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High-throughput transcriptomics (HTTr) provides a scalable way to screen chemicals and generate mechanistic insights relevant to human health risk assessment. We applied HTTr in MCF-7 breast cancer cells to assess chemicals across several concentrations (0.001\u201350\u00a0\u00b5M) used in plastics and dyes. Transcriptomic points of departure (tPODs) were derived from general gene perturbations, including pathway-level and estrogen receptor \u03b1 (ER\u03b1)\u2013specific changes. We also used transcriptomic biomarkers to evaluate ER\u03b1 activity and cellular stress responses. Most plastic chemicals showed similar toxicological potency, with tPODs falling within one order of magnitude. Bisphenol K was the most potent, activating ER\u03b1 at the lowest concentrations, followed by plastic additive 08 and bisphenol A (BPA). Despite similar overall potency, transcriptomic biomarkers revealed distinct mechanisms. Chemicals structurally similar to BPA activated ER\u03b1, whereas others with different functional groups inhibited the ER\u03b1 biomarker. Pathway and upstream regulator analyses further indicated that BPA-like chemicals consistently perturbed ER\u03b1-related pathways, while other chemicals enriched fewer gene sets and often produced opposite directional responses. At the highest concentrations tested, several chemicals also activated stress-response biomarkers and suppressed proliferation. Overall, these results suggest that while many plastic chemicals exhibit comparable in vitro potency, they diverge in ER\u03b1 regulation and downstream biological pathways. This study demonstrates the reproducibility and value of HTTr for chemical screening, supports grouping ER\u03b1-active plastic chemicals for read-across, and underscores the need for additional evaluation of plastic chemicals.<\/jats:p>","DOI":"10.1007\/s00204-026-04376-1","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T19:03:33Z","timestamp":1776711813000},"page":"3011-3024","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemicals in plastics differentially affect the transcriptome of MCF-7 breast cancer cells"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0819-4471","authenticated-orcid":false,"given":"Geronimo","family":"Matteo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-2565","authenticated-orcid":false,"given":"David C.","family":"Eickmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0686-1648","authenticated-orcid":false,"given":"Lauren M.","family":"Bradford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8199-8754","authenticated-orcid":false,"given":"Matthew J.","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-7686","authenticated-orcid":false,"given":"Andrew","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2929-7747","authenticated-orcid":false,"given":"Tara","family":"Barton-Maclaren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6197-2036","authenticated-orcid":false,"given":"J. 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