Gene expression profile in the livers of rats orally administered ethinylestradiol for 28 days using a microarray technique.
To identify genes showing responses to estrogen exposure in the livers of animals in a repeated oral dose toxicity study, dose-dependent gene expression profiles were analyzed using high-density oligonucleotide microarrays in Sprague-Dawley rats of both sexes administered ethinylestradiol (EE) for 28 days at concentrations of 0, 0.01, 0.1, and 1.0 ppm in the diet. Among 3776 genes examined, examples showing increased expression on EE-treatment were detected predominantly in females. Genes showing dose-dependent up-regulation with greater than five-fold change at 1.0 ppm from the control levels were found to, respectively, number 4 in males, and 24 in females. Most of the latter exhibited relatively high basal expression as well as low variability, and many exhibited clear dose-dependence. Genes showing dose-dependent down-regulation were rather few, and many of those affected exhibited relatively low expression levels with large variation between animals, like genes showing dose-unrelated expression patterns in both sexes or dose-dependent up-regulation in males. Considering that detection of changes in endocrine-linked organs and estrous cyclicity is only possible at the high dose of 1.0 ppm, up-regulation of genes dose-dependently in females provides a sensitive tool to detect estrogenic effects in the rat liver in the framework of the 28-day toxicity study.
Kato
Natsumi
N
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Shibutani
Makoto
M
Takagi
Hironori
H
Uneyama
Chikako
C
Lee
Kyoung-Youl
KY
Takigami
Shu
S
Mashima
Keisuke
K
Hirose
Masao
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D045166:Estradiol Congeners / Q000633:toxicity*; D030762:Estrous Cycle / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012727:Sex Characteristics
D045166:Estradiol Congeners; D011960:Receptors, Estrogen; D004997:Ethinyl Estradiol