The Effect of BML-111 in Preeclampsia Rat Model Induced by the Low Dose of Cadmium Chloride
23 December 2018
16 May 2019
04 July 2019 (online)
Aim This article determines the optimal time and dose of cadmium chloride (CdCl2) injected to pregnant rat to establish experimental preeclampsia (PE) model. In addition, the therapeutic potential of BML-111, a lipoxin A4 analogue, in the CdCl2-induced PE model was also evaluated.
Methods Peritoneal injection of two dose of CdCl2 for successive 6 days was tested in the pregnant rats starting from various gestational days (GDs). During this process, the systolic blood pressure and the body weight of pregnant rats and neonatal rats were monitored. The pathological changes of the placenta and kidney were evaluated by hematoxylin and eosin staining. The phosphorylation of extracellular signal-regulated kinase 1/2 and signal transducer and activator of transcription 3 in the placentas was detected by Western blot, and the messenger ribonucleic acid expression of interleukin (IL)-6, tumor necrosis factor-α, and IL-10 in the placentas were detected by real-time polymerase chain reaction. BML-111 at the dose of 1 mg/kg/day was peritoneally injected into the rat after establishing the PE model to test its therapeutic potential.
Results In the present study, we successfully established the PE model in pregnant rats by intraperitoneally injection of CdCl2 at the dose of 0.125 mg/kg/day from GD 9 to 14. We recapitulated multiple features of clinical PE in CdCl2-induced rat, including high blood pressure, renal dysfunction, and inflammatory response in placenta. Furthermore, treatment with BML-111 significantly relieved multiple features in our PE rat model.
Conclusions BML-111 has a potential therapeutic effect in pregnant rats with CdCl2-induced PE, which appears to be mediated through inhibition of inflammatory processes in the placenta.
- 1 Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308 (5728): 1592-1594
- 2 Steegers Ea P, Peter VD, Duvekot JJ. , et al. Pre-eclampsia. Lancet 2010; 376 (9741): 631-644
- 3 Szarka A, Rigó Jr J, Lázár L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol 2010; 11 (01) 59
- 4 Udenze I, Amadi C, Awolola N, Makwe CC. The role of cytokines as inflammatory mediators in preeclampsia. Pan Afr Med J 2015; 20: 219
- 5 Kah M, Levy L, Brown C. Potential for effects of land contamination on human health. 1. The case of cadmium. J Toxicol Environ Health B Crit Rev 2012; 15 (05) 348-363
- 6 Thévenod F, Lee WK. Toxicology of Cadmium and Its Damage to Mammalian Organs. Met Ions Life Sci 2013; 11: 415-490
- 7 Al-Bader A, Omu AE, Dashti H. Chronic cadmium toxicity to sperm of heavy cigarette smokers: immunomodulation by zinc. Arch Androl 1999; 43 (02) 135-140
- 8 Hamden K, Carreau S, Marki FA, Masmoudi H, El Feki A. Positive effects of green tea on hepatic dysfunction, lipid peroxidation and antioxidant defence depletion induced by cadmium. Biol Res 2008; 41 (03) 331-339
- 9 Nishijo M, Satarug S, Honda R, Tsuritani I, Aoshima K. The gender differences in health effects of environmental cadmium exposure and potential mechanisms. Mol Cell Biochem 2004; 255 (1-2): 87-92
- 10 Hu KH, Li WX, Sun MY. , et al. Cadmium induced apoptosis in MG63 cells by increasing ROS, activation of p38 MAPK and inhibition of ERK 1/2 pathways. Cell Physiol Biochem 2015; 36 (02) 642-654
- 11 Kolusari A, Kurdoglu M, Yildizhan R. , et al. Catalase activity, serum trace element and heavy metal concentrations, and vitamin A, D and E levels in pre-eclampsia. J Int Med Res 2008; 36 (06) 1335-1341
- 12 Schroeder HA, Buckman J. Cadmium hypertension. Its reversal in rats by a zinc chelate. Arch Environ Health 1967; 14 (05) 693-697
- 13 Wang F, Fan F, Wang L, Ye W, Zhang Q, Xie S. Maternal cadmium levels during pregnancy and the relationship with preeclampsia and fetal biometric parameters. Biol Trace Elem Res 2018; 186 (02) 322-329
- 14 Zhang Q, Huang Y, Zhang K. , et al. Progesterone attenuates hypertension and autoantibody levels to the angiotensin II type 1 receptor in response to elevated cadmium during pregnancy. Placenta 2018; 62: 16-24
- 15 Bara L, Bara C, Bara V. , et al. Report on the influence of heavy metals on the evolution of the pregnancy in smoking mothers. 2010
- 16 Lin F, Zeng P, Xu Z. , et al. Treatment of Lipoxin A(4) and its analogue on low-dose endotoxin induced preeclampsia in rat and possible mechanisms. Reprod Toxicol 2012; 34 (04) 677-685
- 17 Xu Z, Zhao F, Lin F. , et al. Preeclampsia is associated with a deficiency of lipoxin A4, an endogenous anti-inflammatory mediator. Fertil Steril 2014; 102 (01) 282-290.e4
- 18 Zhang Q, Huang Y, Zhang K. , et al. Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia. Environ Pollut 2016; 218: 770-782
- 19 Kukongviriyapan U, Apaijit K, Kukongviriyapan V. Oxidative stress and cardiovascular dysfunction associated with cadmium exposure: beneficial effects of curcumin and tetrahydrocurcumin. Tohoku J Exp Med 2016; 239 (01) 25-38
- 20 Houston MC. The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. Altern Ther Health Med 2007; 13 (02) S128-S133
- 21 Olszowski T, Baranowska-Bosiacka I, Gutowska I, Chlubek D. Pro-inflammatory properties of cadmium. Acta Biochim Pol 2012; 59 (04) 475-482
- 22 Faroon O, Ashizawa A, Wright S. , et al. Toxicological Profile for Cadmium. Atlanta, GA: Agency for Toxic Substances and Disease Registry; 2012
- 23 Chan HM, Cherian MG. Mobilization of hepatic cadmium in pregnant rats. Toxicol Appl Pharmacol 1993; 120 (02) 308-314
- 24 Szabo S, Mody M, Romero R. , et al. Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome. Pathol Oncol Res 2015; 21 (03) 659-668
- 25 Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory markers (TNF-α, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol 2007; 58 (01) 21-30