Joint Toxicity of a Multi-Heavy Metal Mixture and Chemoprevention in Sprague Dawley Rats

Abstract

Background: China is now facing great challenges in heavy metal contamination in the surface water system as well as farmland soil and aquatic products. Exploring the joint toxicity and bio-accumulation of multi-heavy metals and potential chemoprevention strategies will be important for protecting human health. Methods: Male Sprague Dawley (SD) rats were treated orally with 500mg/kg•bw of eight heavy metal composed mixtures including chromium, manganese, nickel, copper, zinc, cadmium, mercury, and lead once a week for 6 months. At the same time, 200mg/kg•bw of epigallocatechin-3-gallate (EGCG), trisodium citrate dihydrate (TCD) or glutathione (GSH) were administered to evaluate their antagonistic effects against adverse effects or bio-accumulation induced by the heavy-metal mixture. After a Morris water maze test, blood samples were obtained for biochemical analysis, and organs (heart, liver, spleen, lungs, kidneys, brain, testis) were collected for biopsy. Inductively coupled plasma mass spectrometer (ICP-MS) was used to analyze the concentrations of heavy metals in serum, tissues or organs. Findings: Finding indicate that 6 months of exposure to a multi-heavy-metal mixture caused a significant reduction of testicle weight, but a significant increase of lung weight, red cell distribution width, serum total bilirubin, indirect bilirubin, and alkaline phosphatase. Histopathological examinations observed prominent pathological changes in the liver and testicle tissues in animals treated with the heavy-metal mixture. ICP-MS results demonstrated that accumulation characteristics of eight different heavy metals in organs and serum varied dramatically. EGCG, TCD or GSH could attenuate the toxic effects induced by a heavy-metal mixture to a certain degree and reduce the concentrations of some heavy metals in the animal body. Interpretation: In summary, long-term intake of multi-heavy metals under this experimental dosage resulted in accumulation in organs and adverse effects on the blood, reproductive system, and liver function. EGCG, TCD or GSH all showed certain chemoprevention effects against the joint toxicity induced by the heavy-metal mixture, which may be attributed to their ability to help drain metals from animals' bodies or their anti-oxidative properties. Funding: This study was partly supported by the National Nature Science Foundation of China (grant no. 81273111), Scientific Projects of Zhejiang Province (grant no. 2015C33148 and 2015C37117), the Ningbo Scientific Innovation Team for Environmental Hazardous Factor Control and Prevention (grant no. 2016C51001), Zhejiang Key Laboratory of Pathophysiology (201703), and the KC Wong Magna Fund of Ningbo University. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: All animals were housed in a temperature-controlled animal facility (22±2°C) with a 12-hour light/dark cycle (lights on from 7:00 AM to 7:00 PM). All rats had access to water and fodder ad libitum and received humane care in compliance with the Principles of Approval of the Experimental Animal Ethics Committee of Ningbo University.