N-acetylcysteine Alleviates Cadmium-induced Placental Endoplasmic Reticulum Stress And Fetal Growth Restriction In Mice

Objective:Previous studies found that Cadmium?Cd?is a developmental toxicant that induces fetal growth restriction?FGR?.Placental endoplasmic reticulum?ER?stress is associated with FGR.This study investigated the effects of N-acetylcysteine?NAC?on Cd-induced placental ER stress and FGR.Methods:This study consisted of two experiments.Experiment 1.To investigate the effects of NAC on Cd-induced ER stress and FGR in mice,pregnant mice were divided randomly into four groups.In Cd group,pregnant mice were i.p.injected with CdCl₂?1.0 mg/kg?daily from GD13 to GD17.In NAC+Cd group,pregnant mice were i.g.injected with NAC?1.0 g/kg?daily from GD12 to GD17,one dose?300 mg/kg?at 8 h before CdCl₂ injection,one?400 mg/kg?at 30 min before CdCl₂ injection,another?300 mg/kg?at 8 h after CdCl₂ injection.The saline-treated or NAC-treated pregnant mice served as controls.All dams were anesthetized with isoflurane and sacrificed on GD18.The uterine horns were exposed and weighed.Live,dead and resorbed fetuses were counted.Live fetuses were sexed and weighed.The rate of FGR was calculated referred to others.Placentas were weighedandthencollectedformeasurementofhistopathology,immunohistochemistry and ER stress.Experiment 2.To investigate the effects of NAC on Cd-induced down-regulation of growth factors and nutrient transport pumps in mouse placenta,twenty-four pregnant mice were divided randomly into four groups.In Cd group,pregnant mice were i.p.injected with CdCl₂?1.0 mg/kg?daily from GD13 to GD15.In NAC+Cd group,pregnant mice were i.g.injected with NAC?1.0 g/kg?daily from GD12 to GD15,one dose?300 mg/kg?at 8 h before CdCl2 injection,one?400 mg/kg?at 30 min before CdCl₂ injection,another?300 mg/kg?at 8 h after CdCl₂ injection.The saline-treated or NAC-treated pregnant mice served as controls.All dams were anesthetized with isoflurane and sacrificed on GD15.Placentas were collected for real-time RT-PCR.Results:Pregnant mice were injected with CdCl₂ daily from gestational day?GD?13to GD17.As expected,Cd reduced fetal weight and crown-rump length.Cd decreased the internal space of blood vessels in the placental labyrinth layer and inhibited placental cell proliferation.Several genes of growth factors,such as Vegf?,placental growth factor,Igf1 and Igf1r,and several genes of nutrient transport pumps,such as Glut1,Fatp1 and Snat2,were down-regulated in placenta of Cd-treated mice.Moreover,Cd evoked placental ER stress.Of interest,NAC alleviated Cd-induced FGR.Additional experiment showed that NAC inhibited Cd-induced impairment of placental development and placental ER stress.Conclusion:Maternal exposure to Cd during pregnancy causes fetal rat FGR and placental ER stress.NAC significantly alleviated Cd-induced placental ER stress,reduced Cd downregulation of placental growth factor and nutrient transport pump expression,and protected Cd-induced FGR.