The progestin levonorgestrel affects sex differentiation in zebrafish at environmentally relevant concentrations

Hua, Jianghuan; Han, Jian; Guo, Yongyong; Zhou, Bingsheng

doi:10.1016/j.aquatox.2015.06.013

Cited by 57 publications

(27 citation statements)

References 62 publications

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“…This is in accordance with a recent study by Hua et al (Hua et al, 2015), showing allmale populations of zebrafish when exposed to LNG at 10 ng L −1 during development. We found 100% males at an LNG concentration of 5.5 ng L −1 which is one of the lowest concentrations of an androgenic compound ever reported to cause male-biased sex ratio in fish.…”

Section: Discussionsupporting

confidence: 94%

“…Furthermore, this would suggest that sexual maturation in fish can be impacted by all progestins, and that effects are more likely to occur in nature because waters are simultaneously contaminated by several progestins. However, the present results conform to that mainly the androgenic progestins have ecologically important effects, influencing fecundity and phenotypic sex at environmentally relevant concentrations (DeQuattro et al, 2012;Han et al, 2014;Hua et al, 2015;Liang et al, 2015;Paulos et al, 2010;Runnalls et al, 2013;Zeilinger et al, 2009;Zhao et al, 2015). The present study thus supports the contention that the reproductive impairment in fish caused by progestins is to a significant degree mediated by their androgenic properties.…”

Section: Discussionsupporting

confidence: 91%

“…The androgenicity of LNG is well documented in mammals, fish and amphibians (Africander et al, 2011;Hoffmann and Kloas, 2012;Runnalls et al, 2013;Svensson et al, 2013Svensson et al, , 2014. 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.…”

Section: Discussionmentioning

confidence: 75%

See 2 more Smart Citations

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

et al. 2016

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 75%

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

et al. 2016

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“…Some endpoints were showed to be disturbed at lower concentrations such as reduced egg production in female fathead minnow after exposure to 0.8 ng/L for 21 days or masculinization of female zebrafish exposed to 10 ng/L LNG during the process of sexual differentiation (0-63 dpf) (Zeilinger et al 2009, Hua et al 2015.…”

mentioning

confidence: 99%

Additive effects of levonorgestrel and ethinylestradiol on brain aromatase ( cyp19a1b ) in zebrafish specific in vitro and in vivo bioassays

Hinfray¹,

Tebby

Garoche³

et al. 2016

Toxicology and Applied Pharmacology

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Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-tranfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentrationresponse relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures.

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“…Several previous studies showed the effect of progestins on different organs in zebrafish, especially the gonad [5,7,8,32]. For instance, progestins could cause gonadal change at physiological, histological, and biochemical levels at environmentally relevant concentrations [5,7,8,32]. Furthermore, developmentrelated processes, the circadian rhythm network, and the phototransduction cascade were significantly enriched in brain of adult zebrafish after progestin exposure; and transcriptional alterations of the circadian rhythm network were observed in the eyes of adult zebrafish [22,33].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and histological alterations in gonad of adult zebrafish after exposure to the synthetic progestin norgestrel

Shi

Zhao

Jiang

et al. 2017

Enviro Toxic and Chemistry

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The aim of the present study was to investigate the effects of norgestrel (NGT) on gonadal development in adult zebrafish. Adult zebrafish were exposed to NGT for 14 d at 871 ng L for microarray analysis, and a follow-up experiment was conducted to further study the targeted pathway in adult zebrafish after exposure to NGT at 6.7, 83, and 912 ng L by quantitative polymerase chain reaction (qPCR) and histological analysis. The microarray analysis revealed that 11 545 transcripts were identified. Gene ontology analysis showed organ development, system development, multicellular organismal development, single-organism developmental process, and developmental process were significantly enriched. A Venn diagram displayed 434 target genes involved in organ development, and these genes were common in these 5 development-related processes. Kyoto Encyclopedia of Genes and Genomes analysis showed that the notch signaling pathway was the top toxicity pathway, and it was selected as the target pathway for further qPCR analysis. The qPCR analysis revealed significant and dose-dependent alterations of most target genes involved in the notch signaling pathway in the gonads, even at an environmentally relevant concentration of 6.7 ng L . The transcriptional patterns were consistent with the notch signaling cascade. In addition, NGT significantly increased the frequency of mature sperm and decreased the frequency of immature sperm at all concentrations. Meanwhile, NGT treatment increased the percentage of mature vitellogenic oocytes and atretic follicles at 912 ng L but decreased the percentage of immature vitellogenic oocytes. Thus, the present study demonstrated significant developmental toxicity in the gonad of adult zebrafish even at environmentally relevant NGT concentrations. Environ Toxicol Chem 2017;36:3267-3276. © 2017 SETAC.

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The progestin levonorgestrel affects sex differentiation in zebrafish at environmentally relevant concentrations

Cited by 57 publications

References 62 publications

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

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

Additive effects of levonorgestrel and ethinylestradiol on brain aromatase ( cyp19a1b ) in zebrafish specific in vitro and in vivo bioassays

Transcriptional and histological alterations in gonad of adult zebrafish after exposure to the synthetic progestin norgestrel

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