Conversion of Estrone to 17β-Estradiol: A Potential Confounding Factor in Assessing Risks of Environmental Estrogens to Fish

Abstract

Feminization of male fish and the role of endocrine-active chemicals in this phenomenon has been an area of intense study for many years. Estrone (E1), a natural steroid, is found in aquatic environments sometimes at high concentrations relative to the estrogenic steroids 17β-estradiol (E2) and 17α-ethynylestradiol. However, E1 has been less thoroughly studied than E2 or 17α-ethynylestradiol due in part to a relatively lower potency in metabolically limited estrogen receptor (ER) binding/activation assays. Recent evidence suggests that in vivo biotransformation of E1 to E2 may occur in fathead minnows (Pimephales promelas) residing in environments with high concentrations of E1, such as near wastewater treatment plants. The enzymes likely responsible for this biotransformation, 17β-hydroxysteroid dehydrogenases (17βHSDs), have been well characterized in mammals but to a lesser extent in fish species. In the present study, a novel systematic analysis of amino acid sequence data from the National Center for Biotechnology Information database demonstrated that multiple 17βHSD isoforms are conserved across different fish species. Experimentally, we showed that metabolically active hepatic cytosolic preparations from 2 commercially important salmonid species, rainbow trout and lake trout, biotransformed E1 to E2 to a degree sufficient to alter results of competitive ER binding assays. These results from in silico and in vitro analyses indicate that E1 and biotransformation may play a significant role in adverse effects on development and reproduction of a variety of fish species in contaminated aquatic environments.

Increased Endocrine Activity of Xenobiotic Chemicals as Mediated by Metabolic Activation

“…The cytosolic ER (cyto ER) competitive binding assay contains cytosolic enzymes such as alcohol dehydrogenases with endogenous cofactors from the preparation. The presence of 17β-hydroxysteroid dehydrogenases for the demonstrated conversion of estrone to estradiol in rainbow trout was reported by Tapper et al (2020). In the liver slice Vtg assay, liver slices are known to have full metabolic capabilities, and the fate of a chemical incubated with a slice may be different from when incubated in cytosol (Tapper et al, 2018).…”

Assessing Contaminants of Emerging Concern in the Great Lakes Ecosystem: A Decade of Method Development and Practical Application

“…However, E2 was not detected in the vicinity of the caged fish, indicating that it was not accumulated from the water. Also, the less potent E1 usually was present, leading to the hypothesis that elevated plasma E2 might be derived from E1 via a reaction catalyzed by 17β‐hydroxysteroid dehydrogenases, a family of enzymes involved in steroidogenesis in vertebrates, including most fish species (Tapper et al, 2021). Laboratory studies confirmed the ability of male fathead minnows to convert exogenous E1 into endogenous E2, resulting in levels of plasma E2 sufficient to cause estrogenic responses such as induction of VTG (Ankley et al, 2017; Tapper et al, 2021).…”

“…Also, the less potent E1 usually was present, leading to the hypothesis that elevated plasma E2 might be derived from E1 via a reaction catalyzed by 17β‐hydroxysteroid dehydrogenases, a family of enzymes involved in steroidogenesis in vertebrates, including most fish species (Tapper et al, 2021). Laboratory studies confirmed the ability of male fathead minnows to convert exogenous E1 into endogenous E2, resulting in levels of plasma E2 sufficient to cause estrogenic responses such as induction of VTG (Ankley et al, 2017; Tapper et al, 2021). Previous studies had largely discounted E1 as a contributor to in vivo effects, compared to more potent estrogens such as E2 and the synthetic estrogen 17α‐ethinylestradiol.…”

Multi-Approach Assessment for Stress Evaluation in Rainbow Trout Females, Oncorhynchus mykiss (Walbaum, 1792) from Three Different Farms during the Summer Season

“…Fish gonads produce a series of estrogen, androgen, and progesterone steroids. Similarly to mammals, the main estrogen produced by female individuals of teleost fish species is 17β-estradiol [ 25 ]. Testosterone is also one of the most common secreta of teleost fish.…”