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Molybdenum induces hepatic impairments via dysregulating NLRP3, JAK1/STAT3 and NF-κB pathways: A dose dependent
Mahmoud El Safadi1, Abdulaziz Saleh Alkhoshaiban2, Muhammad Faisal Hayat3
1Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, Abu Dhabi, United Arab Emirates.
Background:
Molybdenum (Mo) is an important trace element that is documented to instigate several toxicities in different organs of the body. Mo demonstrates adverse effects by inducing oxidative stress (OS), inflammatory damage as well as apoptotic responses in key regulatory organs of the body.
Aim:
The present experiment was executed to measure the dose-dependent effects of Mo on hepatic tissues of rats by examining histological and biochemical profile.
Methodology:
Thirty-six male rats (albino) were segregated into 4 groups including the group I (control), group II (Mo 10 mg/kg), group III (Mo 30 mg/kg) and IV (Mo 50 mg/kg) intoxicated group. The experiment was conducted for 4 weeks consecutively. The gene expressions were measured through qRT-PCR protocol; however, biochemical assessments were carried out via standard ELISA technique along with numerous other standard assays. The findings are further validated through molecular docking (MD) analysis as well as molecular dynamic simulation (MDS) techniques.
Findings:
Mo intoxication (10 mg/kg, 30 mg/kg and 50 mg/kg) upregulated the gene expression of Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κb), NOD-like receptor protein 3 (NLRP3), interleukin-18 (IL-18), cyclooxygenase-2 (COX-2), interleukin- 1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Moreover, an escalation was recorded in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), however, the activities of glutathione peroxidase (GPx), catalase (CAT), glutathione (GSH), superoxide dismutase (SOD), heme-oxygenase-1 (HO-1), glutathione S- transferase (GST), & glutathione reductase (GSR) following the dose concentration of Mo (10 mg/kg, 30 mg/kg and 50 mg/kg). Besides, Mo exposure (50 mg/kg) escalated the levels of aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) & alanine transaminase (ALT), however, the total proteins as well as albumin levels were decreased. Additionally,Caspase-9, and Caspase-3 levels along with Bax were increased while the levels of Bcl-2 were subsided at all the tested doses of Mo. Furthermore, Mo intoxication (10 mg/kg, 30 mg/kg, and 50 mg/kg) distorted the hepatic morphology.
Conclusion:
Mo is a potent hepatotoxic agent that induces apoptosis, OS along with inflammatory damage in the hepatic tissues at different dose concentrations. These results revealed the toxic nature of Mo at various dose concentrations, indicating the urgent need for a novel therapeutic approach, environmental and regulatory policies to combat these adverse effects.
Insights
Molybdenum (Mo) causes liver damage by increasing oxidative stress and inflammation. This study shows Mo
Area of Science:
- Toxicology
- Biochemistry
- Molecular Biology
- Hepatology
Background:
- Molybdenum (Mo) is an essential trace element with documented toxicities in various organs.
- Mo exposure can induce oxidative stress (OS), inflammation, and apoptosis in vital organs.
Purpose of the Study:
- To investigate the dose-dependent hepatotoxic effects of Molybdenum (Mo) in male albino rats.
- To assess the impact of Mo on hepatic tissues through histological and biochemical analyses.
Main Methods:
- Four groups of male rats (n=36) were administered Mo (10, 30, 50 mg/kg) or saline (control) for 4 weeks.
- Gene expression analyzed via qRT-PCR; biochemical markers assessed using ELISA and other standard assays.
- Molecular docking (MD) and molecular dynamic simulation (MDS) techniques were employed for validation.
Main Results:
- Mo intoxication upregulated pro-inflammatory and apoptosis-related genes (JAK1, STAT3, NF-κb, NLRP3, IL-18, COX-2, IL-1β, IL-6, TNF-α).
- Increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, with decreased antioxidant enzyme activities (GPx, CAT, GSH, SOD, HO-1, GST, GSR).
- Elevated liver enzymes (AST, GGT, ALP, ALT) and apoptosis markers (Caspase-9, Caspase-3, Bax), alongside decreased total protein and albumin levels. Hepatic morphology was distorted.
Conclusions:
- Molybdenum (Mo) acts as a potent hepatotoxin, inducing apoptosis, oxidative stress, and inflammation in liver tissues.
- The observed toxic effects are dose-dependent, highlighting the detrimental impact of Mo exposure.
- Urgent need for novel therapeutic strategies, environmental regulations, and policies to mitigate Mo-induced toxicity.
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