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. Author manuscript; available in PMC: 2018 Oct 22.
Published in final edited form as: Chem Res Toxicol. 2017 Jan 20;30(4):965–979. doi: 10.1021/acs.chemrestox.6b00350

Figure 7. Simulations of toxicant-induced fusion defects in the virtual palate model.

Figure 7.

(A-B) Final states for simulations of chronic TCDD exposure. Scenarios were parameterized via AhR-mediated fold-changes in EGFR (as indicated from 1.1x to 1.3x) for (A) the low-hysteresis version of the EGF-TGFβ3 switch (n=54, tipping point ~1.2x) and (B) the high-hysteresis version (n=34, tipping point ~1.2x). Insets show corresponding EGF and TGFβ3 signal gradients. The phenotype of a thickened MES preventing mesenchymal confluence is similar in appearance to the histology of palatal shelves from a TGFβ3 knockout (with or without additional Alk mutations)44. (C-D) Time-lapse images from simulations of transient acute exposure to ATRA parameterized as time-dependent EGFR fold-changes (top). Palate fusion was delayed using the low-hysteresis switch (n=24, tipping point >1.8x) (C), but failed using the high-hysteresis switch (n=16, tipping point 1.5x) (D) despite being subjected to a smaller maximum EGFR fold-change. Complete time-lapse image sets are available for specific examples as Supplemental Movies S3 (panel A, 1.15x), S4 (panel B, 1.2x), S5 (panel C), and S6 (panel D).