Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats

Abstract

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3β-HSD, CYP17A1, and 17β-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form.

Roles of Nrf2/HO-1 and ICAM-1 in the Protective Effect of Nano-Curcumin against Copper-Induced Lung Injury

“…Moreover, Nrf2 −/− mice exhibited severe lung damage characterized by increased protein permeability, macrophage inflammation, and epithelial injury after hyperoxia exposure [ 59 ]. Previous studies have reported that Cu toxicity can cause downregulation of Nrf2 and HO-1 in the liver [ 60 ], brain [ 61 , 62 ], and testes [ 45 ], which supports our findings.…”

“…As expected, apoptotic cell death was found in the lungs of CuSO 4 -challenged rats, in which Bax and Bcl-2 gene expression was increased and decreased, respectively. These findings align with prior research indicating that overexposure to CuSO 4 elicits cellular apoptosis in several organs [ 43 , 44 , 45 ]. ROS and pro-inflammatory mediators induce the pro-apoptotic Bax, thus disturbing the outer mitochondrial membrane.…”

“…ROS are strong oxidizers that enhance lipid peroxidation, protein damage, DNA fragmentation, and cell death [4,41]. In addition, aberrations in the oxidant/antioxidant balance caused by Cu result in the oxidation of proteins' sulfhydryl groups, thereby depleting GSH stores and reducing SOD activity in the lungs and other organs, as previously reported [42][43][44][45]. MDA is the most prominent byproduct of lipid peroxidation, and it crosslinks to tissue DNA or protein to form adducts, resulting in biomolecular damage [46].…”

Advances in Nrf2 Signaling Pathway by Targeted Nanostructured-Based Drug Delivery Systems

“…The results also revealed NF-κB downregulation and suppressed cytokine levels. Likewise, another study also showed that the liposomal nanocurcumin alleviated copper sulfate (CuSO 4 )-induced testicular lipid peroxidation, inflammation, and apoptosis via Nrf2/HO-1 signaling [62]. Here, it was postulated that the nanocurcumin activates Nrf2/HO-1 signaling by promoting the levels of Nrf2 and Bcl-2 with the enhancement of endogenous antioxidants, such as HO-1, GSH, and SOD, thereby protecting from tissue injury.…”

Quercetin Alleviates Toxicity Induced by High Levels of Copper in Porcine Follicular Granulosa Cells by Scavenging Reactive Oxygen Species and Improving Mitochondrial Function

“…However, excess copper will lead to cytotoxicity [4], and the recent literature reports cuproptosis mainly due to proteotoxic stress caused by aggregation of lipated proteins and loss of iron-sulfur cluster proteins [5]. At the same time, a large number of studies have shown that one of mechanisms of copper toxicity is oxidative stress [6][7][8][9][10][11]. When high levels of copper act on the ovaries, it Animals 2023, 13, 2745 2 of 17 will affect the reproductive performance of animals [12,13].…”