title: Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta.
abstract: The placenta is essential for sustaining the growth of the fetus. An increased endoplasmic reticulum (ER) stress has been associated with the impaired placental and fetal development. Cadmium (Cd) is a potent teratogen that caused fetal malformation and growth restriction. The present study investigated the effects of maternal Cd exposure on placental and fetal development. The pregnant mice were intraperitoneally injected with CdCl(2) (4.5mg/kg) on gestational day 9. As expected, maternal Cd exposure during early limb development significantly increased the incidences of forelimb ectrodactyly in fetuses. An obvious impairment in the labyrinth, a highly developed tissue of blood vessels, was observed in placenta of mice treated with CdCl(2). In addition, maternal Cd exposure markedly repressed cell proliferation and increased apoptosis in placenta. An additional experiment showed that maternal Cd exposure significantly upregulated the expression of GRP78, an ER chaperone. Moreover, maternal Cd exposure induced the phosphorylation of placental eIF2α, a downstream molecule of PERK signaling. In addition, maternal Cd exposure significantly increased the level of placental CHOP, another target of PERK signaling, indicating that the unfolded protein response (UPR) signaling was activated in placenta of mice treated with CdCl(2). Interestingly, alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, significantly alleviated Cd-induced placental ER stress and UPR. Taken together, these results suggest that reactive oxygen species (ROS)-mediated ER stress might be involved in Cd-induced impairment on placental and fetal development. Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction.
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Zhong Mei
authors.initials: ZM
authors.lastname: Xu
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Ji
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiu-Hong
authors.initials: XH
authors.lastname: Meng
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006651:Histocytochemistry; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008813:Mice, Inbred ICR; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D012313:RNA; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D003497:Cyclic N-Oxides; D000091342:Endoplasmic Reticulum Chaperone BiP; D016166:Free Radical Scavengers; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species; D002104:Cadmium; D051742:Transcription Factor CHOP; C029217:phenyl-N-tert-butylnitrone; D012313:RNA