Nortestosterone-derived synthetic progestogens do not activate the progestogen receptor of Murray–Darling rainbowfish (Melanotaenia fluviatilis) but are potent agonists of androgen receptors alpha and beta

Developmental exposure to progestins causes male bias and precocious puberty in zebrafish (Danio rerio)

“…Furthermore, the similar effect of LNG on sex differentiation reported by Hua et al (Hua et al, 2015) was inhibited by co-exposure to the specific AR antagonist flutamide. The absence of effect of P4 on sex differentiation is in concordance with the very low affinity of P4 for both mammalian and fish AR (Bain et al, 2015;Bauer et al, 2000), and the absence of androgenic effects of P4 in fish (Jolly et al, 2006;Jones et al, 2001;Liang et al, 2015), it is therefore intriguing that P4 induced precocious puberty in males in the present study. Since P4 is virtually non-androgenic, its effect on male puberty appears to be mediated via PR activation.…”

“…However, from published studies it is apparent that the progestins causing reproductive impairment in fish at concentrations as low as those found in the environment are the ones that activate androgen receptors (ARs), besides being strong PR agonists (Africander et al, 2011;Runnalls et al, 2013). There are several studies highlighting the androgenic effects of certain progestins in fish (Bain et al, 2015;Runnalls et al, 2013;Svensson et al, 2013Svensson et al, , 2014. Most previous studies have investigated effects of progestin exposure on adult animals.…”

“…Levonorgestrel (LNG) was chosen as the model androgenic progestin due to its high AR affinity (58% of that of testosterone to rat AR) (Africander et al, 2011;Philibert et al, 1999;Runnalls et al, 2013), environmental presence (Al-Odaini et al, 2010;Chang et al, 2011;Vulliet and Cren-Olivé, 2011;Vulliet et al, 2008), and known androgenic effects in fish (Runnalls et al, 2013;Svensson et al, 2013Svensson et al, , 2014. P4 was chosen as the model non-androgenic progestin due to its low AR affinity (3% of that of testosterone to rat AR) (Bain et al, 2015;Bauer et al, 2000;Philibert et al, 1999), frequent environmental detection (Ammann et al, 2014;Chang et al, 2011;Velicu and Suri, 2009;Vulliet and Cren-Olivé, 2011;Vulliet et al, 2008), and absence of androgenic effects on fish (Jolly et al, 2006;Jones et al, 2001). Zebrafish larvae were exposed to either LNG or P4 during the critical developmental period of sex differentiation and puberty.…”

Progestins as endocrine disrupters in aquatic ecosystems: Concentrations, effects and risk assessment

“…Sasagawa et al (2008) showed that P4 activates the PR with antagonistic activity on the androgen and mineralocorticoid receptors. Also estrogenic activities have been reported for some progestins Ellestad et al, 2014;Bain et al, 2015).…”

“…A recombinant mammalian cell system was used to determine the removal efficiency of progestogenic activity in wastewater treatment (Bain et al, 2014). Limitations of these bioassays are the difference in the potency of progestins between human and fish PR Bain et al, 2015), as also shown for ERα (Kunz and Fent, 2006). Moreover, identification of progestins responsible for the activity is only possible in combination with chemical analysis.…”