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Di-n-butyl phthalate (DBP), an environmental contaminant that can affect reproductive health negatively, was used as a model compound to illustrate the utility of the in vitro model. The cells were treated with DBP (1\u00a0nM to 100\u00a0\u00b5M) for 7\u00a0days. Automated high-content imaging confirmed the presence of cell-specific markers of Leydig cells (CYP11A1\u2009+), Sertoli cells (SOX9\u2009+), and germ cells (DAZL\u2009+). Steroidogenic activity of Leydig cells was demonstrated by analyzing testosterone levels in\u00a0the culture medium. DBP induced a concentration-dependent reduction in testosterone levels and decreased the number of Leydig cells compared to vehicle control. The levels of steroidogenic regulator StAR and the steroidogenic enzyme CYP11A1 were decreased already at the lowest DBP concentration (1\u00a0nM), demonstrating upstream effects in the testosterone biosynthesis pathway. Furthermore, exposure to 10\u00a0nM DBP decreased the levels of the germ cell-specific RNA binding protein DAZL, central for the spermatogenesis. The 3D\u00a0model also captured the development of the Sertoli cell junction proteins, N-cadherin and Zonula occludens protein 1 (ZO-1), critical for the blood\u2013testis barrier. However, DBP exposure did not significantly alter the cadherin and ZO-1 levels. Altogether, this 3D in vitro system models testicular cellular signaling and function, making it a powerful tool for mechanistic screening of developmental testicular toxicity. This can open a new avenue for high throughput screening of chemically-induced reproductive toxicity during sensitive developmental phases.<\/jats:p>","DOI":"10.1007\/s00204-024-03767-6","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T15:01:43Z","timestamp":1716217303000},"page":"2695-2709","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations"],"prefix":"10.1007","volume":"98","author":[{"given":"Radwa","family":"Almamoun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Pierozan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-0015","authenticated-orcid":false,"given":"Oskar","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"3767_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.3389\/fendo.2020.00187","volume":"11","author":"C Bizzarri","year":"2020","unstructured":"Bizzarri C, Cappa M (2020) Ontogeny of hypothalamus-pituitary gonadal axis and minipuberty: an ongoing debate? 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