Screening and detection of the in vitro agonistic activity of xenobiotics on the retinoic acid receptor.
The retinoic acid receptors (RARs) play key roles in various biological processes in response to endogenous retinoic acids. However, excessive embryonic exposure to specific ligands for each subtype of the RAR was reported to induce specific developmental abnormalities. We measured the RAR agonistic activity of 543 chemicals using an assay system adopting yeast cells transfected with the human RAR gamma and a coactivator. Eighty-five of the 543 chemicals, including 16 organochlorine pesticides, 14 styrene dimers, 9 monoalkylphenols and 6 parabens, exhibited RAR gamma agonistic effects in this assay. In particular, monoalkylphenols having a 6-9 carbon alkyl group para to the phenolic hydroxyl group possessed high affinity for the RAR gamma, and their activities were 1.363-0.446% of that of all-trans RA. para-Alkylphenols chlorinated at the ortho position also were about as active or more active than their unchlorinated analogs. In addition, all tested styrene dimers showed positive effects, and the activity of 1-phenyltetralin, the strongest in this category, was 1.169% that of all-trans RA. A number of chemicals having binding affinity for the RAR gamma were revealed in this study (both newly identified and confirmed), further comprehensive studies of in vitro and in vivo effects via the RARs are required for the reliable risk assessment of chemicals. In vitro receptor binding studies represent an important step in hazard identification and suggest a potential mechanism of action, which can be an important step in risk assessment and in particular for screening studies to identify potential toxicity and inform mechanistic studies.
Kamata
Ryo
R
Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan. kamata.ryo@nies.go.jp <kamata.ryo@nies.go.jp>
Shiraishi
Fujio
F
Nishikawa
Jun-ichi
J
Yonemoto
Junzo
J
Shiraishi
Hiroaki
H
D006801:Humans; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D018570:Risk Assessment / Q000379:methods; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D020798:Two-Hybrid System Techniques; D015262:Xenobiotics / Q000737:chemistry / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
D018168:Receptors, Retinoic Acid; D015262:Xenobiotics; D000097768:Retinoic Acid Receptor gamma