{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T19:07:31Z","timestamp":1772651251524,"version":"3.50.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["K22ES027510 T32ES007046 P30ES025128"],"award-info":[{"award-number":["K22ES027510 T32ES007046 P30ES025128"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Cadmium (Cd) is a toxic heavy metal found throughout the environment and one of the top ten toxicants of major public health concern identified by the World Health Organization. <jats:italic>In utero<\/jats:italic> Cd exposure causes fetal growth restriction, malformation, and spontaneous abortion; however, the mechanisms by which Cd impacts these outcomes are poorly understood. Cd accumulates in the placenta, suggesting that these negative outcomes may be a consequence of disrupted placental function and placental insufficiency. To understand the impact of Cd on gene expression within the placenta, we developed a mouse model of Cd-induced fetal growth restriction through maternal consumption of CdCl<jats:sub>2<\/jats:sub> and performed RNA-seq on control and CdCl<jats:sub>2<\/jats:sub> exposed placentae. The top differentially expressed transcript was the <jats:italic>Tcl1 Upstream Neuron-Associated<\/jats:italic> (<jats:italic>Tuna<\/jats:italic>) long non-coding RNA, which was upregulated over 25-fold in CdCl<jats:sub>2<\/jats:sub> exposed placentae. <jats:italic>Tuna<\/jats:italic> has been shown to be critical for neural stem cell differentiation. However, within the placenta, there is no evidence that <jats:italic>Tuna<\/jats:italic> is normally expressed or functional at any developmental stage. To determine the spatial expression of Cd-activated <jats:italic>Tuna<\/jats:italic> within the placenta, we used <jats:italic>in situ<\/jats:italic> hybridization as well as placental layer-specific RNA isolation and analysis. Both methods confirmed the absence of <jats:italic>Tuna<\/jats:italic> expression in control samples and determined that Cd-induced <jats:italic>Tuna<\/jats:italic> expression is specific to the junctional zone. Since many lncRNAs regulate gene expression, we hypothesized that <jats:italic>Tuna<\/jats:italic> forms part of the mechanism of Cd-induced transcriptomic changes. To test this, we over-expressed <jats:italic>Tuna<\/jats:italic> in cultured choriocarcinoma cells and compared gene expression profiles to those of control and CdCl<jats:sub>2<\/jats:sub> exposed cells. We demonstrate significant overlap between genes activated by <jats:italic>Tuna<\/jats:italic> overexpression and genes activated by CdCl<jats:sub>2<\/jats:sub> exposure, with enrichment in the NRF2-mediated oxidative stress response. Herein we analyze the NRF2 pathway and show that <jats:italic>Tuna<\/jats:italic> increases <jats:italic>NRF2<\/jats:italic>\/NRF2 both at the transcript and protein levels. <jats:italic>Tuna<\/jats:italic> drives increased NRF2 target gene expression, a result that is abrogated with the use of an NRF2 inhibitor, confirming that <jats:italic>Tuna<\/jats:italic> activates oxidative stress response genes through this pathway. This work identifies the lncRNA <jats:italic>Tuna<\/jats:italic> as a potential novel player in Cd-induced placental insufficiency.<\/jats:p>","DOI":"10.3389\/fcell.2023.1151108","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T05:00:11Z","timestamp":1685595611000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["LncRNA Tuna is activated in cadmium-induced placental insufficiency and drives the NRF2-mediated oxidative stress response"],"prefix":"10.3389","volume":"11","author":[{"given":"Mark D.","family":"Simmers","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dereje D.","family":"Jima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Cowley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq - a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.siny.2017.11.004","article-title":"Screening for fetal growth restriction and placental insufficiency","volume":"23","author":"Audette","year":"2018","journal-title":"Semin. 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