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Low Concentrations of Tetrabromobisphenol A Disrupt Notch Signaling and Intestinal Development in in Vitro and in Vivo Models
journal contribution
posted on 2020-02-21, 20:37 authored by Min Zhu, Yue Niu, Yuanyuan Li, Mengqi Dong, Jinbo Li, Ran Zeng, Zhanfen QinTetrabromobisphenol
A (TBBPA) was recently reported to upregulate
Notch target gene expression in embryonic stem cells differentiating
to neurons in vitro, implying activation on Notch
signaling, a crucial signaling involved in multiple organ development
and homeostasis.The present study aimed to determine whether TBBPA
at low concentrations can disrupt Notch signaling in the intestine
and subsequently its development using in vitro and in vivo models, given TBBPA uptake mainly via the intestine.
In rat intestinal epithelium cells (IEC-6), an in vitro model for intestinal development and homeostasis, we found 5–500
nM TBBPA upregulated Notch-related gene expression and stimulated
cell proliferation as well as the growth of microvilli in a linear
concentration-dependent manner. When Notch inhibitor DAPT had no obvious
effects on all end points, DAPT significantly antagonized all changes
caused by TBBPA, indicating that TBBPA activated Notch signaling in
IEC-6 cells and subsequently stimulated cell proliferation and differentiation.
Then we employed Xenopus laevis, an ideal model species
for intestinal development with the strong similarities to mammals,
to further confirm the action of TBBPA in vivo. Expectedly,
we observed the stimulatory effects of TBBPA on Notch signaling and
cell proliferation and differentiation in X. laevis intestines, which agrees with the results in vitro. Antagonistic actions of Notch inhibitor DBZ on TBBPA-caused intestinal
changes show that TBBPA affected intestinal development via disrupting
Notch signaling. Interestingly, TBBPA stimulated cell differentiation
into secretory cells, which is generally believed to be regulated
by Wnt signaling, suggesting disruption of Wnt signaling besides Notch
signaling. All the results for the first time demonstrate that TBBPA
at low concentrations, including environmentally relevant concentrations,
disrupt Notch signaling and subsequently affect intestinal development
by altering cell proliferation and differentiation in vertebrates.
Our study highlights the intestine as a new target of TBBPA and broaden
our understanding of developmental toxicity of TBBPA.