The estrogen-related receptor alpha (ERR alpha) and the peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha) play critical roles in the control of several physiological functions, including the regulation of genes involved in energy homeostasis. However, little is known about the ability of environmental chemicals to disrupt or modulate this important bioenergetics pathway in humans. The goal of this study was to develop a cell-based assay system with an intact PGC-1 alpha/ERR alpha axis that could be used as a screening assay for detecting such chemicals. To this end, we successfully generated several stable cell lines expressing PGC-1 alpha and showed that the reporter driven by the native ERRa hormone response unit (AAB-Luc) is active in these cell lines and that the activation is PGC-1 alpha-dependent. Furthermore, we show that this activation can be blocked by the ERR alpha selective inverse agonist, XCT790. In addition, we find that genistein and bisphenol A further stimulate the reporter activity, while kaempferol has minimal effect. These cell lines will be useful for identifying environmental chemicals that modulate this important pathway. Published by Elsevier Inc.