Fig. 5

Fig. 5. Upstream regulator and downstream effect analysis of T3/6-PTU target genes. (A) Upstream regulator analysis of the common target gene set of T3 and 6-PTU indicates T3 signaling to be most significantly responsible for the observed gene expression changes. Direct and indirect T3/THRB signaling impacts the expression of different genes involved in muscle contraction and function. The observed up- (red) and down-regulation (blue) of genes is displayed as a colour code after exposure to T3. Functional connections are indicated as colored lines and arrows. For reasons of perceptibility, not all genes are shown. (B) Downstream effect analysis of the common target gene set of T3 and 6-PTU. The top ten statistically significantly enriched physiological functions are displayed ordered by their -log(p-value). The z-score indicates, whether a function is increased (positive) or decreased (negative value) after T3 (orange) and 6-PTU exposure (blue). (C) Proposed refinement of thyroid-related AOPs in fish. Both, induced thyroid signaling by exogenous T3 and reduced thyroid signaling by 6-PTU-mediated inhibition of TPO and DIO, significantly affect the expression of genes involved in muscle function and contraction via direct and indirect pathways shown in (B). The resulting impaired muscle function and contractility may directly affect swim bladder inflation and may indirectly also contribute to a reduced swimming performance. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)