Effect of TCDD on the fate of epithelial cells isolated from human fetal palatal shelves (hFPECs)

Gao, Zhan; Bu, Yongjun; Zhang, Guofu; Liu, Xiaozhuan; Wang, Xugang; Ding, Shibin; Wang, Erhui; Shi, Ruihan; Li, Qiaoyun; Fu, Jianhong; Yu, Zengli

doi:10.1016/j.taap.2016.06.016

Cited by 15 publications

(6 citation statements)

References 42 publications

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“…AhR is known to regulate cell cycle progression by interacting with retinoblastoma protein (RB) and blocking E2F-dependent transcription of target genes such as Cyclin E ( Gao et al., 2016 , Mitchell et al., 2006 , Pohjanvirta, 2012 , Puga et al., 2002 ). AhR activation by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) also increases tumor suppressor p27 Kip1 , which, in turn, inactivates Cyclin E ( Kolluri et al., 1999 , Siu et al., 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

et al. 2018

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SummaryAryl hydrocarbon receptor (AhR) deficiency alters tissue homeostasis. However, how AhR regulates organ maturation and differentiation remains mostly unknown. Liver differentiation entails a polyploidization process fundamental for cell growth, metabolism, and stress responses. Here, we report that AhR regulates polyploidization during the preweaning-to-adult mouse liver maturation. Preweaning AhR-null (AhR−/−) livers had smaller hepatocytes, hypercellularity, altered cell cycle regulation, and enhanced proliferation. Those phenotypes persisted in adult AhR−/− mice and correlated with compromised polyploidy, predominance of diploid hepatocytes, and enlarged centrosomes. Phosphatidylinositol-3-phosphate kinase (PI3K), extracellular signal-regulated kinase (ERK), and Wnt/β-catenin signaling remained upregulated from preweaning to adult AhR-null liver, likely increasing mammalian target of rapamycin (mTOR) activation. Metabolomics revealed the deregulation of mitochondrial oxidative phosphorylation intermediates succinate and fumarate in AhR−/− liver. Consistently, PI3K, ERK, and Wnt/β-catenin inhibition partially rescued polyploidy in AhR−/− mice. Thus, AhR may integrate survival, proliferation, and metabolism for liver polyploidization. Since tumor cells tend to be polyploid, AhR modulation could have therapeutic value in the liver.

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Section: Resultsmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

et al. 2018

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“…However, this does not exclude changes in cell-cycle as a potential factor contributing to the observed changes in brain size. The impact of AHR agonist exposure on cell cycle appears to be tissue and stage specific with some studies indicating an increase in proliferation following exposure and others demonstrating an impairment (increase: ( Andrysík et al, 2007 ; Umannová et al, 2007 ; Xu et al, 2014 ; Gao et al, 2016 ; Wu et al, 2019 ) decrease: ( Jönsson et al, 2007 ; Faust et al, 2013 ; Li et al, 2014 ; Burns et al, 2015 ). Future studies should address the impact of TCDD exposure on cell cycle during early embryonic waves of neuro- and gliogenesis.…”

Section: Discussionmentioning

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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“…Gao et al [41] reported the possibility of cleft palate development in TCDD-treated mice through inhibited differentiation of cells in the epithelial cord via accelerated cell proliferation. In this study, Ki67-positive cells were found around the posterior palatal cleft in the TCDD-treated group, suggesting that abnormal cell proliferation may inhibit the differentiation of epithelial cord cells during palatal fusion, resulting in palatal cleft formation [42].…”

Section: Discussionmentioning

confidence: 99%

Histological and Immunohistochemical Studies to Determine the Mechanism of Cleft Palate Induction after Palatal Fusion in Mice Exposed to TCDD

Sakuma

Imura

Yamada

et al. 2022

IJMS

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Rupture of the basement membrane in fused palate tissue can cause the palate to separate after fusion in mice, leading to the development of cleft palate. Here, we further elucidate the mechanism of palatal separation after palatal fusion in 8–10-week-old ICR female mice. On day 12 of gestation, 40 μg/kg of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), sufficient to cause cleft palate in 100% of mice, was dissolved in 0.4 mL of olive oil containing toluene and administered as a single dose via a gastric tube. Fetal palatine frontal sections were observed by H&E staining, and epithelial cell adhesion factors, apoptosis, and cell proliferation were observed from the anterior to posterior palate. TUNEL-positive cells and Ki67-positive cells were observed around the posterior palatal dissection area of the TCDD-treated group. Moreover, in fetal mice exposed to TCDD, some fetuses exhibited cleft palate dehiscence during fusion. The results suggest that palatal dehiscence may be caused by abnormal cell proliferation in epithelial tissues, decreased intercellular adhesion, and inhibition of mesenchymal cell proliferation. By elucidating the mechanism of cleavage after palatal fusion, this research can contribute to establishing methods for the prevention of cleft palate development.

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Effect of TCDD on the fate of epithelial cells isolated from human fetal palatal shelves (hFPECs)

Cited by 15 publications

References 42 publications

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

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

Histological and Immunohistochemical Studies to Determine the Mechanism of Cleft Palate Induction after Palatal Fusion in Mice Exposed to TCDD

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