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Increased apoptosis, reduced Wnt/β-catenin signaling, and altered tail development in zebrafish embryos exposed to a chemical mixture that has been inversely associated with birth weight in humans
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.ORCID iD: 0000-0002-7389-8849
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology.ORCID iD: 0000-0002-6699-4015
Public Health Sciences, Karlstad University.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

A wide variety of anthropogenic chemicals is detected in humans and wildlife and the health effects of such exposure are not well understood. The early developmental period is generally most susceptible to chemical disruption and early-life exposure is a suggested cause for disease in adulthood. Two developmentally important signaling networks that can be targeted by pollutants are those of apoptosis and Wnt/β-catenin signaling. We used zebrafish embryo models to determine effects of a mixture of chemicals that was defined within the EU-project EDC-MixRisk based on its inverse association with birth weight in a human pregnancy cohort (SELMA). The mixture (Mixture G) was composed of five phthalate monoesters, triclosan, and three perfluoroalkyl acids. We recently showed that developmental exposure to Mixture G leads to increased formation of adipocytes in zebrafish larvae. Here we determined its effects on apoptosis and Wnt/β-catenin signaling in zebrafish embryos. Apoptosis was assayed by TUNEL, caspase-3 activity, and acridine orange staining while Wnt/β-catenin signaling was studied using a transgenic zebrafish line expressing an EGFP reporter in response to Tcf/Lef-mediated Wnt/ß-catenin signaling. We found that Mixture G increased the incidence of apoptosis and suppressed Wnt/β-catenin signaling in the caudal fin at human-relevant concentrations (20 or 100 times the geometric mean serum levels in the cohort). Furthermore, caudal fin shape was altered in Mixture G-exposed embryos. These results suggest that chemicals that human embryos/fetuses are exposed to can induce morphological and/or physiological alterations, effects that could result in adverse health effects.

Keywords [en]
Mixtures, Zebrafish, Apoptosis, Wnt/beta-catenin, PFOS
National Category
Environmental Sciences Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-409016OAI: oai:DiVA.org:uu-409016DiVA, id: diva2:1424543
Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2020-04-17
In thesis
1. Developmental exposure to mixtures of environmental pollutants: Studies on metabolism, developmental processes, and reproductive organs in zebrafish and chicken embryos
Open this publication in new window or tab >>Developmental exposure to mixtures of environmental pollutants: Studies on metabolism, developmental processes, and reproductive organs in zebrafish and chicken embryos
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Humans and wildlife are continuously exposed to mixtures of environmental pollutants. Mixture toxicity can be challenging to predict due to interactions between chemicals and thus whole-mixture approaches are crucial in toxicology. Developing organisms are generally more sensitive to chemical insult than adults and early exposure has been linked to metabolic and reproductive disorders later in life. It is thus imperative to clarify how mixtures of environmental pollutants affect early development.

Within this thesis, consequences of early exposure to human-relevant chemical mixtures have been demonstrated using zebrafish and chicken embryos. The mixtures were designed previously based on negative associations with birth weight (mixture G) or anogenital distance (mixture S) in Swedish children. Mixture G consist of phthalate monoesters, perfluoroalkyl acids, and triclosan (TCS). It was assessed for effects on developmental processes (apoptosis and wnt/β-catenin signaling) and lipid metabolism in zebrafish. Two components of mixture G were assessed as single compounds: perfluorooctane sulfonate (PFOS) and TCS. Exposure to mixture G induced apoptosis, reduced wnt/β-catenin signalling, increased visceral adiposity, and reduced blood- and whole body-lipid levels in developing zebrafish. PFOS induced apoptosis but not Wnt/β-catenin signaling and TCS had similar effects on lipid levels as the mixture, although the effect of TCS on adipogenesis was not as pronounced. Mixture S, which consists of four phthalate monoesters, and a suggested bisphenol A metabolite (4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene; MBP) were assessed for disruption of reproductive organ development in chicken embryos. No effects were observed by mixture S. MBP caused feminization in male embryos (left ovotestis, feminized gonadal mRNA expression pattern, and Müllerian duct retention). MBP-exposed females displayed smaller left ovaries, malformed left Müllerian ducts, and right Müllerian duct retention.

In conclusion, a mixture that has been implicated in altered intrauterine metabolism and growth in Swedish children caused developmental and metabolism disrupting effects in larval zebrafish. PFOS and TCS most likely contribute to the effects by the mixture. Furthermore, the suggested bisphenol A metabolite MBP, but not a mixture of phthalate monoesters, altered both male and female reproductive organ development in chicken embryos. The results were generated using models of both environmental and human relevance. The results in this thesis demonstrate the value of combining epidemiological and experimental studies to assess mixture toxicity. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 57
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1937
Keywords
Mixtures, Developmental toxicology, Endocrine disrupting chemicals, Metabolism, Feminization, Zebrafish, Chicken embryo
National Category
Pharmacology and Toxicology Environmental Sciences Developmental Biology
Research subject
Biology with specialization in Environmental Toxicology; Biology with specialization in Environmental Toxicology; Biology with specialization in Environmental Toxicology; Biology with specialization in Environmental Toxicology
Identifiers
urn:nbn:se:uu:diva-409018 (URN)978-91-513-0954-5 (ISBN)
Public defence
2020-06-10, Ekmansalen, Evolutionsbiologiskt centrum, Norbyvägen 14, Uppsala, 13:00 (English)
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Supervisors
Available from: 2020-05-19 Created: 2020-04-17 Last updated: 2020-05-19

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Mentor, AnnaRanefall, PetterBrunström, BjörnMattsson, AnnaJönsson, Maria

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