Bone morphogenetic proteins (BMPs) comprise a large group of polypeptides in the transforming growth factor ␤ superfamily with essential physiological functions in morphogenesis and organogenesis in both vertebrates and invertebrates. At present, the role of BMPs in the reproductive system of any species is poorly understood. Here, we have established the existence of a functional BMP system in the ovary, replete with ligand, receptor, and novel cellular functions. In situ hybridization histochemistry identified strong mRNA labeling for BMP-4 and -7 in the theca cells and BMP receptor types IA, IB, and II in the granulosa cells and oocytes of most follicles in ovaries of normal cycling rats. To explore the paracrine function of this BMP system, we examined the effects of recombinant BMP-4 and -7 on FSH (folliclestimulating hormone)-induced rat granulosa cytodifferentiation in serum-free medium. Both BMP-4 and -7 regulated FSH action in positive and negative ways. Specifically, physiological concentrations of the BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. These effects were dose-and timedependent. Furthermore, the BMPs increased granulosa cell sensitivity to FSH. Thus, BMPs have now been identified as molecules that differentially regulate FSH-dependent estradiol and progesterone production in a way that ref lects steroidogenesis during the normal estrous cycle. As such, it can be hypothesized that BMPs might be the long-sought ''luteinization inhibitor'' in Graafian follicles during their growth and development.

Female reproductive function depends upon the exquisite control of ovarian steroidogenesis that enables folliculogenesis, ovulation, and pregnancy. These mechanisms are set during fetal and/or neonatal development and undergo phases of differentiation throughout pre-and post-pubescent life. Ovarian development and function are collectively regulated by a host of endogenous growth factors, cytokines, gonadotropins, and steroid hormones as well as exogenous factors such as nutrients and environmental agents. Endocrine disruptors represent one class of environmental agent that can impact female fertility by altering ovarian development and function, purportedly through estrogenic, anti-estrogenic, and/or anti-androgenic effects. This review discusses ovarian development and function and how these processes are affected by some of the known estrogenic and anti-androgenic endocrine disruptors. Recent information suggests not only that exposure to endocrine disruptors during the developmental period causes reproductive abnormalities in adult life but also that these abnormalities are transgenerational. This latter finding adds another level of importance for identifying and understanding the mechanisms of action of these agents. 1-IntroductionThe primary function of an adult ovary is to produce the steroid and protein hormones needed to support (1) the development and maturation of ovarian follicles (i.e., folliculogenesis) including oocytes, (2) ovulation, and (3) the initiation and maintenance of pregnancy in mammals. In order for this to collectively occur, the secretion of ovarian hormones is tightly regulated by the neuroendocrine system and is locally controlled by many intraovarian feedback mechanisms (reviewed in [1]).Two major developmental events within the ovary are follicular assembly (i.e., the formation of primordial follicles) and the primordial-to-primary follicle transition (the "initial" recruitment) [1]. The initial phase of folliculogenesis is regulated by paracrine growth factors Correspondence: Dr. Mehmet Uzumcu, Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, 84 Lipman Drive, New Brunswick, NJ Supported by NIH grant R21 ES013854-01A1 (MU) and funds from Robert Wood Johnson Medical School-UMDNJ (RZ).Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptReprod Toxicol. Author manuscript; available in PMC 2007 August 21. Published in final edited form as:Reprod Toxicol. 2007 ; 23(3): 337-352. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-...

Leptin blocks the insulin-like growth factor-I-induced increase in FSH-dependent estradiol-17beta (E(2)) production by rat ovarian granulosa cells (GC) in vitro. To determine whether the leptin effect extended to another positive modulator of FSH-dependent E(2) production, the direct ovarian effects of leptin on transforming growth factor beta (TGF-beta) were investigated. Reverse transcription-polymerase chain reaction demonstrated that theca-interstitial cells (TIC) from hypophysectomized rats expressed only a nonsignal-transducing isoform (OB-Ra) of leptin receptor mRNA. Leptin had no effect on TIC androgen production. In contrast, mRNAs for OB-Ra and the signal-transducing (OB-Rb) leptin receptor isoforms were expressed in GC. When GC obtained from 26-day-old rats were cultured (48 h) with FSH and androstenedione, both estrone (E(1)) and E(2) levels increased over those in untreated controls. In the presence of FSH (0.1 IU/ml), TGF-beta (10 ng/ml) potentiated E(2) and E(1) accumulation by 2.7- and 1.45-fold, respectively. Leptin did not alter basal or FSH-stimulated E(2) and E(1) levels. However, leptin suppressed the effect of TGF-beta on FSH-dependent E(2) and E(1) production by 39% and 29%, respectively. Aromatase cytochrome P450 (P450(arom)) mRNA expression and P450(arom) activity were increased by FSH and further augmented by the addition of TGF-beta. Leptin abolished the TGF-beta effect on P450(arom) mRNA expression, and it decreased P450(arom) activity by approximately 27%. These data support the hypothesis that leptin antagonizes the stimulatory effects of TGF-beta on FSH-dependent estrogen production by a mechanism involving the leptin-induced attenuation of P450(arom) activity and mRNA expression in GC.

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