Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 15;279(Pt 1):121797.
doi: 10.1016/j.envres.2025.121797. Epub 2025 May 7.

Effects of phthalate exposure on human ovarian extracellular matrix composition: insights from a 3D spheroid model

Saba Nikanfar  1 , Ellen C R Leonel  2 , Pauliina Damdimopoulou  3 , Jodi A Flaws  4 , Christiani A Amorim  5
Affiliations

Effects of phthalate exposure on human ovarian extracellular matrix composition: insights from a 3D spheroid model

Saba Nikanfar et al. Environ Res. .

Abstract

Phthalates, widely used as plasticizers in consumer products, have become a significant public health concern due to their toxic effects on reproductive and endocrine systems. However, the specific mechanisms by which phthalates affect ovarian function remain poorly understood. To address this knowledge gap, we employed 3D spheroids derived from human ovarian stromal cells, which mimic the ovarian tissue. Since remodeling the ovarian extracellular matrix (ECM) is centrally involved in follicle growth, ovulation, and ovarian aging, we decided to study the impact of environmentally relevant phthalate mixtures (PM) on ECM components. Spheroids were generated from both reproductive-aged and menopausal ovarian tissues, then treated with PM for four days. Collagen deposition was assessed using picrosirius red staining, while immunofluorescence was used to evaluate the proliferation and deposition of collagen type VI, elastin, fibrillin-1, and elastin microfibril interfacer 1 (EMILIN-1). Our results revealed that PM exposure significantly increased collagen deposition (p < 0.0001) in spheroids from reproductive-aged ovaries, while reducing collagen VI levels (p < 0.05), potentially compromising the structural and functional integrity of the ovarian ECM. In contrast, spheroids from menopausal ovaries exhibited a decrease in EMILIN-1 (p < 0.05) and fibrillin-1 (p < 0.001), both crucial for maintaining tissue elasticity. These findings underscore the detrimental effects of phthalates on ovarian ECM across different age groups, with a particular emphasis on ECM elastisity. Additionally, this study highlights the utility of 3D spheroids as a reliable in vitro model for mechanistic research, drug screening and toxicology testing.

Keywords: Extracellular matrix; Ovarian ECM toxicity; Phthalate exposure; Spheroids.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christiani A. Amorim reports a relationship with Fund for Scientific Research that includes: funding grants. Christiani A. Amorim reports a relationship with Federation of Wallonia and Brussels that includes: funding grants. Saba Nikanfar reports a relationship with Fonds spécial de recherche that includes: funding grants. Jody Flaws reports a relationship with National Institute of Environmental Health Sciences that includes: funding grants. Pauliina Damdimopoulou reports a relationship with Swedish Research Council Formas that includes: funding grants. Ellen Leonel reports a relationship with Foundation for Research Support of Goiás State that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

    1. Kavlock R, Boekelheide K, Chapin R, Cunningham M, Faustman E, Foster P, et al. NTP Center for the Evaluation of Risks to Human Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reproductive toxicology (Elmsford, NY). 2002;16(5):529–653. - PubMed
    1. Bergé A, Cladière M, Gasperi J, Coursimault A, Tassin B, Moilleron R. Meta-analysis of environmental contamination by phthalates. Environmental science and pollution research international. 2013;20(11):8057–76. - PubMed
    1. Hongjun Y, Wenjun X, Qing L, Jingtao L, Hongwen Y, Zhaohua L. Distribution of phthalate esters in topsoil: a case study in the Yellow River Delta, China. Environmental monitoring and assessment. 2013;185(10):8489–500. - PMC - PubMed
    1. Martine B, Marie-Jeanne T, Cendrine D, Fabrice A, Marc C. Assessment of adult human exposure to phthalate esters in the urban centre of Paris (France). Bulletin of environmental contamination and toxicology. 2013;90(1):91–6. - PubMed
    1. Hong Y, Wu S, Wei G. Adverse effects of microplastics and nanoplastics on the reproductive system: A comprehensive review of fertility and potential harmful interactions. The Science of the total environment. 2023;903:166258. - PubMed

LinkOut - more resources