Citation:

Ellestad, L., M. Cardon, I. Chambers, J. Farmer, P. Hartig, Dan Villeneuve, K. Stevens, V. Wilson, AND E. Orlando. Environmental gestagens activate fathead minnow (Pimephales promelas) nuclear progesterone and androgen receptors in vitro. ENVIRONMENTAL SCIENCE AND TECHNOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 48(14):8179-8187, (2014).

Impact/Purpose:

Progestins are an important class of reproductive steroid hormones which, to date, have received less attention than estrogens, androgens, and thyroid hormone with regard to potential endocrine disruption. A number of recent studies have shown that exposure to gestagens (endogenous or synthetic progesterone receptor agonists) can lead to reproductive impairment in fish. Additionally, exposure to some gestagens has elicited phenotypic masuclinization of female fish, a response typically thought to be diagnostic of exposure to androgens. The present study demonstrates that five progestins, as well as progesterone, which are ligands for the human nuclear progesterone receptor were capable of activating the nuclear androgen receptor in fish. These results have implications regarding the extrapolation of mammalian high throughput screening assays for endocrine activity (e.g., EDSP21 assays) to predicted responses and hazards in fish via adverse outcome pathways (AOPs). Specifically, chemicals that activate mammalian nuclear progesterone receptors in vitro may have potential to trigger androgen receptor mediated AOPs in fish, and potentially other lower vertebrates. Consequently, these data provide important insights into cross-species of potential endocrine effects based on pathway-based bioactivity screening data. These results directly inform on-going research being conducted as part of Adverse Outcome Pathway Discovery and Development project within the Chemical Safety for Sustainability research program.

Description:

Gestagen is a collective term for endogenous and synthetic progesterone receptor (PR) ligands. In teleost fishes, 17á,20â-dihydroxy-4-pregnen-3-one (DHP) and17á,20â,21- trihydroxy-4-pregnen-3-one (20â-S) are the predominant progestogens, whereas in other vertebrates the major progestogen is progesterone (P4). Progestins are components of human contraceptives and hormone replacement pharmaceuticals, and with P4, these gestagens enter the environment and alter the reproductive health of fish and amphibians. In this study, our primary objectives were to clone the fathead minnow (FHM) nuclear PR (nPR), to develop an in vitro assay for FHM nPR transactivation, and to screen eight gestagens for their ability to transactivate FHM nPR. Study gestagens were chosen for their known effects on fish and amphibian reproductive health, presence in the environment, or because they represent progestin generations used in contraceptives and hormone replacement therapeutics. We also investigated the ability of the same gestagens to transactivate FHM androgen receptor (AR). Fish progestogens activated FHM nPR with DHP being more potent than 20â-S. Interestingly, the progestin drospirenone and P4 transactivated the FHM nPR, whereas five progestins and P4 transactivated FHM AR at approximately environmentally-relevant concentrations. Progestins are designed to activate human PR, and the older generation progestins are know to cross react with human AR and cause side effects. In FHMs, only one recent generation progestin activated FHM PR, and the remainder were strong agonists of the fish AR. Here, we present the first mechanistic evidence that environmental gestagens activate FHM nPR and AR, suggesting that gestagens may affect phenotype through nPR- and AR-mediated pathways.

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