Microarray analysis of early adipogenesis in C3H10T1/2 cells: Cooperative inhibitory effects of growth factors and 2,3,7,8-tetrachlorodibenzo- p-dioxin

• Published in: Toxicology and applied pharmacology 2005-08, Vol.207 (1), p.39-58
• Main Authors: Hanlon, Paul R., Cimafranca, Melissa A., Liu, Xueqing, Cho, Young C., Jefcoate, Colin R.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ADHESION; Adipocytes - cytology; Adipocytes - drug effects; Adipogenesis; AhR; Animals; Biological and medical sciences; Cell Adhesion; CELL CYCLE; Cell Differentiation - drug effects; Cell Division; Cell Line; CHOLESTEROL; DIOXIN; DNA; EGF; EMBRYOS; Epidermal Growth Factor - pharmacology; FGF; Fibroblast Growth Factors - pharmacology; FIBROBLASTS; Gene Expression Profiling; GENES; GROWTH FACTORS; HYDROCARBONS; Lipids - biosynthesis; Medical sciences; METABOLISM; MICE; Microarray; MITOSIS; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Polychlorinated Dibenzodioxins - pharmacology; PPAR gamma - genetics; RECEPTORS; Receptors, Aryl Hydrocarbon - physiology; Toxicology; TRIGLYCERIDES
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2004.12.004

C3H10T1/2 mouse embryo fibroblasts differentiate into adipocytes when stimulated by a standard hormonal mixture (IDMB). 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD), via the aryl hydrocarbon receptor (AhR), inhibits induction of the key adipogenic gene peroxisome proliferator-activated receptor γ (PPARγ) and subsequent adipogenesis. This TCDD-mediated inhibition requires activation of the extracellular signal-regulated kinase (ERK) pathway, which can be accomplished by serum, epidermal growth factor (EGF), or fibroblast growth factor (FGF). In the absence of serum or growth factors, IDMB induced adipogenesis without mitosis. Microarray analysis identified 200 genes that exhibited expression changes of at least twofold after 24 h of IDMB treatment. This time precedes most PPARγ stimulation but follows the period of TCDD/ERK cooperation and periods of increased cell contraction and DNA synthesis. Functionally related gene clusters include genes associated with cell structure, triglyceride and cholesterol metabolism, oxidative regulation, and secreted proteins. In the absence of growth factors TCDD inhibited 30% of these IDMB responses without inhibiting the process of differentiation. A combination of EGF and TCDD that blocks differentiation cooperatively blocked a further 44 IDMB-responsive genes, most of which have functional links to differentiation, including PPARγ. Cell cycle regulators that are stimulated by EGF were substantially inhibited by IDMB but these responses were unaffected by TCDD. By contrast, TCDD and EGF cooperatively reversed IDMB-induced changes in cell adhesion complexes immediately prior to increases in PPARγ1 expression. Changes in adhesion-linked signaling may play a key role in TCDD affects on differentiation.