AHR Activation Mediates Sodium Pentachlorophenol-Induced Mitochondrial Dysfunction and Cardiomyocyte Apoptosis...

Area of Science:

• Environmental toxicology
• Cardiovascular toxicology
• Molecular toxicology

Background:

• Sodium pentachlorophenol (PCP-Na) is a persistent halogenated aromatic compound with inadequately understood cardiotoxicity.
• Persistent organic pollutants pose risks to environmental and human health, necessitating mechanistic toxicity studies.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying PCP-Na-induced cardiotoxicity.
• To identify key molecular targets and pathways involved in PCP-Na toxicity.
• To evaluate the potential protective effects of specific inhibitors against PCP-Na cardiotoxicity.

Main Methods:

• Utilized mouse models and HL-1 cardiomyocytes.
• Integrated network toxicology and molecular docking approaches.
• Employed targeted interventions with AHR inhibitor CH223191, antioxidant N-acetylcysteine (NAC), and CYP1A1 inhibitor α-naphthoflavone (ANF).

Main Results:

• PCP-Na induced aryl hydrocarbon receptor (AHR) nuclear translocation and dose-dependent activation of its target gene, CYP1A1.
• The AHR/CYP1A1/ROS signaling pathway was identified as a key mediator of PCP-Na toxicity.
• PCP-Na exposure resulted in oxidative stress, mitochondrial dysfunction, impaired ATP production, and cardiomyocyte apoptosis.

Conclusions:

• AHR is a direct molecular target of PCP-Na.
• The AHR/CYP1A1/ROS axis is crucial in PCP-Na-induced cardiotoxicity.
• AHR and CYP1A1 inhibitors show potential for mitigating cardiac injury caused by halogenated contaminants.