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Shotgun metagenomic analysis of gut microbiota in dibutyl phthalate exposed mice
Stockholm University, Faculty of Science, Department of Environmental Science. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0002-9483-0886
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.ORCID iD: 0000-0002-6111-7435
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Environmental Science.
(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:su:diva-225852OAI: oai:DiVA.org:su-225852DiVA, id: diva2:1830771
Available from: 2024-01-23 Created: 2024-01-23 Last updated: 2024-02-26Bibliographically approved
In thesis
1. Toxicological studies of di-n-butyl phthalate (DBP): Impact on the reproductive system and gut microbiota
Open this publication in new window or tab >>Toxicological studies of di-n-butyl phthalate (DBP): Impact on the reproductive system and gut microbiota
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The potential health impact of exposure to anthropogenic chemicals has raised major concerns worldwide. Phthalates are mainly used in the plastic industry and have been associated with adverse effects in humans. Di-n-butyl phthalate (DBP) is one of the dominant phthalates with a ubiquitous presence in the environment. While many studies have examined the endocrine disrupting properties of DBP, with a focus on developmental and reproductive dysfunctions, studies of its effects on the adult reproductive system and gut microbiota are limited. This thesis aimed to determine persistent effects of DBP on the adult male reproductive system, provide a high-throughput screening tool for identifying reproductive toxicants, and characterize the effects of DBP on the gut microbiota.

   Paper I investigated if adult DBP exposure can induce persistent effects on the mature reproductive system. Adult male mice were orally exposed to 10 or 100 mg/kg/day for five weeks and testes were collected one week after the last dose. The results demonstrated a significant decrease in testosterone levels in the DBP-exposed groups. Mechanistically, the levels of steroidogenic enzymes, cell-specific markers and oxidative stress were increased. In paper II, elements of the in vivo testicular microenvironment, including functional testosterone production, were modeled using a three-dimensional (3D) heterogenous testicular cell co-culture derived from neonatal mice. Automated high-content imaging of cell-specific markers confirmed the presence of germ cells (DAZL+), Leydig cells (CYP11A1+), and Sertoli cells (SOX9+). DBP exposure decreased testosterone production, as well as levels of the steroidogenic enzyme CYP11A1, and the steroidogenic regulator StAR. Overall, this in vitro 3D model recapitulates the testicular pathways involved in DBP toxicity, making it a relevant tool for assessing reprotoxic effects of chemicals.

   Paper III investigated the impact of oral DBP exposure on the gut microbiota and the potential interplay with immune and testicular toxicity using 16S rRNA sequencing. DBP-treated mice showed a distinct microbial composition and numerous differentially abundant amplicon sequence variants. Interestingly, the microbial alterations correlated with an increase in non-classical monocytes observed in DBP-exposed mice. In paper IV, a shotgun metagenomic analysis was conducted to achieve a more comprehensive characterization of the DBP-induced effects on gut microbiota composition and function. The DBP-exposed mice had a higher abundance of Adlercreutzia mucosicola, a bacterium linked with intestinal inflammation. In contrast, the beneficial Akkermansia muciniphila was less abundant in DBP-exposed mice. Functional analysis demonstrated that DBP exposure increased the abundance of genes involved in environmental sensing and antimicrobial resistance.

   In conclusion, this doctoral thesis demonstrates the antiandrogenic effects of DBP as well as potential underlying mechanisms of testicular dysfunction in adult mice. In addition, we established a powerful in vitro tool for screening reprotoxic effects. The gut microbiota was also impaired by DBP exposure, which may play a potential role in initiating or exacerbating the DBP-induced toxicity. Overall, this work highlights the potential health impact of the interplay between the two exposome components, chemical exposure and gut microbiota.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science, Stockholm University, 2024. p. 56
Keywords
Dibutyl phthalate, Antiandrogen, Gut microbiota, Reproductive toxicity, Endocrine disrupting chemicals, Environmental contaminants, Phthalates, Plastics, 3D cell culture model, Exposome, Toxicology
National Category
Pharmacology and Toxicology
Research subject
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-225853 (URN)978-91-8014-651-7 (ISBN)978-91-8014-652-4 (ISBN)
Public defence
2024-03-08, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 09:00 (English)
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Supervisors
Available from: 2024-02-14 Created: 2024-01-24 Last updated: 2024-02-08Bibliographically approved

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Almamoun, RadwaPierozan, PaulaKarlsson, Oskar

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