Transcriptional and Physiological Responses Induced by Binary Mixtures of Drospirenone and Progesterone in Zebrafish (Danio rerio)

Abstract

Drospirenone (DRS) is a synthetic progestin increasingly used in oral contraceptives with similar effects to progesterone (P4). Wild fish are exposed to DRS and P4 through wastewater. However, the effects of DRS on fish, both as an individual compound and in mixtures, have not been extensively studied. Therefore, in this study, global gene expression profiles of ovary and brain of female zebrafish (Danio rerio) were characterized after exposure to 55, 553, and 5442 ng/L DRS for 14 days. The effects were then compared to the observed responses after exposure to mixtures of DRS and P4 (DRS+P4: 27 + 0.8, 277 + 8 and 3118 + 123 ng/L). Transcriptomics findings were related to the changes in vitellogenin protein concentrations in the blood, morphology, and histology of gonads. Multivariate analysis indicated tissue-, dose-, and treatment-dependent expression profiles. Genes involved in steroid hormone receptor activity and circadian rhythm were enriched in DRS and mixture groups, among other pathways. In mixtures, the magnitude of response was dose- and transcript-dependent, both at the molecular and physiological levels. Effects of DRS and P4 were additive for most of the investigated parameters and occurred at environmentally relevant concentrations. They may translate to adverse reproductive effects in fish.

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

“…In fish, synthetic progestins have an endocrine activity, similar to EE2 or trenbolone. They exhibited adverse effects on fertility and reproduction (Zeilinger et al, 2009;Paulos et al, 2010;Runnalls et al, 2013), altered hormone levels , induced transcriptional effects in adults (Zucchi et al, 2013(Zucchi et al, , 2014 and embryos (Zucchi et al, 2012), altered sex development (Liang et al, 2015a,b) and induced development of male secondary sexual characteristics in female fish (Zeilinger et al, 2009;Runnalls et al, 2013). Together with synthetic estrogenic steroids, progestins are among the most important group of environmental pharmaceuticals of concern.…”

Pond Snail Reproduction as Model in the Environmental Risk Assessment: Reality and Doubts

“…In females, DHP is responsible for maturation of oocytes [78] and ovulation [79], while in males it is involved in spermiation and sperm motility [80]. Synthetic progestogen contaminations altered hormone levels [81], induced transcriptional effects in adults [82] and embryos [83], altered sex development and induced development of male secondary sexual characteristics in female fish [81,84]. Therefore, there are evidences that progestogen contamination interferes with endogen steroids and adversely affect fish reproduction.…”

The other side of progestins: effects in the brain

“…Indeed, norgestrel induced the gene expression of the sodium/iodide symporter that is responsible for the intake of iodide anion into the follicular cells (Liang et al 2015c). DRSP affects central functions in zebrafish brain, disturbing the circadian rhythm network (Zucchi et al 2014, Zhao et al 2015b. Environmental relevant doses of LNG (31 ng/L) affects the reproductive system of male pubertal roach (Rutilus rutilus), acting on the pituitary expression of gonadotrophins and on the sex steroid levels.…”