Impact of maternal dietary exposure to endocrine-acting chemicals on progesterone receptor expression in microdissected hypothalamic medial preoptic areas of rat offspring.
We have previously examined the impact of perinatal exposure to ethinylestradiol (EE), methoxychlor (MXC), diisononyl phthalate (DINP), and genistein (GEN) in maternal diet on rat offspring, and found developmental and/or reproductive toxicity with 0.5 ppm EE, 1200 ppm MXC, and 20,000 ppm DINP. Although the toxicological profile with MXC was similar to the EE case, the population changes in pituitary hormone-producing cells totally differed between the two cases, changes being evident from 240 ppm with MXC. In the present study, to assess the impact of these agents on brain sexual differentiation, region-specific mRNA expression of estrogen receptors (ER) alpha and beta, the progesterone receptor (PR), gonadotrophin-releasing hormone, steroid receptor coactivators (SRC)-1 and -2, and calbindin-D in microdissected hypothalamic medial preoptic areas (MPOAs) at postnatal day 10 was first analyzed in rats exposed to 0.5 ppm-EE from gestational day 15 by real-time RT-PCR. Sexually dimorphic expression of ER alpha and PR was noted with predominance in females and males, respectively, EE up-regulating SRC-1 in males and ER beta and PR in females. Next, we similarly examined expression changes of ER alpha and beta, PR, and SRC-1 in animals exposed to MXC at 24, 240, and 1200 ppm, DINP at 4000 and 20,000 ppm, and GEN at 1000 ppm. MXC at 1200 ppm down- and up-regulated PR in males and females, respectively, and DINP at 20,000 ppm down-regulated PR in females, while GEN did not exert any clear effects. The results thus suggest that agents causing developmental and/or reproductive abnormalities in later life may affect hypothalamic PR expression during the exposure period in early life.
Takagi
Hironori
H
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Shibutani
Makoto
M
Lee
Kyoung-Youl
KY
Masutomi
Naoya
N
Fujita
Haruka
H
Inoue
Kaoru
K
Mitsumori
Kunitoshi
K
Hirose
Masao
M
D000818:Animals; D017931:DNA Primers; D004032:Diet; D004703:Endocrine System / Q000187:drug effects*; D045166:Estradiol Congeners / Q000633:toxicity; D004997:Ethinyl Estradiol / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000633:toxicity; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity; D008297:Male; D008731:Methoxychlor / Q000633:toxicity; D010795:Phthalic Acids / Q000633:toxicity; D011247:Pregnancy; D011301:Preoptic Area / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D012733:Sex Differentiation
D017931:DNA Primers; D045166:Estradiol Congeners; D007306:Insecticides; D010795:Phthalic Acids; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C012125:diisononyl phthalate; D004997:Ethinyl Estradiol; D019833:Genistein; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007041:Hypoxanthine Phosphoribosyltransferase; D008731:Methoxychlor