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Mechanistic screening of reproductive toxicity in a 3D testicular co-culture shows significant impairments following exposure to low dibutyl phthalate concentrations
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap. Stockholms universitet, Science for Life Laboratory (SciLifeLab).ORCID-id: 0000-0002-9483-0886
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap. Stockholms universitet, Science for Life Laboratory (SciLifeLab).ORCID-id: 0000-0002-6111-7435
Stockholms universitet, Science for Life Laboratory (SciLifeLab). Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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Identifikatorer
URN: urn:nbn:se:su:diva-225851OAI: oai:DiVA.org:su-225851DiVA, id: diva2:1830768
Tilgjengelig fra: 2024-01-23 Laget: 2024-01-23 Sist oppdatert: 2024-02-26bibliografisk kontrollert
Inngår i avhandling
1. Toxicological studies of di-n-butyl phthalate (DBP): Impact on the reproductive system and gut microbiota
Åpne denne publikasjonen i ny fane eller vindu >>Toxicological studies of di-n-butyl phthalate (DBP): Impact on the reproductive system and gut microbiota
2024 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Environmental Science, Stockholm University, 2024. s. 56
Emneord
Dibutyl phthalate, Antiandrogen, Gut microbiota, Reproductive toxicity, Endocrine disrupting chemicals, Environmental contaminants, Phthalates, Plastics, 3D cell culture model, Exposome, Toxicology
HSV kategori
Forskningsprogram
miljövetenskap
Identifikatorer
urn:nbn:se:su:diva-225853 (URN)978-91-8014-651-7 (ISBN)978-91-8014-652-4 (ISBN)
Disputas
2024-03-08, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2024-02-14 Laget: 2024-01-24 Sist oppdatert: 2024-02-08bibliografisk kontrollert

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