A critical review of the environmental occurrence and potential effects in aquatic vertebrates of the potent androgen receptor agonist 17β‐trenbolone

Abstract

Trenbolone acetate is widely used in some parts of the world for its desirable anabolic effects on livestock. Several metabolites of the acetate, including 17b-trenbolone, have been detected at low nanograms per liter concentrations in surface waters associated with animal feedlots. The 17b-trenbolone isomer can affect androgen receptor signaling pathways in various vertebrate species at comparatively low concentrations/doses. The present article provides a comprehensive review and synthesis of the existing literature concerning exposure to and biological effects of 17b-trenbolone, with an emphasis on potential risks to aquatic animals. In vitro studies indicate that, although 17b-trenbolone can activate several nuclear hormone receptors, its highest affinity is for the androgen receptor in all vertebrate taxa examined, including fish. Exposure of fish to nanograms per liter water concentrations of 17b-trenbolone can cause changes in endocrine function in the short term, and adverse apical effects in longer exposures during development and reproduction. Impacts on endocrine function typically are indicative of inappropriate androgen receptor signaling, such as changes in sex steroid metabolism, impacts on gonadal stage, and masculinization of females. Exposure of fish to 17b-trenbolone during sexual differentiation in early development can greatly skew sex ratios, whereas adult exposures can adversely impact fertility and fecundity. To fully assess ecosystem-level risks, additional research is warranted to address uncertainties as to the degree/breadth of environmental exposures and potential population-level effects of 17b-trenbolone in sensitive species.

Differential Hepatic Gene Expression Profile of Male Fathead Minnows Exposed to Daily Varying Dose of Environmental Contaminants Individually and in Mixture

“…There is evidence that EDCs can interact with a variety of hormones and/or hormone receptors, and exert actions as agonists or antagonists. As a result, EDCs can disrupt the activity of hormones and alter normal physiological function at different levels [Reviewed in (1–3)]. Adverse effects of EDCs on the reproductive system can result from interaction with sex steroids or their receptors and other types of receptors, including aryl hydrocarbon receptor (AhR), Peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), thyroid hormone receptors (TR), and retinoid X receptor (RXR).…”

Sex‐ and Developmental Stage–Related Differences in the Hepatic Transcriptome of Japanese Quail (Coturnix japonica) Exposed to 17β‐Trenbolone

“…Our results also suggest that exposure to 17β‐trenbolone results in immunomodulation in male Japanese quail. Whether or not these are primary responses to 17β‐trenbolone exposure or compensatory responses that are triggered to maintain normal levels (Ankley et al 2018) is unclear. Future studies should examine transcriptomic signatures in other target organs such as the brain, gonads, and muscle, and receptor binding during early stages of 17β‐trenbolone exposure to help provide additional insight into the mechanisms of action and functional consequences of exposure to androgenic pollutants.…”

“…A well‐established mechanism of action for the effects of 17β‐trenbolone is its high affinity for the androgen receptor (Ankley et al 2018). However, no differentially expressed genes in our study belonged to gene ontology categories or pathways directly related to the androgen receptor.…”

“…Unlike other natural and synthetic androgens (for example, testosterone and methyltestosterone), 17β-trenbolone is not aromatized to estrogenic metabolites (Neumann 1976). Thus, exposure to 17β-trenbolone results in a relatively specific AR-mediated response (Ankley et al 2018). Wildlife can be exposed to 17β-trenbolone in waterways, livestock fields, or feedlots that have been fertilized with manure from livestock with TbA implants.…”

Adverse Outcome Pathway Network–Based Assessment of the Interactive Effects of an Androgen Receptor Agonist and an Aromatase Inhibitor on Fish Endocrine Function

“…In the present study, we used 2 chemicals relatively specific to the molecular initiating events of interest: fadrozole, a pharmaceutical inhibitor of aromatase designed to treat breast cancer in humans (Miller 1989), and 17β‐trenbolone, a nonaromatizable synthetic steroid registered as a veterinary drug, and an active AR agonist in a wide variety of vertebrate species (Ankley et al 2018). Due to the complexity of the complete matrix mixture design, we used comparatively short exposure durations (48 and 96 h) to assess the network‐based predictions.…”