Platform Session 9. Signaling Pathways in the Ovarian Follicle
Monday, July 25, 2005
2:00 PM–4:00 PM
Location: CCQ 204AB
(66) NEONATAL EXPOSURE TO ESTROGENS OR PHYTOESTROGENS SUPPRESSES ACTIVIN GENE EXPRESSION AND INDUCES MULTI-OOCYTIC FOLLICLES IN MOUSE OVARIES.
Kipp, Jingjing Liu1, Kilen, Signe1, Lisowski, Andrew1, Bristol, Sarah1, Woodruff, Teresa1, Mayo, Kelly1, 1 Northwestern University, Evanston, IL
ABSTRACT- We have previously shown that neonatal genistein exposure suppresses activin gene expression and enhances the formation of multi-oocytic follicles (MOFs) in mouse ovaries, indicating a possible linkage between aberrant activin signaling and the abnormal follicles. In order to examine if the observed effects of genistein were due to its estrogenic activity, and also to test further the hypothesis that increased formation of MOFs in mouse ovaries may relate to early alterations in activin signaling caused by estrogen exposure, we investigated the actions of two additional estrogenic compounds -- diethylstilbestrol (DES) and estradiol (E2). In this study, CD-1 mouse pups were given daily injections of DES (1g), E2 (20g), genistein (50g) or oil on postnatal days 1-5, and ovaries were collected on day 19. Consistent with earlier reports by others, all of these estrogenic compounds induced significant MOF formation as compared to controls in which MOFs were rarely observed (<0.2 MOF per ovary). DES (∼48 MOFs) was the most potent MOF inducer, while E2 (∼8 MOFs) and genistein (∼17 MOFs) gave lesser responses. The mRNA levels of ovarian activin A and B subunits were decreased 60-80% by DES or E2 treatment, consistent with our previous observation in genistein treated mouse ovaries (30-45% decrease). The mRNAs for follistatin, activin types I and II receptors, and Smads 2, 3, 4, and 7 did not change following any of the treatments. Quantification of activin/inhibin subunit protein levels showed that DES or E2 significantly decreased the precursor and mature proteins of activin A by 25-40% while the decrease in activin B was not statistically significant. Genistein decreased the precursor but not mature proteins of both activin A and B by ∼28%. Inhibin levels were not altered by any of the treatments. Immunohistochemistry showed no difference in inhibin , A or B expression in the MOFs than in the single-oocytic follicles, suggesting that the observed decrease in activin subunit mRNA and protein levels were at whole ovary level. Overall, our data suggest that alterations in activin expression as a result of DES, E2 or genistein exposure correlate with and may be partially responsible for the formation of aberrant multi-oocytic follicles. However, the possible involvement of other ovarian factors may not be excluded.
KEY WORDS: activin, ovary, estrogens, follicle