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Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.

ABSTRACT: To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 μg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.

SUBMITTER: Bhuju J

PROVIDER: S-EPMC8402454 | biostudies-literature |

REPOSITORIES: biostudies-literature

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<i>In utero</i> and lactational 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin (TCDD) exposure exacerbates urinary dysfunction in hormone-treated C57BL/6J mice through a non-malignant mechanism involving proteomic changes in the prostate that differ from those elicited by testosterone and estradiol.

Project description:A recent study directed new focus on the fetal and neonatal environment as a risk factor for urinary dysfunction in aging males. Male mice were exposed in utero and via lactation (IUL) to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and then administered slow-release, subcutaneous implants of testosterone and estradiol (T+E2) as adults to mimic the hormonal environment of aging men. IUL TCDD exposure worsened T+E2-induced voiding dysfunction. Mice in the previous study were genetically prone to prostatic neoplasia and it was therefore unclear whether TCDD exacerbates voiding dysfunction through a malignant or non-malignant mechanism. We demonstrate here that IUL TCDD exposure acts via a non-malignant mechanism to exacerbate T+E2-mediated male mouse voiding dysfunction characterized by a progressive increase in spontaneous void spotting. We deployed a proteomic approach to narrow the possible mechanisms. We specifically tested whether IUL TCDD exacerbates urinary dysfunction by acting through the same prostatic signaling pathways as T+E2. The prostatic protein signature of TCDD/T+E2-exposed mice differed from that of mice exposed to T+E2 alone, indicating that the mechanism of action of TCDD differs from that of T+E2. We identified 3641 prostatic proteins in total and determined that IUL TCDD exposure significantly changed the abundance of 102 proteins linked to diverse molecular and physiological processes. We shed new light on the mechanism of IUL TCDD-mediated voiding dysfunction by demonstrating that the mechanism is independent of tumorigenesis and involves molecular pathways distinct from those affected by T+E2.

| S-EPMC7076297 | biostudies-literature

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

Project description: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.

| S-EPMC7595248 | biostudies-literature

Hepatic transcriptional networks induced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Project description:The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) serves as a prototype for a range of environmental toxicants and as a pharmacologic probe to study signal transduction by the aryl hydrocarbon receptor (AHR). Despite a detailed understanding of how TCDD exposure leads to the transcriptional up-regulation of cytochrome P450-dependent monooxygenases, we know little about how compounds like TCDD lead to a variety of AHR-dependent toxic end points such as liver pathology, terata, thymic involution, and cancer. Using an acute exposure protocol and the toxic response of the mouse liver as a model system, we have begun a detailed microarray analysis to describe the transcriptional changes that occur after various TCDD doses and treatment times. Through correlation analysis of time- and dose-dependent toxicological end points, we are able to identify coordinately responsive transcriptional events that can be defined as primary transcriptional events and downstream events that may represent mechanistically linked sequelae or that have potential as biomarkers of toxicity.

| S-EPMC2515491 | biostudies-literature

Application of pharmacokinetic modelling for 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure assessment.

Project description:Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as 'dioxins' or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry's computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001-2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

| S-EPMC8204318 | biostudies-literature

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Alters Lipid Metabolism and Depletes Immune Cell Populations in the Jejunum of C57BL/6 Mice.

Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor agonist that elicits dose-dependent hepatic fat accumulation and inflammation that can progress to steatohepatitis. To investigate intestine-liver interactions that contribute to TCDD-elicited steatohepatitis, we examined the dose-dependent effects of TCDD (0.01, 0.03, 0.1, 0.3, 1, 3, 10, or 30 µg/kg) on jejunal epithelial gene expression in C57BL/6 mice orally gavaged every 4 days for 28 days. Agilent 4x44K whole-genome microarray analysis of the jejunal epithelium identified 439 differentially expressed genes (|fold change| ≥ 1.5, P1(t) ≥ 0.999) across 1 or more doses, many related to lipid metabolism and immune system processes. TCDD-elicited differentially expressed genes were associated with lipolysis, fatty acid/cholesterol absorption and transport, the Kennedy pathway, and retinol metabolism, consistent with increased hepatic fat accumulation. Moreover, several major histocompatibility complex (MHC) class II genes (H2-Aa, H2-Ab1, H2-DMb1, Cd74) were repressed, coincident with decreased macrophage and dendritic cell levels in the lamina propria, suggesting migration of antigen-presenting cells out of the intestine. In contrast, hepatic RNA-Seq analysis identified increased expression of MHC class II genes, as well as chemokines and chemokine receptors involved in macrophage recruitment (Ccr1, Ccr5, Ccl5, Cx3cr1), consistent with hepatic F4/80 labeling and macrophage infiltration into the liver. Collectively, these results suggest TCDD elicits changes that support hepatic lipid accumulation, macrophage migration, and the progression of hepatic steatosis to steatohepatitis.

| S-EPMC5009443 | biostudies-literature

2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure prevents cardiac valve formation in developing zebrafish.

Project description:Cardiovascular malformations are one of the most common congenital birth defects observed in humans. Defects in cardiac valves disrupt normal blood flow. Zebrafish are an outstanding experimental model for studying the effects that environmental contaminants have on developmental processes. Previous research has shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes blood regurgitation in the heart and reduces peripheral blood flow in embryonic zebrafish, suggesting some form of valve failure. To test this we used video microscopy to examine valve function and structure in developing zebrafish exposed to TCDD. TCDD exposure produced blood regurgitation at both the atrioventricular (AV) and bulboventricular (BV) junctions. In marked contrast to control embryos exposed to the vehicle dimethyl sulfoxide, embryos exposed to TCDD failed to form valve leaflets as the heart matured. In addition, whereas TCDD did not block initial formation of the bulbus arteriosus, we found that TCDD exposure prevented the normal growth and development of this portion of the outflow tract. TCDD altered the localization of endothelial cells at the AV and BV junctions and altered the localized expression of mRNAs bmp4 and notch1b normally associated with the nascent valves. Taken together, our results demonstrate that although TCDD does not prevent the initial specification of the presumptive valve locations, TCDD exposure produces severe alterations in valve development, leading to blood regurgitation and failing circulation in the developing zebrafish.

| S-EPMC2464817 | biostudies-literature

Proteomic analysis of human keratinocyte response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure.

Project description:Chronic exposure to 2,3,7,8-tetrachlorodibeno-p-dioxin (TCDD) and related polyhalogenated organic pollutants occurs as a consequence of modern life. Exploring the cellular basis for their action is anticipated to help understand the risk they pose and improve the foundation for their regulation. A basis for the striking change in human keratinocyte colony morphology due to TCDD exposure has been investigated by shotgun proteomics. Concentrating on changes in protein levels among three cell strains has revealed significant decreases in the differentiation markers filaggrin, keratin 1, and keratin 10. EGF treatment in concert with TCDD enhanced the changes in these markers and several other proteins while reducing the levels of certain other proteins. The only protein stimulated by TCDD in all three strains and reversed by EGF in them was vimentin, not previously observed to be in the aryl hydrocarbon receptor response domain. Although TCDD is often proposed to enhance keratinocyte differentiation, proteomic analysis reveals it uncouples the differentiation program and suggests that reduced levels of differentiation marker proteins contribute to the observed excessive stratification it induces.

| S-EPMC4026210 | biostudies-literature

A single gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts the adult uterine response to estradiol in mice.

Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) given as a cotreatment with estrogen exhibits antiestrogenic properties on the rodent adult uterus, but less is understood regarding hormonal responsiveness of the adult uterus from animals having been exposed to TCDD during critical periods of development. We characterized the inhibitory effects of TCDD (T) exposure at gestational day 15 (GD15), 4 weeks, and 9 weeks of age (TTT) on the adult uterus following hormone treatment. TTT-exposed mice in response to hormone treatment exhibited a blunted weight increase, had fewer uterine glands, displayed morphological anomalies, and had marked decreases in the hormonal regulation of genes involved in fluid transport (Aqp3 and Aqp5), cytoarchitectural (Dsc2 and Sprr2A), and immune (Lcn2 and Ltf) regulation. To determine if the 9-week exposure was responsible for the blunted uterine response, due to the 7- to 11-day half-life of TCDD in mice, a second set of experiments was performed to examine exposure to TCDD given at GD15, GD15 only (cross-fostered at birth), only during lactation (cross-fostered at birth), or at GD15 and 4 weeks of age. Our studies demonstrate that a single developmental TCDD exposure at GD15 is sufficient to elicit a blunted adult uterine response to estradiol and is due in part to fewer gland numbers and the reduced expression of forkhead box A2 (FoxA2), a gene involved in gland development. Together, these results provide insight regarding the critical nature of in utero exposure and the potential impact on ensuing uterine biology and reproductive health later in life.

| S-EPMC3858195 | biostudies-literature

Developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice.

Project description:BackgroundNecrotizing enterocolitis (NEC) is a rare, but potentially fatal intestinal inflammatory condition most often arising in premature infants. Infants provided formula are also at greater risk of developing this disease. Although the majority of formula-fed, preterm infants do not develop NEC, up to 30% of infants with the disease do not survive. Thus, identifying additional, currently unrecognized factors, which may predispose a specific infant to NEC development would be a significant clinical advancement. In this regard, we have previously reported that offspring of female or male mice with a history of developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit altered sensitivity to inflammatory challenges and are frequently born premature. Herein, we examined the possibility that, compared to unexposed mice (F1NONE ), developmental TCDD exposure of either parent (maternal, F1MTCDD , or paternal, F1PTCDD ) would enhance the risk of NEC in offspring (F2TCDD mice) in association with supplemental formula feeding.MethodsBeginning on postnatal day 7, all neonates were randomized to maternal milk only or maternal milk with up to 20 supplemental formula feedings. All pups remained with the Dams and were additionally allowed to nurse ad libitum.ResultsFormula-fed F2NONE pups rarely developed NEC while this disease was common in formula-fed F2MTCDD and F2PTCDD mice. Unexpectedly, 50% of F2MTCDD pups that were not provided supplemental formula also developed NEC.ConclusionsOur studies provide evidence that a history of parental TCDD exposure enhances the risk of NEC in offspring and suggest exposure to environmental immunotoxicants such as TCDD may also contribute to this inflammatory disease in humans.

| S-EPMC8274937 | biostudies-literature

2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice.

Project description:Aryl hydrocarbon receptor (AhR) activation is reported to alter the hepatic expression of circadian clock regulators, however the impact on clock-controlled metabolism has not been thoroughly investigated. This study examines the effects of AhR activation on hepatic transcriptome and metabolome rhythmicity in male C57BL/6 mice orally gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. TCDD diminished the rhythmicity of several core clock regulators (e.g. Arntl, Clock, Nr1d1, Per1, Cry1, Nfil3) in a dose-dependent manner, involving either a ≥ 3.3-fold suppression in amplitude or complete loss of oscillation. Accordingly, protein levels (ARNTL, REV-ERBα, NFIL3) and genomic binding (ARNTL) of select regulators were reduced and arrhythmic following treatment. As a result, the oscillating expression of 99.6% of 5,636 clock-controlled hepatic genes was abolished including genes associated with the metabolism of lipids, glucose/glycogen, and heme. For example, TCDD flattened expression of the rate-limiting enzymes in both gluconeogenesis (Pck1) and glycogenesis (Gys2), consistent with the depletion and loss of rhythmicity in hepatic glycogen levels. Examination of polar hepatic extracts by untargeted mass spectrometry revealed that virtually all oscillating metabolites lost rhythmicity following treatment. Collectively, these results suggest TCDD disrupted circadian regulation of hepatic metabolism, altering metabolic efficiency and energy storage.

| S-EPMC6478849 | biostudies-literature

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