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Hitting the mark: Studies of alterations in behaviour and fertility in ethinyl estradiol-exposed zebrafish and search related biomarkers
Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro universitet.
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Resurstyp
Text
Abstract [en]

In this thesis, we have analysed the effects of EE2 on non-reproductive behaviours and fertility. We have showed that two doses of EE2 in male adult short-term exposures evokes opposite behaviours in the novel tank test. A lower dose induced increased bottom-dwelling, a sign of increased anxiety and a higher dose increased surface-dwelling, which would likely expose themselves to predation in a natural environment. Increased shoaling was observed in both exposures, possibly affecting feeding and reproduction opportunities. Fertility analysis of these fish demonstrated a complete inhibition of spawning in the highest dose group. To investigate mechanisms behind the spawning failure, we examined expression levels of genes involved in zebrafish sex differentiation and maintenance of gonadal function. We found downregulated transcription levels of male-predominant genes, suggesting a demasculinization of the testes contributing to functional sterility in these fish. We have demonstrated that non-reproductive behaviour in zebrafish is highly sensitive to EE2 exposure during development. After exposing male and female zebrafish to low doses of EE2 followed by remediation in clean water until adulthood, the fish displayed increased anxiety and shoaling behaviour, demonstrating persistent effects of EE2. Furthermore, behavioural effects were transferred to their progeny. Decreased fertilisation success of the developmentally exposed fish was observed in both sexes when mated to untreated animals of the opposite sex. These fertility effects persisted although the fish had a long remediation period, implying likely reduced fitness of fish populations in aquatic environments. Based on our findings on non-reproductive behaviours and fertility, we performed RNAsequencing analysis of the brain and testes in order to investigate possible biological mechanisms behind the persistent effects. There is a need for biomarkers allowing detection of both reversible and irreversible effects in animals exposed to estrogenic substances, hopefully contributing to better risk assessments for EDCs. Results from RNA-sequencing would serve as a basis for continued studies in pursuit of potential biomarkers.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro university , 2016. , s. 55
Serie
Örebro Studies in Biology, ISSN 1650-8793 ; 10Södertörn doctoral dissertations, ISSN 1652-7399 ; 115
Nyckelord [en]
Endocrine disrupting compounds, 17α-ethinylestradiol, fertility, anxiety, behaviour, zebrafish, biomarkers, stress
Nationell ämneskategori
Annan biologi
Identifikatorer
URN: urn:nbn:se:sh:diva-29440ISBN: 978-91-7529-115-4 (tryckt)OAI: oai:DiVA.org:sh-29440DiVA, id: diva2:900395
Disputation
2016-02-25, Sal MA636, Alfred Nobels allé 7, Huddinge, 13:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
ÖstersjöstiftelsenTillgänglig från: 2016-02-04 Skapad: 2016-02-04 Senast uppdaterad: 2016-02-04Bibliografiskt granskad
Delarbeten
1. Short-term treatment of adult male zebrafish (Danio Rerio) with 17α-ethinyl estradiol affects the transcription of genes involved in development and male sex differentiation.
Öppna denna publikation i ny flik eller fönster >>Short-term treatment of adult male zebrafish (Danio Rerio) with 17α-ethinyl estradiol affects the transcription of genes involved in development and male sex differentiation.
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2014 (Engelska)Ingår i: Comparative Biochemistry and Physiology - Part C: Toxicology & Pharmacology, ISSN 1532-0456, E-ISSN 1878-1659, Vol. 164, s. 35-42Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The synthetic estrogen 17α-ethinyl estradiol (EE2) disturbs reproduction and causes gonadal malformation in fish. Effects on the transcription of genes involved in gonad development and function that could serve as sensitive biomarkers of reproductive effects in the field is, however, not well known. We have studied mRNA expression in testes and liver of adult zebrafish (Danio rerio) males treated with 0, 5 or 25ng/L EE2for 14days. qPCR analysis showed that the mRNA expression of four genes linked to zebrafish male sex determination and differentiation, Anti-Mullerian Hormone, Double sex and mab-related protein, Sry-related HMG box-9a and Nuclear receptor subfamily 5 group number 1b were significantly decreased by 25ng/L, but not 5ng/L EE2 compared with the levels in untreated fish. The decreased transcription was correlated with a previously shown spawning failure in these males (Reyhanian et al., 2011. Aquat Toxicol 105, 41-48), suggesting that decreased mRNA expression of genes regulating male sexual function could be involved in the functional sterility. The mRNA level of Cytochrome P-45019a, involved in female reproductive development, was unaffected by hormone treatment. The transcription of the female-specific Vitellogenin was significantly induced in testes. While testicular Androgen Receptor and the Estrogen Receptor-alpha mRNA levels were unchanged, Estrogen receptor-beta was significantly decreased by 25ng/L EE2. Hepatic Estrogen Receptor-alpha mRNA was significantly increased by both exposure concentrations, while Estrogen Receptor-beta transcription was unaltered. The decreased transcription of male-predominant genes supports a demasculinization of testes by EE2 and might reflect reproductive disturbances in the environment.

Nyckelord
landscape scars, industrial heritage, waste, nuclear power, mining, Malmberget, Ignalina, Sweden, Lithuania
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:sh:diva-23362 (URN)10.1016/j.cbpc.2014.04.003 (DOI)000337769100005 ()24747828 (PubMedID)2-s2.0-84899872779 (Scopus ID)
Forskningsfinansiär
Östersjöstiftelsen
Tillgänglig från: 2014-04-25 Skapad: 2014-04-25 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
2. Developmental exposure of zebrafish (Danio rerio) to 17α-Ethinylestradiol affects non-reproductive behavior and fertility as adults, and increases anxiety in unexposed progeny
Öppna denna publikation i ny flik eller fönster >>Developmental exposure of zebrafish (Danio rerio) to 17α-Ethinylestradiol affects non-reproductive behavior and fertility as adults, and increases anxiety in unexposed progeny
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2015 (Engelska)Ingår i: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 73, s. 30-38Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Exposure to estrogenic endocrine disruptors (EDCs) during of development affects fertility, reproductive and non-reproductive behavior in mammals and fish. These effects can also be transferred to coming generations. In fish, the effects of developmental EDC exposure on non-reproductive behavior is less well studied. Here, we analyze the effects of 17α-Ethinylestradiol (EE2) on anxiety, shoaling behavior and fertility in zebrafish after developmental treatment and remediation in clean water until adulthood. Zebrafish embryos were exposed from day 1 to day 80 post fertilization to actual concentrations of 1.2 and 1.6ng/L EE2. After remediation for 82days non-reproductive behavior and fertilization success were analyzed in both sexes. Males and females from the 1.2ng/L group, as well as control males and females, were bred, and behavior of the untreated F1 offspring was tested as adults. Developmental treatment with 1.2 and 1.6ng/L EE2 significantly increased anxiety in the Novel Tank test and increased shoaling intensity in both sexes. Fertilization success was significantly reduced by EE2 in both sexes when mated with untreated fish of opposite sex. Progeny of fish treated with 1.2ng/L EE2 showed increased anxiety in the Novel tank test and increased light avoidance in the Scototaxis test compared to control offspring. In conclusion, developmental exposure of zebrafish to low doses of EE2 resulted in persistent changes in behavior and fertility. The behavior of unexposed progeny were affected by their parents' exposure, which might suggest transgenerational effects.

Ort, förlag, år, upplaga, sidor
Academic Press, 2015
Nyckelord
17α-Ethinylestradiol; Anxiety; Developmental exposure; Endocrine disruptors; F1 effects; Fertility; Neuroendocrinology; Social behavior; Stress behavior; Zebrafish
Nationell ämneskategori
Biologiska vetenskaper Miljövetenskap
Forskningsämne
Miljövetenskapliga studier; Östersjö- och Östeuropaforskning
Identifikatorer
urn:nbn:se:sh:diva-27795 (URN)10.1016/j.yhbeh.2015.05.014 (DOI)000360251800005 ()26072466 (PubMedID)2-s2.0-84934983120 (Scopus ID)1556/42/2011 (Lokalt ID)1556/42/2011 (Arkivnummer)1556/42/2011 (OAI)
Forskningsfinansiär
Östersjöstiftelsen, A037-2008Östersjöstiftelsen, A065-2011
Tillgänglig från: 2015-06-18 Skapad: 2015-06-18 Senast uppdaterad: 2020-07-17Bibliografiskt granskad
3. Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17α-ethinyl estradiol
Öppna denna publikation i ny flik eller fönster >>Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17α-ethinyl estradiol
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2018 (Engelska)Ingår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 262, s. 44-58Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

17α-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non-coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations.

Ort, förlag, år, upplaga, sidor
Academic Press, 2018
Nationell ämneskategori
Annan biologi Miljövetenskap
Forskningsämne
Östersjö- och Östeuropaforskning
Identifikatorer
urn:nbn:se:sh:diva-29441 (URN)10.1016/j.ygcen.2018.03.011 (DOI)000430995100006 ()29526718 (PubMedID)2-s2.0-85044314644 (Scopus ID)1556/42/2011 (Lokalt ID)1556/42/2011 (Arkivnummer)1556/42/2011 (OAI)
Forskningsfinansiär
Östersjöstiftelsen, A065-2011Stockholms läns landsting, 806/3.1.1/2014
Anmärkning

Som manuskript i avhandling. As manuscript in dissertation.

Tillgänglig från: 2016-02-02 Skapad: 2016-02-04 Senast uppdaterad: 2020-07-17Bibliografiskt granskad
4. Persistent effects of developmental exposure to 17α-ethinylestradiol on the zebrafish (Danio rerio) brain transcriptome and stress behavior
Öppna denna publikation i ny flik eller fönster >>Persistent effects of developmental exposure to 17α-ethinylestradiol on the zebrafish (Danio rerio) brain transcriptome and stress behavior
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Zoologi Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:sh:diva-28425 (URN)
Anmärkning

Som manuskript i avhandling. As manuscript in dissertation.

Tillgänglig från: 2015-09-30 Skapad: 2015-10-01 Senast uppdaterad: 2017-10-24Bibliografiskt granskad

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Caspillo, Nasim Reyhanian

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