{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:26:05Z","timestamp":1789655165867,"version":"4.0.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007036","name":"Milj\u00f8styrelsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007036","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Intrauterine exposure to endocrine disrupting chemicals (EDCs), particularly anti-androgens, has been implicated in hypospadias by disrupting fetal masculinization of the genital tubercle (GT). Other pathways, including estrogen signaling, may also contribute but remain poorly characterized, especially in rats \u2013 a key model in chemical toxicity testing. Estrogen signaling has also been linked to hypospadias in mice, raising questions about androgen-estrogen interactions in guiding GT differentiation. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We induced hypospadias in male rat offspring via intrauterine exposure to the antiandrogenic drug flutamide and characterized androgen and estrogen receptor expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed key structural and transcriptional changes in the developing penis, including altered estrogen receptor a (ERa, Esr1) expression. Notably, beyond this established androgen-estrogen relationship in hormone-sensitive tissues, anti-androgenic exposure also induced spatial changes in Esr1 expression in specific regions of the GT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Future toxicological testing using new approach methodologies (NAMs) should consider androgen-estrogen balance and crosstalk in reproductive tissues as a mechanism of action.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1654965","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:06:36Z","timestamp":1757678796000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Androgen receptor antagonist flutamide modulates estrogen receptor alpha expression in distinct regions of the hypospadiac rat 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