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A suggested bisphenol A metabolite (MBP) interfered with reproductive organdevelopment in the chicken embryo while a human-relevant mixture ofphthalate monoesters had no such effects
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).ORCID iD: 0000-0002-7389-8849
Karlstad Univ, Publ Hlth Sci, Karlstad, Sweden;Icahn Sch Med Mt Sinai, New York, NY 10029 USA.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Reproductive Biology in Uppsala (CRU).ORCID iD: 0000-0002-5328-6255
2020 (English)In: Journal of Toxicology and Environmental Health, ISSN 1528-7394, E-ISSN 1087-2620, Vol. 83, no 2, p. 66-81Article in journal (Refereed) Published
Abstract [en]

Bisphenol A (BPA) and phthalate diesters are ubiquitous environmental contaminants. While thesecompounds have been reported as reproductive toxicants, their effects may partially be attributedto metabolites. The aim of this study was to examine reproductive organ development in chickenembryos exposed to the BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP;100 μg/g egg) or a human-relevant mixture of 4 phthalate monoesters (85 μg/g egg). The mixturewas designed within the EU project EDC-MixRisk based upon a negative association with anogenitaldistance in boys at 21 months of age in a Swedish pregnancy cohort. Chicken embryoswere exposed in ovo from an initial stage of gonad differentiation (embryonic day 4) anddissected two days prior to anticipated hatching (embryonic day 19). No discernible effectswere noted on reproductive organs in embryos exposed to the mixture. MBP-treated malesexhibited retention of Müllerian ducts and feminization of the left testicle, while MBPadministeredfemales displayed a diminished the left ovary. In the left testicle of MBP-treatedmales, mRNA expression of female-associated genes was upregulated while the testicular markergene SOX9 was downregulated, corroborating a feminizing effect by MBP. Our results demonstratethat MBP, but not the phthalate monoester mixture, disrupts both male and femalereproductive organ development in an avian embryo model.

Place, publisher, year, edition, pages
Taylor & Francis, 2020. Vol. 83, no 2, p. 66-81
Keywords [en]
Chicken embryo, feminization, mixture, phthalates, 4-methyl-2, 4-bis(4-hydroxyphenyl)pent-1-ene (MBP)
National Category
Environmental Sciences Developmental Biology
Research subject
Biology with specialization in Environmental Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-406961DOI: 10.1080/15287394.2020.1728598ISI: 000514984300001PubMedID: 32077375OAI: oai:DiVA.org:uu-406961DiVA, id: diva2:1415125
Funder
EU, Horizon 2020, 634880Available from: 2020-03-17 Created: 2020-03-17 Last updated: 2020-04-17Bibliographically approved
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)
Opponent
Supervisors
Available from: 2020-05-19 Created: 2020-04-17 Last updated: 2020-05-19

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Mentor, AnnaJönsson, MariaMattsson, Anna

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