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Developmental exposure to mixtures of environmental pollutants: Studies on metabolism, developmental processes, and reproductive organs in zebrafish and chicken embryos
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.ORCID iD: 0000-0002-7389-8849
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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 [en]
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: urn:nbn:se:uu:diva-409018ISBN: 978-91-513-0954-5 (print)OAI: oai:DiVA.org:uu-409018DiVA, id: diva2:1424600
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
List of papers
1. 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
Open this publication in new window or tab >>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
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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
Mixtures, Zebrafish, Apoptosis, Wnt/beta-catenin, PFOS
National Category
Environmental Sciences Developmental Biology
Identifiers
urn:nbn:se:uu:diva-409016 (URN)
Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2020-04-17
2. Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio)
Open this publication in new window or tab >>Developmental exposure to a human relevant mixture of endocrine disruptors alters metabolism and adipogenesis in zebrafish (Danio rerio)
2020 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 238, article id 124584Article in journal (Refereed) Published
Abstract [en]

Exposure to endocrine disrupting chemicals has been suggested to contribute to the ongoing globally increasing obesity trend. The complex chemical mixtures that humans and wildlife are exposed to include a number of compounds that may have obesogenic properties. In this study we examined a mixture consisting of phthalate-monoesters, triclosan, and perfiuorinated compounds. The mixture was designed within the EDC-MixRisk project based on serum levels of the compounds in pregnant women of a Swedish mother-child cohort. The compounds were negatively associated with birth weight of the children. We assessed whether developmental exposure to this mixture in combination with a calorie-rich diet affected metabolic rate, blood lipids, adipogenesis and lipid storage, and the whole-body level of neutral lipids in zebrafish (Danio rerio). Wildtype zebrafish were exposed to the mixture from 3 h post fertilization to 5, 14 or 17 days post fertilization (dpf) at water concentrations corresponding to 1, 10, 20, or 100 times the geometrical mean of the serum concentration (hsc) in the women. Exposure to the mixture at 20 times hsc lowered metabolic rate at 2-5 dpf, and increased the number of adipocytes and the amount of visceral adipose tissue at 14 and 17 dpf respectively. Also, mRNA expression of fatty acid binding protein a was increased at 17 dpf by 10 and 20 times hsc of the mixture. This study shows that a human-relevant mixture of environmental pollutants affects metabolic rate, adipogenesis and lipid storage in young zebrafish fed a calorie-rich diet, thus demonstrating its potential to disrupt metabolism.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2020
Keywords
Mixtures, Metabolism, Adipogenesis, Zebrafish, Endocrine disrupting chemicals
National Category
Environmental Sciences
Identifiers
urn:nbn:se:uu:diva-398425 (URN)10.1016/j.chemosphere.2019.124584 (DOI)000497885800054 ()31470313 (PubMedID)
Funder
EU, Horizon 2020, 634880
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2020-04-17Bibliographically approved
3. Metabolic disruption by a human-relevant chemical mixture, triclosan, and tributyltin in larval zebrafish (Danio rerio)
Open this publication in new window or tab >>Metabolic disruption by a human-relevant chemical mixture, triclosan, and tributyltin in larval zebrafish (Danio rerio)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Exposure to metabolism disrupting compounds during development may have short- and long-term health consequences. We have studied the effects of a mixture that consists of perfluoroalkyl acids, phthalate monoesters, and triclosan (TCS) on metabolic endpoints in developing zebrafish (Danio rerio). The mixture has previously been negatively associated with birth weight in the Swedish pregnancy cohort SELMA. We also studied one of the mixture components (TCS) and the known obesogen tributyltin (TBT). Water concentrations of the mixture and TCS corresponded to 1, 20, 60, and 100 times the geometrical mean of the gestational week 10 serum concentration in the SELMA women. The fish were exposed from 3 hours post fertilization and effects on metabolic rate were assessed at 2-5 days post fertilization (dpf) and lipid content in the blood, whole-body neutral lipid content, and adiposity were determined at 7 dpf. Exposure to the mixture and TCS altered metabolic rate. The mixture and both single compounds reduced lipid levels in whole-body samples and in the blood. A higher proportion of fish in the mixture- and TBT-exposed groups had visible adipocytes at 7 dpf compared with the control group and a similar tendency was observed in TCS-exposed fish. Our results demonstrate metabolism disrupting properties of the mixture and its component TCS that were similar to those of TBT. The results further indicate that TCS contributes to, but is not solely responsible for, the effect by the mixture.

Keywords
Mixtures, Zebrafish, adipogenesis, Lipid metabolism, Endocrine disrupting chemicals, Triclosan, Tributyltin
National Category
Environmental Sciences Developmental Biology
Identifiers
urn:nbn:se:uu:diva-408801 (URN)
Available from: 2020-04-14 Created: 2020-04-14 Last updated: 2020-04-17
4. 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
Open this publication in new window or tab >>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
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
Keywords
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:nbn:se:uu:diva-406961 (URN)10.1080/15287394.2020.1728598 (DOI)000514984300001 ()32077375 (PubMedID)
Funder
EU, Horizon 2020, 634880
Available from: 2020-03-17 Created: 2020-03-17 Last updated: 2020-04-17Bibliographically approved

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