2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure disrupts development of the visceral and ocular vasculature

Yue, Monica S.; Martin, Shannon E.; Martin, Nathan R.; Taylor, Michael R.; Plavicki, Jessica

doi:10.1016/j.aquatox.2021.105786

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…To determine how early embryonic TCDD exposure affects brain development, we used an exposure paradigm that is sufficient to induce prolonged AHR activation throughout embryogenesis and into early larval stages [ Supplementary Figure 1 and ( Yue et al, 2021 )]. Newly fertilized embryos were exposed to TCDD for 1 h at 4 hpf.…”

Section: Resultsmentioning

confidence: 99%

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain

Martin

Patel

Kossack

et al. 2022

Front. Mol. Neurosci.

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2,3,7,8-tetrachlorodibenzo-[p]-dioxin (TCDD) is a persistent global pollutant that exhibits a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. Epidemiological studies have associated AHR agonist exposure with multiple human neuropathologies. Consistent with the human data, research studies using laboratory models have linked pollutant-induced AHR activation to disruptions in learning and memory as well as motor impairments. Our understanding of endogenous AHR functions in brain development is limited and, correspondingly, scientists are still determining which cell types and brain regions are sensitive to AHR modulation. To identify novel phenotypes resulting from pollutant-induced AHR activation and ahr2 loss of function, we utilized the optically transparent zebrafish model. Early embryonic TCDD exposure impaired embryonic brain morphogenesis, resulted in ventriculomegaly, and disrupted neural connectivity in the optic tectum, habenula, cerebellum, and olfactory bulb. Altered neural network formation was accompanied by reduced expression of synaptic vesicle 2. Loss of ahr2 function also impaired nascent network development, but did not affect gross brain or ventricular morphology. To determine whether neural AHR activation was sufficient to disrupt connectivity, we used the Gal4/UAS system to express a constitutively active AHR specifically in differentiated neurons and observed disruptions only in the cerebellum; thus, suggesting that the phenotypes resulting from global AHR activation likely involve multiple cell types. Consistent with this hypothesis, we found that TCDD exposure reduced the number of oligodendrocyte precursor cells and their derivatives. Together, our findings indicate that proper modulation of AHR signaling is necessary for the growth and maturation of the embryonic zebrafish brain.

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Section: Resultsmentioning

confidence: 99%

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain

Martin

Patel

Kossack

et al. 2022

Front. Mol. Neurosci.

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“…Correspondingly, in mice, loss of Bmp4 impaired cristae and semicircular canal establishment (Chang et al, 2008) and in zebrafish, excess Bmp4 treatment resulted in ectopic or absent pillar formation, suggesting Bmp4 is involved in semicircular canal establishment. Although previous studies have not investigated the effects of TCDD exposure on expression of Bmp4 and Fgf8 specifically in the ear, previous research found that following TCDD exposure Bmp4 expression was expanded in the heart and, based on whole embryo qPCR data, is globally upregulated in embryos and larvae (Mehta, Peterson, & Heideman, 2008; Yue, Martin, Martin, Taylor, & Plavicki, 2021). TCDD was shown not affect Fgf8 expression following fin amputation (Andreasen, Mathew, Löhr, Hasson, & Tanguay, 2007); however, it is not clear whether Fgf8 expression is altered in other tissues in response to TCDD exposure.…”

Section: Discussionmentioning

confidence: 99%

Exposure to the persistent organic pollutant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) disrupts development of the zebrafish inner ear

Cintrón-Rivera¹,

Oulette²,

Prakki³

et al. 2023

Preprint

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Dioxins are a class of highly toxic and persistent environmental pollutants that have been shown through epidemiological and laboratory-based studies to act as developmental teratogens. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent dioxin congener, has a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. TCDD-induced AHR activation during development impairs nervous system, cardiac, and craniofacial development. Despite the robust phenotypes previously reported, the characterization of developmental malformations and our understanding of the molecular targets mediating TCDD-induced developmental toxicity remains limited. In zebrafish, TCDD-induced craniofacial malformations are produced, in part, by the downregulation of SRY-box transcription factor 9b (sox9b), a member of the SoxE gene family. Sox9b, along with fellow SoxE gene family members sox9a and sox10, have important functions in the development of the otic placode, the otic vesicle, and, ultimately, the inner ear. Given that sox9b is a known target of TCDD and that transcriptional interactions exist among SoxE genes, we asked whether TCDD exposure impaired the development of the zebrafish auditory system, specifically the otic vesicle, which gives rise to the sensory components of the inner ear. Using immunohistochemistry, in vivo confocal imaging, and time-lapse microscopy, we assessed the impact of TCDD exposure on zebrafish otic vesicle development. We found exposure resulted in structural deficits, including incomplete pillar fusion and altered pillar topography, leading to defective semicircular canal development. The observed structural deficits were accompanied by reduced collagen type II expression in the ear. Together, our findings reveal the otic vesicle as a novel target of TCDD-induced toxicity, suggest that the function of multiple SoxE genes may be affected by TCDD exposure, and provide insight into how environmental contaminants contribute to congenital malformations.

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“…Freshwater fish contained the highest TEQ (1.72 ppt), while a purely vegan diet had the lowest TEQ (0.09 ppt), intermediate levels were detected in chicken (0.33 ppt), ocean fish (0.39 ppt), and human milk (0.42 ppt, (54)). Using the previously reported dechorionated dry weight of a zebrafish embryo (39.5 ± 15.5 µg) at 24 we calculated the TCDD concentration within each embryo in our experiments and found that following: the 10 ppb exposure the internal TCDD concentration was approximately 0.96 ppt, 1 ppb exposure had an internal TCDD concentration of 0.67 ppt, and a 50 ppt dose the internal concentration was 0.22 ppt (56). This rough estimate suggests that our measured tissue concentrations of TCDD were within the same order of magnitude observed in human food sources and reflect environmental relevant levels of TCDD.…”

Section: Tcdd Body Burdens Following Waterborne 10 Ppb or 50 Ppt Expo...mentioning

confidence: 99%

“…Zebrafish have become a popular model system in developmental biology and toxicology due to their rapid external embryonic development, optical transparency, and high degree of sequence homology to humans (17). In zebrafish, embryonic exposure to TCDD for 1 hour at a concentration of either 1 parts-per-billion (ppb) or 10 ppb is sufficient for sustained AHR activation and produces developmental defects including cardiovascular malformations, hemorrhaging, loss of the proepicardial progenitor cells, cardiac and cerebral edema, and craniofacial defects (18)(19)(20)(21)(22)(23)(24). Studies in zebrafish have revealed that one of the critical molecular mechanisms underlying a number of the observed TCDD-induced phenotypes is the reduced expression and function of the high mobility group transcription factor sox9b (22,25,26).…”

Section: Introductionmentioning

confidence: 99%

High-resolution mass spectrometry reveals environmentally relevant uptake, elimination, and metabolic alterations following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish

Kossack

Manz

Martin

et al. 2022

Preprint

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Dioxin and dioxin-like compounds are ubiquitous environmental contaminants that induce toxicity by binding to the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The zebrafish model has been used to define the developmental toxicity observed following exposure to exogenous AHR ligands such as the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD). While the model has successfully identified cellular targets of TCDD and molecular mechanisms mediating TCDD-induced phenotypes, fundamental information such as the body burden produced by standard exposure paradigms is still unknown. We performed targeted gas chromatography (GC) high-resolution mass spectrometry (HRMS) in tandem with non-targeted liquid chromatography (LC) HRMS to quantify TCDD uptake, model the elimination dynamics of TCDD, and determine how TCDD exposure affects the zebrafish metabolome. We found that 10 ppb, 1 ppb, and 50 ppt waterborne exposures during early embryogenesis produced environmentally relevant body burden of TCDD: 38 +/- 4.34, 26.6 +/- 1.2, and 8.53 +/- 0.341 pg/embryo, respectively, at 24 hours post fertilization. In addition, we discovered that TCDD exposure was associated with the dysregulation of several metabolic pathways that are critical for brain development and function including glutamate metabolism, chondroitin sulfate biosynthesis, and tyrosine metabolism pathways. Together, these data demonstrate that existing exposure paradigms produce environmentally relevant body burdens of TCDD in zebrafish and provide insight into the biochemical pathways impacted by toxicant-induced AHR activation.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin exposure disrupts development of the visceral and ocular vasculature

Cited by 9 publications

References 43 publications

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain

Exposure to the persistent organic pollutant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) disrupts development of the zebrafish inner ear

High-resolution mass spectrometry reveals environmentally relevant uptake, elimination, and metabolic alterations following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish

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