, but the youngest women had not yet attempted pregnancy. Now, 40 years after the explosion, when most women will have completed their families, we aim to re-examine the relationship of TCDD exposure with TTP and assess whether variations in AhR pathway genes modify this relationship. Methods: Of 617 women who had attempted pregnancy after the explosion, 367 delivered a live birth not associated with contraceptive failure. We examined the relationship of 1976 serum TCDD levels to TTP (parameterized as the monthly probability of conception within the first 12 months of trying) using discrete-time Cox proportional hazards regression. We also utilized genotype data (87 SNPs across 7 AhR pathway genes) to examine gene-environment interactions between AhR pathway variants and TCDD levels on TTP. Results: Women averaged 26.7 (±4.3) years at the time of attempting pregnancy. Median TTP was 2 months, with 17.2% taking 12 or more months to conceive. Consistent with our previous findings, a 10-fold increase in serum TCDD was associated with longer TTP (adjusted fecundability odds ratio = 0.80; 95%CI: 0.66, 0.98). In preliminary analyses, we found one SNP in AHRR which adversely modified the association between TCDD levels and TTP, implicating gene-environment interaction. Conclusions: These results suggest that TCDD exposure is associated with reduced fertility in the Seveso cohort; gene-environment interaction may play a role.

Transcriptomic analysis of Anabas testudineus and its defensive mechanisms in response to persistent organic pollutants exposure

The freshwater climbing perch (Anabas testudineus) can tolerate water environments contaminated with persistent organic pollutants (POPs). The mechanisms underlying this tolerance are unknown. We used de novo transcriptomic analysis to investigate the defensive mechanisms of A. testudineus against POPs based on its genetic features and biological responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Our results revealed a specific expansion of cytochrome P450 (CYP) 3A subfamily, which may be involved in the elimination of certain POPs. In xenobiotic responses, the aryl-hydrocarbon receptor (AhR) pathway represents a critical signaling mechanism, and we characterized four AhR and two AhR nuclear translocator homologs and one AhR repressor (AhRR) gene in A. testudineus. TCDD-induced AhRR and CYP1A mRNA upregulation suggests that negative-feedback regulation of AhR signaling through AhRR helps avoid excessive xenobiotic responses. Furthermore, liver and gill transcriptomic profiles were markedly altered after TCDD exposure, with some of the altered genes being related to common defensive responses reported in other species. Based on the newly identified TCDD-altered genes, several A. testudineus-specific responses are proposed, such as enhanced fatty acid β-oxidation. The genetic features of CYP3A subfamily and AhR pathway and the TCDD-induced defensive biological processes elucidated here enhance our understanding of A. testudineus defensive responses against POPs.

Cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure through lactation in mice.

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 μg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, β-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.

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.

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.

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.