{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T04:16:16Z","timestamp":1783224976883,"version":"3.54.6"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T00:00:00Z","timestamp":1640822400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009930","name":"Navicent Health Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100009930","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mercury is a heavy metal toxicant that is prevalent throughout the environment. Organic forms of mercury, such as methylmercury (MeHg), can cross the placenta and can lead to lasting detrimental effects in the fetus. The toxicological effects of MeHg on the placenta itself have not been clearly defined. Therefore, the purpose of the current study was to assess the transport of MeHg into placental syncytiotrophoblasts and to characterize the mechanisms by which MeHg exerts its toxic effects. Cultured placental syncytiotrophoblasts (BeWo) were used for these studies. The transport of radioactive MeHg was measured to identify potential mechanisms involved in the uptake of this compound. The toxicological effects of MeHg on BeWo cells were determined by assessing visible pathological change, autophagy, mitochondrial viability, and oxidative stress. The findings of this study suggest that MeHg compounds are transported into BeWo cells primarily by sodium-independent amino acid carriers and organic anion transporters. The MeHg altered mitochondrial function and viability, decreased mitophagy and autophagy, and increased oxidative stress. Exposure to higher concentrations of MeHg inhibited the ability of cells to protect against MeHg-induced injury. The findings show that MeHg is directly toxic to syncytiotrophoblasts and may lead to disruptions in the fetal\/maternal transfer of nutrients and wastes.<\/jats:p>","DOI":"10.3390\/ijms23010394","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T21:41:21Z","timestamp":1640900481000},"page":"394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Transport and Toxicity of Methylmercury-Cysteine in Cultured BeWo Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Srividya","family":"Ganapathy","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1221-3778","authenticated-orcid":false,"given":"Elisa R.","family":"Farrell","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simran","family":"Vaghela","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Joshee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"IV","given":"Earl G.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Uchakina","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"McKallip","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Barkin","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1603-1445","authenticated-orcid":false,"given":"Christy C.","family":"Bridges","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Mercer University School of Medicine, Macon, GA 31207, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,30]]},"reference":[{"key":"ref_1","unstructured":"ATSDR, Agency for Toxic Substances and Disease Registry, Toxicological Profile for Mercury (2021, July 21). U.S. Department of Health and Human Services, Available online: https:\/\/www.atsdr.cdc.gov\/toxprofiles\/tp46.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41370-018-0033-1","article-title":"Blood total mercury and methylmercury among pregnant mothers in Charleston, South Carolina, USA","volume":"28","author":"Donohue","year":"2018","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41370-020-0233-3","article-title":"Exposure to total and methylmercury among pregnant women in Suriname: Sources and public health implications","volume":"31","author":"Wickliffe","year":"2020","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jtemb.2019.09.008","article-title":"Evaluation of blood mercury and serum selenium levels in the pregnant population of the Community of Madrid, Spain","volume":"57","year":"2020","journal-title":"J. Trace Elements Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00204-016-1803-y","article-title":"Mechanisms involved in the transport of mercuric ions in target tissues","volume":"91","author":"Bridges","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1289\/ehp.02110523","article-title":"Inorganic mercury and methylmercury in placentas of Swedish women","volume":"110","author":"Ask","year":"2002","journal-title":"Environ. Health Perspect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/BF00316251","article-title":"Developmental disturbances of the fetal brain in guinea-pigs caused by methylmercury","volume":"62","author":"Inouye","year":"1988","journal-title":"Arch. Toxicol."},{"key":"ref_8","first-page":"227","article-title":"Behavioral and neuropathological effects of prenatal methylmercury exposure in mice","volume":"7","author":"Inouye","year":"1985","journal-title":"Neurobehav. Toxicol. Teratol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.reprotox.2020.02.005","article-title":"Chronic kidney disease in pregnant mothers affects maternal and fetal disposition of mercury","volume":"93","author":"Moss","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/0041-008X(77)90077-1","article-title":"Response model analysis for cross-fostering studies: Prenatal versus postnatal effects on offspring exposed to methylmercury dicyandiamide","volume":"40","author":"Spyker","year":"1977","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0041-008X(76)90174-5","article-title":"Embryocidal and teratogenic effects of methylmercury in mice","volume":"38","author":"Su","year":"1976","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_12","first-page":"33","article-title":"Embryo-fetotoxic effect of some organic mercury compounds","volume":"18","author":"Murakami","year":"1970","journal-title":"Annu. Rep. Res. Inst. Environ. Med. Nagoya Univ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.envint.2017.11.001","article-title":"Placental transfer and levels of mercury, selenium, vitamin E, and docosahexaenoic acid in maternal and umbilical cord blood","volume":"111","author":"Sakamoto","year":"2018","journal-title":"Environ. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1007\/s002040050279","article-title":"Methylmercury transport across the placenta via neutral amino acid carrier","volume":"70","author":"Kajiwara","year":"1996","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1042\/bj20020841","article-title":"Transport of a neurotoxicant by molecular mimicry: The methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2","volume":"367","author":"Koh","year":"2002","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Balthasar, C., Stangl, H., Widhalm, R., Granitzer, S., Hengstschlager, M., and Gundacker, C. (2017). Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081730"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.tox.2015.12.005","article-title":"Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters","volume":"340","author":"Straka","year":"2016","journal-title":"Toxicology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00726-007-0006-5","article-title":"Transport of amino acids through the placenta and their role","volume":"34","author":"Grillo","year":"2008","journal-title":"Amino Acids"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111520","DOI":"10.1016\/j.ecoenv.2020.111520","article-title":"Methylmercury cytotoxicity and possible mechanisms in human trophoblastic HTR-8\/SVneo cells","volume":"207","author":"Liao","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1172\/JCI104186","article-title":"The Concentrations of Cysteine and Cystine in Human Blood Plasma","volume":"39","author":"Brigham","year":"1960","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1080\/15548627.2016.1277312","article-title":"The molecular mechanism of Atg13 function in autophagy induction: What is hidden behind the data?","volume":"13","author":"Popelka","year":"2017","journal-title":"Autophagy"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.freeradbiomed.2016.04.015","article-title":"Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond","volume":"100","author":"Bingol","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cca.2020.02.024","article-title":"Bnip3 in mitophagy: Novel insights and potential therapeutic target for diseases of secondary mitochondrial dysfunction","volume":"506","author":"Gao","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0753-3322(03)00043-X","article-title":"The importance of glutathione in human disease","volume":"57","author":"Townsend","year":"2003","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.taap.2004.09.007","article-title":"Molecular and ionic mimicry and the transport of toxic metals","volume":"204","author":"Bridges","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12958-015-0054-8","article-title":"Expression and functional characterisation of System L amino acid transporters in the human term placenta","volume":"13","author":"Gaccioli","year":"2015","journal-title":"Reprod. Biol. Endocrinol. RBE"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S70","DOI":"10.1002\/jcph.1491","article-title":"Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal-Fetal Drug Transfer","volume":"59","author":"Dallmann","year":"2019","journal-title":"J. Clin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5511","DOI":"10.1113\/JP274883","article-title":"A systems perspective on placental amino acid transport","volume":"596","author":"Cleal","year":"2018","journal-title":"J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49390","DOI":"10.1074\/jbc.M107517200","article-title":"Identification and characterization of a novel member of the heterodimeric amino acid transporter family presumed to be associated with an unknown heavy chain","volume":"276","author":"Chairoungdua","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1111\/j.1476-5381.2011.01724.x","article-title":"OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies","volume":"165","author":"Roth","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1053\/plac.2002.0907","article-title":"Expression of organic anion transporting polypeptide E (OATP-E) in human placenta","volume":"24","author":"Sato","year":"2003","journal-title":"Placenta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0143-4004(05)80182-1","article-title":"Functional characterization of L-alanine transport in a placental choriocarcinoma cell line (BeWo)","volume":"15","author":"Moe","year":"1994","journal-title":"Placenta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1039\/C8TX00060C","article-title":"In vitro modulation of mercury-induced rat liver mitochondria dysfunction","volume":"7","author":"Ma","year":"2018","journal-title":"Toxicol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.toxlet.2019.01.003","article-title":"Potential mechanisms of cellular injury following exposure to a physiologically relevant species of inorganic mercury","volume":"304","author":"Orr","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"643972","DOI":"10.3389\/fphar.2021.643972","article-title":"Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium, Cadmium, and Arsenic","volume":"12","author":"Naseri","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/jcp.20476","article-title":"Loss of mitochondrial membrane potential is associated with increase in mitochondrial volume: Physiological role in neurones","volume":"206","author":"Safiulina","year":"2006","journal-title":"J. Cell Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1016\/j.jtemb.2010.10.007","article-title":"In vitro modulation of heavy metal-induced rat liver mitochondria dysfunction: A comparison of copper and mercury with cadmium","volume":"25","author":"Belyaeva","year":"2011","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_38","first-page":"453","article-title":"Malondialdehyde (MDA) as a lipid peroxidation marker","volume":"57","author":"Gawel","year":"2004","journal-title":"Wiad. Lek."},{"key":"ref_39","first-page":"15593258211011360","article-title":"Vitamin E and Lactobacillus Provide Protective Effects against Liver Injury Induced by HgCl2: Role of CHOP, GPR87, and mTOR Proteins","volume":"19","author":"Alhusaini","year":"2021","journal-title":"Dose-Response A Publ. Int. Hormesis Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1007\/s00284-021-02454-4","article-title":"Comparative Study of Cytotoxicity, DNA Damage and Oxidative Stress Induced by Heavy Metals Cd(II), Hg(II) and Cr(III) in Yeast","volume":"78","author":"Wang","year":"2021","journal-title":"Curr. Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1089\/ars.2010.3779","article-title":"The interplay between mitochondrial dynamics and mitophagy","volume":"14","author":"Twig","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110667","DOI":"10.1016\/j.ecoenv.2020.110667","article-title":"Methylmercury disrupts autophagic flux by inhibiting autophagosome-lysosome fusion in mouse germ cells","volume":"198","author":"Chen","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"116578","DOI":"10.1016\/j.lfs.2019.116578","article-title":"Selenium protection against mercury neurotoxicity: Modulation of apoptosis and autophagy in the anterior pituitary","volume":"231","author":"Mohammed","year":"2019","journal-title":"Life Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41419-019-1632-z","article-title":"MeHg-induced autophagy via JNK\/Vps34 complex pathway promotes autophagosome accumulation and neuronal cell death","volume":"10","author":"Lin","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101854","DOI":"10.1016\/j.redox.2021.101854","article-title":"Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2\/ATF4\/BNIP3-dependent mitophagy in placental trophoblasts","volume":"40","author":"Zhu","year":"2021","journal-title":"Redox. Biol."},{"key":"ref_47","first-page":"1512","article-title":"Global signatures of protein and mRNA expression levels","volume":"5","author":"Penalva","year":"2009","journal-title":"Mol. Biosyst."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1097\/01.ASN.0000113553.62380.F5","article-title":"Mercuric conjugates of cysteine are transported by the amino acid transporter system b(0,+): Implications of molecular mimicry","volume":"15","author":"Bridges","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/S0002-9440(10)63396-2","article-title":"Homocysteine, system b0, + and the renal epithelial transport and toxicity of inorganic mercury","volume":"165","author":"Bridges","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1021\/tx3001847","article-title":"Relationships between the renal handling of DMPS and DMSA and the renal handling of mercury","volume":"25","author":"Zalups","year":"2012","journal-title":"Chem. Res. Toxicol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/394\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:56:01Z","timestamp":1760169361000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,30]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010394"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010394","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,30]]}}}