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SummaryThe aim of this study is to characterize the changes of CD4 +

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Cypermethrin (CMN) is a man-made insecticide, and its abuse has led to potential adverse effects, particularly in sensitive populations such as aquatic organisms. The present study was focused on the toxic phenotype and detoxification mechanism in grass carp (Ctenopharyngodon idella) after treatment with waterborne CMN (0.651 μg/L) for 6 weeks in vivo or 6.392 μM for 24 h in vitro. In vivo, we describe the toxic phenotype of the liver of grass carp in terms of pathological changes, serum transaminase levels, oxidative stress indexes, and apoptosis rates. RNA-Seq analysis (2 × 3 cDNA libraries) suggested a compromise of proteasome and oxidative phosphorylation signaling pathways under CMN exposure. Thus, these two pathways were chosen for the in vitro study, which suggested that the CMN intoxicationinduced proteasome pathway caused hepatotoxicity in the liver cell line of grass carp (L8824 cells). Moreover, pretreatment with MG132, a proteasome inhibitor, displayed protection against the toxic effects of CMN by enhancing antioxidative and antiinflammatory capability by directly inhibiting the proteasomal degradation of nuclear factor erythroid-2 related factor (Nrf2) and IκB-α, thus turning on the transcription of downstream genes of Nrf2 and NF-κB, respectively. Taken together, these results suggest proteasome activity as a reason for CMN-induced hepatotoxicity.

Excessive amount of copper (Cu) and inorganic arsenic (iAs) coexists in drinking water in many regions, this is associated with high risk of nephropathy, defined as chronic structural and functional disorders of the kidney. However, the underlying mechanisms are not well understood. In this study, a total of 72 day-old Hy-line chickens were exposed to 300 mg/kg copper sulphate or/and 30 mg/kg arsenic trioxide for 12 weeks. Indicators of oxidative stress, inflammation and heat shock proteins (HSPs) production were analyzed in kidney. The results showed that, when the toxicant was administrated alone, there is an antagonism between redox homeostasis during the first 4 weeks, which follows a collapse of antioxidant system manifested by damaged biomembrane structure. What's worse, oxidative damage-cascaded histopathological lesions were accompanied by increases of proinflammatory mediators and an imbalance of “Th1/Th2 drift” (Th, helper T cell) regulated by nuclear factor kappa B (NF-κB). Simultaneously, intense heat shock response went with the organism. The above-mentioned renal lesions and indicators changes were time-dependent, more complex and deteriorated effects were observed in Cu/iAs combined groups compared with the others. This study supports Cu and iAs have a synergistic type on the nephro-toxicological process additively. In conclusion, oxidative stress and inflammatory induced by Cu or/and iAs are potential mechanisms in their nephrotoxicity, increased heat shock response may play a renoprotection function in tissues damage.

In many organ dysfunctions, arsenic and its compounds are well known to induce apoptosis by the mitochondria and death receptor apoptotic pathways in liver and airway. However, it is less reported that which signaling pathways contribute to excessive apoptosis of chicken immune organs, a major target of toxic metals biotransformation, which suffer from subchronic arsenism. In this study, we investigated whether the mitochondria or death receptor apoptotic pathways activated in the immune organs (spleen, thymus and bursa of Fabricius) of one-day-old male Hy-line chickens exposed to arsenic trioxide (As2O3), which were fed on diets supplemented with 0, 0.625, 1.25 and 2.5 mg/kg BW of As2O3 for 30, 60 and 90 days. We found that (1) Oxidative damage and inflammatory response were confirmed in the immune organs of chickens fed on As2O3 diet. (2) Subchronic arsenism induced typical apoptotic changes in ultrastructure. (3) TdT-mediated dUTP Nick-End Labeling (TUNEL) showed that the number of apoptotic cells significantly increased under subchronic arsenism. (4) As2O3-induced apoptosis of immune organs involved in mitochondrial pathway (decrease of B-cell lymphoma-2 (Bcl-2) and increase of protein 53 (p53), Bcl-2 Associated X Protein (Bax), caspase-9, caspase-3) and death receptor pathway (increase of factor associated suicide (Fas) and caspase-8). In conclusion, this work is the first to demonstrate that the activation of mitochondria and death receptor apoptosis pathways can lead to excessive apoptosis in immune organs of chickens, which suffer from subchronic arsenism, meanwhile, oxidative stress as well as subsequent inflammatory is a crucial driver of apoptosis.

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