Alteration of gene expression of G protein-coupled receptors in endocrine disruptors-caused hyperactive rats.
We examined the effects of endocrine disruptors on rat behavioral and cellular responses. Single intracisternal administration of bisphenol A, p-octylphenol, nonylphenol, dibutylphthalate (DBP), dicyclohexylphthalate (DCHP), or diethylhexylphthalate (DEHP) into 5-day-old male Wistar rats caused significant hyperactivity at 4-5 weeks of age. It was about 1.3- to 1.6-fold more active in the nocturnal phase than control rats. Based on DNA macroarray analyses of the midbrain at 8 weeks of age, the endocrine disruptors altered the levels of gene expression of G protein-coupled receptors that were involved in not only dopaminergic neurotransduction but also many peptidergic neurotransduction. The gene expression of dopamine receptor D1A was decreased by nonylphenol, DBP, or DEHP by 0.23- to 0.4-fold, whereas that of dopamine D2 was increased by nonylphenol or DBP by 2- to 2.8-fold. It was notable that four of six endocrine disruptors tested, i.e. nonylphenol, DBP, DCHP, and DEHP largely downregulated the levels of gene expression of galanin receptor 2 by 0.11- to 0.28-fold. Bisphenol A, DBP or DCHP significantly decreased the levels of gene expression of dopamine transporter at 8 weeks more than 0.5-fold. Immunohistochemical analyses revealed that p-octylphenol impaired the immunoreactivity for tyrosine hydroxylase in substantia nigra pars compacta. Thus, endocrine disruptors caused hyperactivity in the rat, probably regulating the levels not only of gene expression but also of proteins of both G-protein-coupled receptors systems and dopaminergic neurotransduction system.
Ishido
Masami
M
Endocrine Disruptors and Dioxin Research Projects, National Institute for Environmental Studies, Tsukuba 305-8506, Japan. ishidou@nies.go.jp
Morita
Masatoshi
M
Oka
Syuichi
S
Masuo
Yoshinori
Y
D000818:Animals; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010636:Phenols / Q000008:administration & dosage*; D010795:Phthalic Acids / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism*
D010636:Phenols; D010795:Phthalic Acids; D043562:Receptors, G-Protein-Coupled