Jun Hu1, Hua Wang2, Yong-Fang Hu3, Xiao-Feng Xu4, Yuan-Hua Chen5, Mi-Zhen Xia6, Cheng Zhang1, De-Xiang Xu7. 1. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, China. 2. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, China. Electronic address: wanghuadev@126.com. 3. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China. 4. First Affiliated Hospital, Anhui Medical University, Hefei, China. 5. Department of Histology and Embryology, Anhui Medical University, Hefei, China. 6. Life Science College, Anhui Medical University, Hefei, China. 7. Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China; Laboratory of Environmental Toxicology, Anhui Medical University, Hefei, China. Electronic address: xudex@126.com.
Abstract
INTRODUCTION: Several reports demonstrated that cadmium (Cd) had proinflammatory activities. The present study aimed to investigate whether Cd induces inflammatory cytokines in mouse placenta and human trophoblast cells. METHODS: Human JEG-3 cells were treated with different concentration of CdCl2 (0-50 μM) or CdCl2 (25 μM) for different times. The pregnant mice were administered with CdCl2 (3.0 mg/kg, i.p.) on GD15. RESULTS: TNF-α, IL-8 and IL-6 mRNAs were elevated in CdCl2-treated JEG-3 cells. Several inflammatory cytokines were up-regulated in Cd-treated placenta of mice. Moreover, keratinocyte chemokine (KC), a functional analogue of human IL-8, was increased in maternal serum and amniotic fluid from CdCl2-exposed mice. Additional experiment showed that gestational Cd exposure activated Akt signaling in mouse placenta. Co-culture with CdCl2 elevated pAkt level in JEG-3 cells in concentration- and time-dependent manners. LY294002, a specific inhibitor of PI3K, blocked CdCl2-evoked Akt phosphorylation in JEG-3 cells. Concomitantly, LY294002 inhibited CdCl2-induced IL-8 in JEG-3 cells. N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, blocked CdCl2-evoked Akt phosphorylation in mouse placenta and human trophoblast cells. Additionally, NAC attenuated Cd-induced up-regulation of KC in amniotic fluid. DISCUSSION: Cd induces inflammatory cytokines partially through activating Akt signaling in mouse placenta and human trophoblast cells. NAC may be exploited for prevention of Cd-induced placental inflammation.
INTRODUCTION: Several reports demonstrated that cadmium (Cd) had proinflammatory activities. The present study aimed to investigate whether Cd induces inflammatory cytokines in mouse placenta and human trophoblast cells. METHODS:Human JEG-3 cells were treated with different concentration of CdCl2 (0-50 μM) or CdCl2 (25 μM) for different times. The pregnant mice were administered with CdCl2 (3.0 mg/kg, i.p.) on GD15. RESULTS: TNF-α, IL-8 and IL-6 mRNAs were elevated in CdCl2-treated JEG-3 cells. Several inflammatory cytokines were up-regulated in Cd-treated placenta of mice. Moreover, keratinocyte chemokine (KC), a functional analogue of humanIL-8, was increased in maternal serum and amniotic fluid from CdCl2-exposed mice. Additional experiment showed that gestational Cd exposure activated Akt signaling in mouse placenta. Co-culture with CdCl2 elevated pAkt level in JEG-3 cells in concentration- and time-dependent manners. LY294002, a specific inhibitor of PI3K, blocked CdCl2-evoked Akt phosphorylation in JEG-3 cells. Concomitantly, LY294002 inhibited CdCl2-induced IL-8 in JEG-3 cells. N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, blocked CdCl2-evoked Akt phosphorylation in mouse placenta and human trophoblast cells. Additionally, NAC attenuated Cd-induced up-regulation of KC in amniotic fluid. DISCUSSION: Cd induces inflammatory cytokines partially through activating Akt signaling in mouse placenta and human trophoblast cells. NAC may be exploited for prevention of Cd-induced placental inflammation.
Authors: Jeliyah Clark; Vennela Avula; Caroline Ring; Lauren A Eaves; Thomas Howard; Hudson P Santos; Lisa Smeester; Jacqueline T Bangma; Thomas Michael O'Shea; Rebecca C Fry; Julia E Rager Journal: Toxicol Sci Date: 2021-09-28 Impact factor: 4.109