Thiram induces myocardial oxidative damage and apoptosis in broilers via interfering their cardiac metabolism

Abstract

Thiram is a dithiocarbamate pesticide extensively used as a fungicide to preserve crops and seeds. Long-term exposure to thiram causes potential harm to the health of human beings and animals. So far, most of the researches on thiram focused on erythrocyte toxicity, immune system, kidney damage, and tibial dyschondroplasia; however, there is less data on cardiac toxicity. In this study, we examined cardiac histopathology, inflammatory factors, oxidative stress indicators, and apoptosis markers in the heart of broilers that were exposed to thiram. According to our findings, the continuous exposure to thiram caused pathological changes and abnormal function of myocardial tissues with increased level of inducible nitric oxide synthase (iNOS), inflammatory factors (IL-6, IL-8, TNF-α and NF-κB), and decreased level of anti-inflammatory factor (IL-10). In addition, thiram significantly upregulated the protein expression of cleaved-caspase 3, cleaved-PARP, and caused cardiomyocyte apoptosis. Meanwhile, the expression of heat shock proteins (HSP60, HSP70, HSP90) markedly decreased in the thiram-treated groups. An excessive accumulation of peroxidation products (MDA, H₂O₂), a decrease in T-AOC, and antioxidant activity enzymes (T-SOD, GST and GPX) were also noticed, all of which led to oxidative stress and activation of Nrf2 signal pathway by up-regulating key target genes (HO-1 and SODs). Thiram-induced metabolites were further identified via non-targeted metabonomic analysis. Correlation analysis revealed eighteen differentially expressed metabolites, closely related to cardiac injury. Importantly, thiram primarily affected the taurine and hypotaurine metabolism, pyrimidine metabolism as well as glycerol metabolism. Collectively, our study suggests that thiram could cause cardiotoxicity by interfering with taurine and hypotaurine metabolism, pyrimidine metabolism, and glycerolipid metabolism, which further induce oxidative stress via triggering Nrf2 signal pathway. This study may provide new evidence for the molecular mechanism of cardiotoxicity caused by thiram and resonate the alarm for animals and workers who have been exposed to thiram for a long time.

Keywords: Cardiotoxicity; Inflammation; Metabolomics; Oxidative stress; Thiram.