N-acetylcysteine alleviates cadmium-induced placental endoplasmic reticulum stress and fetal growth restriction in mice.

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. Pregnant mice were intraperitoneally injected with CdCl2 daily from gestational day (GD)13 to 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-a, 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. Therefore, NAC may be exploited for prevention of Cd-induced placental insufficiency and FGR.

Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport.

Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl2 (2.5 or 5.0mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl2. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters.