{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:37:31Z","timestamp":1776955051938,"version":"3.51.4"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Endocrine-disrupting and carcinogenic effects of glyphosate have long been suspected, but little is known about the effect of compounds used in real life at different concentrations, neither in normal nor in thyroid tumor cells. As cancer cells may have different sensitivities and the effect of the product containing glyphosate may be different from that produced by the active ingredient alone, including the Acceptable Occupational Exposure Level (AOEL=160\u00b5g\/L) and the Acceptable Daily Intake (ADI=830\u00b5g\/L) determined by ANVISA, we used two human thyroid-derived cell lines, Nthy-ori 3-1 (from normal follicular cells) and TPC-1 (from papillary carcinoma), to test 15 different concentrations of Roundup\u00ae Original DI. Trypan blue (TB), CCK-8 and BrdU assays were used to evaluate cytotoxicity, metabolic activity and proliferation with 24h and 48h exposures in technical and biological triplicates. TB showed an important toxic effect, especially after 24h of exposure, in both cell lines. The AOEL concentration caused the death of 43% and 50% of the Nthy-ori and TPC-1 cells, respectively, in 24 h, while ADI resulted in 35% and 58% of cell death. After 48h of exposure, AOEL and ADI caused a lower number of dead Nthy-ori (33% and 18%) and TPC-1 (33% and 37%) cells, respectively, suggesting that the toxic effect of the product disappears and\/or both strains have repair mechanisms that protect them from longer exposures. On the other hand, the CCK-8 assay showed that small concentrations of Roundup have a proliferative effect: 6.5\u00b5g\/L increased the number of both Nthy-ori and TPC-1 cells at 24h, and the BrdU assay confirmed the stimulatory effect with a 321% increase in the absorbance of Nthy-ori cells at 48h. The herbicide produced even more frequent increases in the BrdU absorbance of TPC-1 cells, mainly at 24h. We conclude that thyroid cells exposed to Roundup present a nonmonotonic dual dose\u2013response curve. Low concentrations of the pesticide, considered acceptable, cause significant cell death but also have an important proliferative effect, especially on TPC-1 cells. This herbicide, widely used around the world, may play a role in the increased incidence rate of thyroid nodules and cancer that has been observed in recent decades.<\/jats:p>","DOI":"10.3389\/fendo.2022.904437","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T04:51:32Z","timestamp":1659070292000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Alternation between toxic and proliferative effects of Roundup\u00ae on human thyroid cells at different concentrations"],"prefix":"10.3389","volume":"13","author":[{"given":"Izabela Fernanda","family":"Dal\u2019 B\u00f3","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elis\u00e2ngela Souza","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa Teodoro","family":"Rabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina Colombera","family":"Peres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matheus","family":"Nascimento","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Izabel","family":"Chiamolera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valdemar","family":"M\u00e1ximo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nat\u00e1ssia Elena","family":"Bufalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura Sterian","family":"Ward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e208759","DOI":"10.1001\/jamanetworkopen.2020.8759","article-title":"Global burden of thyroid cancer from 1990 to 2017","volume":"3","author":"Deng","year":"2020","journal-title":"JAMA network Open"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2017.05.002","article-title":"Evolution of the histologic classification of thyroid neoplasms and its impact on clinical management","volume":"44","author":"Xu","year":"2018","journal-title":"Eur J Surg Oncol J Eur Soc Surg Oncol Br Assoc Surg Oncol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/genes10090709","article-title":"Molecular alterations in thyroid cancer: From bench to clinical practice","volume":"10","author":"Tirro","year":"2019","journal-title":"Genes"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpedm.2014.10.002","article-title":"A influ\u00eancia da exposi\u00e7\u00e3o ambiental a disruptores end\u00f3crinos no crescimento e desenvolvimento de crian\u00e7as e adolescentes","volume":"10","author":"C. Castro-Correia","year":"2015","journal-title":"Rev Portuguesa Endocrinologia Diabetes e Metabolismo"},{"key":"B5","article-title":"Introduc\u0327a\u00e3o aos disruptores endo\u00edcrinos (DEs)","volume-title":"Um guia para governos e organizac\u0327o\u00e3es de interesse pu\u00edblico","author":"Gore A","year":"2014"},{"key":"B6","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1210\/er.2009-0002","article-title":"Endocrine-disrupting chemicals: an endocrine society scientific statement","volume":"30","author":"Diamanti-Kandarakis","year":"2009","journal-title":"Endocrine Rev"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4274\/jcrpe.v3i1.01","article-title":"Effects of environmental endocrine disruptors on pubertal development","volume":"3","author":"Ozen","year":"2011","journal-title":"J Clin Res Pediatr endocrinol"},{"key":"B8","first-page":"1","article-title":"Exposi\u00e7\u00e3o ambiental a desreguladores end\u00f3crinos: altera\u00e7\u00f5es na homeostase dos horm\u00f4nios esteroidais e tireoideanos","volume":"21","author":"Moraes","year":"2008","journal-title":"Rev Bras Toxicol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1006\/faat.1996.0138","article-title":"Mode of action of thyroid tumor formation in the male long-Evans rat administered high doses of alachlor","volume":"33","author":"Wilson","year":"1996","journal-title":"Fundam Appl Toxicol Off J Soc Toxicol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2008.05.020","article-title":"Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes","volume":"232","author":"Axelstad","year":"2008","journal-title":"Toxicol Appl Pharmacol"},{"key":"B11","article-title":"From naturally occurring goitrogens to the effects of anthropogenic endocrine disruptors on the thyroid in Slovakia","volume":"104","author":"Langer","year":"2003","journal-title":"Bratislavske lekarske listy"},{"key":"B12","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12940-016-0117-0","article-title":"Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement","volume":"15","author":"Myers","year":"2016","journal-title":"Environ Health Global Access Sci source"},{"key":"B13","unstructured":"IARC monographs volume 112: evaluation of five organophosphate insecticides and herbicides2015"},{"key":"B14","unstructured":"Monografias autorizadas (G01 \u2013 glifosato)"},{"key":"B15","unstructured":"VargasL\n            RomanES"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-40422002000400014","article-title":"Glifosato: propriedades, toxicidade, usos e legisla\u00e7\u00e3o","volume":"25","author":"Amarante Junior","year":"2002","journal-title":"Qu\u00edmica Nova"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2012.09.021","article-title":"Mixtures of glyphosate and surfactant TN20 accelerate cell death via mitochondrial damage-induced apoptosis and necrosis","volume":"27","author":"Kim","year":"2013","journal-title":"Toxicol Vitro an Int J Published Assoc BIBRA"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00244-006-0151-y","article-title":"Toxicity of three polyethoxylated tallowamine surfactant formulations to laboratory and field collected fairy shrimp, thamnocephalus platyurus","volume":"52","author":"Brausch","year":"2007","journal-title":"Arch Environ Contamination Toxicol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2012.09.006","article-title":"Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity","volume":"313","author":"Mesnage","year":"2013","journal-title":"Toxicology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0045-6535(03)00306-0","article-title":"Aquatic toxicity of glyphosate-based formulations: comparison between different organisms and the effects of environmental factors","volume":"52","author":"Tsui","year":"2003","journal-title":"Chemosphere"},{"key":"B21","doi-asserted-by":"publisher","first-page":"128619","DOI":"10.1016\/j.chemosphere.2020.128619","article-title":"Glyphosate and the key characteristics of an endocrine disruptor: A review","volume":"270","author":"Munoz","year":"2021","journal-title":"Chemosphere"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16279","article-title":"Bisphenol a at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAF(V600E) mutation","volume":"25","author":"Li","year":"2021","journal-title":"J Cell Mol Med"},{"key":"B23","year":"2018"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.5380\/pes.v13i0.3161","article-title":"Determina\u00e7\u00e3o de glifosato e acido aminometilfosf\u00f4nico em aguas superficiais do arroio passo do pil\u00e3o","volume":"2003","author":"Da Silva","year":"2003","journal-title":"Pesticidas: Rev Ecotoxicol e Meio Ambiente"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2008.01.015","article-title":"Levels of glyphosate in surface waters, sediments and soils associated with direct sowing soybean cultivation in north pampasic region of Argentina","volume":"156","author":"Peruzzo","year":"2008","journal-title":"Environ Pollut"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijheh.2018.06.007","article-title":"Characterising glyphosate exposures among amenity horticulturists using multiple spot urine samples","volume":"221","author":"Connolly","year":"2018","journal-title":"Int J Hyg Environ Health"},{"key":"B27","volume-title":"PARECER T\u00c9CNICO n. 02\/2015","year":"2015"},{"key":"B28","first-page":"304","volume-title":"Tratado de fisiologia m\u00e9dica","author":"Guyton","year":"2011"},{"key":"B29","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12940-015-0029-4","article-title":"Assessing dose-response relationships for endocrine disrupting chemicals (EDCs): a focus on non-monotonicity","volume":"14","author":"Zoeller","year":"2015","journal-title":"Environ Health Global Access Sci source"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/em.20495","article-title":"Evaluation of genome damage and its relation to oxidative stress induced by glyphosate in human lymphocytes in vitro","volume":"50","author":"Mladinic","year":"2009","journal-title":"Environ Mol Mutagenesis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-017-9438-y","article-title":"Effects of low doses of glyphosate on DNA damage, cell proliferation and oxidative stress in the HepG2 cell line","volume":"24","author":"Kasuba","year":"2017","journal-title":"Environ Sci pollut Res Int"},{"key":"B32","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1177\/1091581813517906","article-title":"Glyphosate commercial formulation causes cytotoxicity, oxidative effects, and apoptosis on human cells: differences with its active ingredient","volume":"33","author":"Chaufan","year":"2014","journal-title":"Int J Toxicol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3795","article-title":"Activation of the n-methyl-d-aspartate receptor is involved in glyphosate-induced renal proximal tubule cell apoptosis","volume":"39","author":"Gao","year":"2019","journal-title":"J Appl Toxicol JAT"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.5380\/pes.v12i0.3156","article-title":"Monitoramento ambiental do glifosato e do seu metab\u00f3lito (\u00e1cido aminometilfosf\u00f4nico) na \u00e1gua de lavoura de arroz irrigado","volume":"12","author":"Mattos M","year":"2002","journal-title":"Pesticidas: Rev Ecotoxicol e Meio Ambiente"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijerph14060595","article-title":"Glyphosate residues in groundwater, drinking water and urine of subsistence farmers from intensive agriculture localities: A survey in hopelchen, campeche, Mexico","volume":"14","author":"Rendon-von Osten","year":"2017","journal-title":"Int J Environ Res Public Health"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.9b07819","article-title":"Analysis of glyphosate residues in foods from the Canadian retail markets between 2015 and 2017","volume":"68","author":"Kolakowski","year":"2020","journal-title":"J Agric Food Chem"},{"key":"B37","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S1383-5718(99)00164-3","article-title":"DNA Damage and repair: consequences on dose-responses","volume":"464","author":"Moustacchi","year":"2000","journal-title":"Mutat Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpc.2014.07.009","article-title":"Progression of DNA damage induced by a glyphosate-based herbicide in fish (Anguilla anguilla) upon exposure and post-exposure periods\u2013insights into the mechanisms of genotoxicity and DNA repair","volume":"166","author":"Marques","year":"2014","journal-title":"Comp Biochem Physiol Toxicol Pharmacol CBP"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mrgentox.2011.10.017","article-title":"DNA Damage in fish (Anguilla anguilla) exposed to a glyphosate-based herbicide \u2013 elucidation of organ-specificity and the role of oxidative stress","volume":"743","author":"Guilherme","year":"2012","journal-title":"Mutat Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2013.12.012","article-title":"Genotoxic effects of the herbicide roundup transorb and its active ingredient glyphosate on the fish prochilodus lineatus","volume":"37","author":"Moreno","year":"2014","journal-title":"Environ Toxicol Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00244-006-0154-8","article-title":"Time- and dose-dependent effects of roundup on human embryonic and placental cells","volume":"53","author":"Benachour","year":"2007","journal-title":"Arch Environ Contamination Toxicol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.fct.2017.07.025","article-title":"Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents","volume":"108","author":"Mesnage","year":"2017","journal-title":"Food Chem Toxicol an Int J Published Br Ind Biol Res Assoc"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/00984100050033494","article-title":"In vitro studies of cellular and molecular developmental toxicity of adjuvants, herbicides, and fungicides commonly used in red river valley, Minnesota","volume":"60","author":"Lin","year":"2000","journal-title":"J Toxicol Environ Health Part A"},{"key":"B44","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1007\/s13205-018-1464-z","article-title":"Moderate levels of glyphosate and its formulations vary in their cytotoxicity and genotoxicity in a whole blood model and in human cell lines with different estrogen receptor status","volume":"8","author":"De Almeida","year":"2018","journal-title":"3 Biotech"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2009.06.006","article-title":"Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines","volume":"262","author":"Gasnier","year":"2009","journal-title":"Toxicology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.05.057","article-title":"Glyphosate induces human breast cancer cells growth via estrogen receptors","volume":"59","author":"Thongprakaisang","year":"2013","journal-title":"Food Chem Toxicol an Int J Published Br Ind Biol Res Assoc"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2012.00133","article-title":"Thyroid cancer cell lines: an overview","volume":"3","author":"Saiselet","year":"2012","journal-title":"Front endocrinol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb04102.x","article-title":"Molecular mechanisms of RET activation in human cancer","volume":"963","author":"Santoro","year":"2002","journal-title":"Ann New York Acad Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00102","article-title":"Update on fundamental mechanisms of thyroid cancer","volume":"11","author":"Prete","year":"2020","journal-title":"Front endocrinol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.path.2019.08.002","article-title":"Molecular alterations in thyroid carcinoma","volume":"12","author":"Haroon Al Rasheed","year":"2019","journal-title":"Surg Pathol Clinics"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.29935","article-title":"Papillary thyroid cancer: Genetic alterations and molecular biomarker investigations","volume":"16","author":"Abdullah","year":"2019","journal-title":"Int J Med Sci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1177\/1066896909333749","article-title":"Absence of peritumoral fibrosis or inflammatory infiltrate may be related to clinical progression of papillary thyroid microcarcinoma","volume":"17","author":"Ramos","year":"2009","journal-title":"Int J Surg Pathol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fenvs.2016.00028","article-title":"Glyphosate: Too much of a good thing","volume":"4","author":"Cuhra","year":"2016","journal-title":"Front Environ Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"e05862","DOI":"10.2903\/j.efsa.2019.5862","article-title":"Review of the existing maximum residue levels for glyphosate according to article 12 of regulation (EC) no 396\/2005 - revised version to take into account omitted data","volume":"17","author":"European Food Safety","year":"2019","journal-title":"EFSA J Eur Food Saf Authority"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2009.05.001","article-title":"Effect of pesticides on cell survival in liver and brain rat tissues","volume":"72","author":"Astiz","year":"2009","journal-title":"Ecotoxicol Environ Safety"},{"key":"B56","doi-asserted-by":"publisher","first-page":"4302","DOI":"10.2903\/j.efsa.2017.4979","article-title":"Conclusion on the peer review of the pesticide risk assessment of the active substance glyphosate","volume":"13","year":"2015","journal-title":"EFSA J"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.772911","article-title":"Editorial: Glyphosate herbicide as endocrine disruptor and probable human carcinogen: Current knowledge and future direction","volume":"12","author":"Lorenz","year":"2021","journal-title":"Front endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.904437\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T11:36:16Z","timestamp":1659526576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.904437\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,29]]},"references-count":57,"alternative-id":["10.3389\/fendo.2022.904437"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.904437","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,29]]},"article-number":"904437"}}