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<p>Co-exposure to heavy metals can result in additive or synergistic toxicity in the brain, culminating in neurotoxicity. This study investigated the neurotoxic effects of a low-dose mixture of two toxic heavy metals—lead (Pb, 20&#xa0;mg/kg) and aluminium (Al, 35&#xa0;mg/kg)—and one essential metal, manganese (Mn, 0.564&#xa0;mg/kg), on the cerebellum of rats. Animals were divided into five groups (<i>n</i> = 5) and orally treated for 90 days as follows: Group I received normal drinking water and served as the control; Group II received a heavy metal mixture of Pb (20&#xa0;mg/kg), Al (35&#xa0;mg/kg), and Mn (0.564&#xa0;mg/kg) body weight; Group III received Pb (20&#xa0;mg/kg) alone; Group IV received Al (35&#xa0;mg/kg) alone; and Group V received Mn (0.564&#xa0;mg/kg) alone. Chronic exposure to heavy metals resulted in a significant (<i>p</i> &lt; 0.05) reduction in rotarod performance compared with the control group, indicating impaired cerebellar motor function. The low-dose heavy metal mixture significantly depressed antioxidant defences (<i>p</i> &lt; 0.05), increased lipid peroxidation (<i>p</i> &lt; 0.05), elevated amyloid-β peptide levels (Aβ₁–₄₀ and Aβ₁–₄₂) (<i>p</i> &lt; 0.05), and markedly reduced occludin expression (<i>p</i> &lt; 0.05) in the cerebellum relative to controls. These biochemical alterations were more pronounced in the mixture-exposed group than in animals treated with individual metals. Overall, chronic low-dose exposure to an environmentally relevant heavy metal mixture induces cerebellar neurotoxicity through enhanced amyloid-β accumulation and downregulation of occludin, a key tight junction protein, in adult male Wistar rats. These findings underscore the role of mixed metal exposure in amyloid-β dysregulation, tight junction disruption, and cerebellar dysfunction.</p>

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Amyloid beta levels and occludin depletion in low dose heavy metal mixture mediated cerebellar toxicity in Wistar rats

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Baridoo Donatus Dooka,
  • Chinna N. Orish,
  • Anthonet N. Ezejiofor,
  • Theresa C. Umeji,
  • Kpobari W. Nkpaa,
  • Cecilia N. Obasi,
  • Orish Ebere Orisakwe

摘要

Co-exposure to heavy metals can result in additive or synergistic toxicity in the brain, culminating in neurotoxicity. This study investigated the neurotoxic effects of a low-dose mixture of two toxic heavy metals—lead (Pb, 20 mg/kg) and aluminium (Al, 35 mg/kg)—and one essential metal, manganese (Mn, 0.564 mg/kg), on the cerebellum of rats. Animals were divided into five groups (n = 5) and orally treated for 90 days as follows: Group I received normal drinking water and served as the control; Group II received a heavy metal mixture of Pb (20 mg/kg), Al (35 mg/kg), and Mn (0.564 mg/kg) body weight; Group III received Pb (20 mg/kg) alone; Group IV received Al (35 mg/kg) alone; and Group V received Mn (0.564 mg/kg) alone. Chronic exposure to heavy metals resulted in a significant (p < 0.05) reduction in rotarod performance compared with the control group, indicating impaired cerebellar motor function. The low-dose heavy metal mixture significantly depressed antioxidant defences (p < 0.05), increased lipid peroxidation (p < 0.05), elevated amyloid-β peptide levels (Aβ₁–₄₀ and Aβ₁–₄₂) (p < 0.05), and markedly reduced occludin expression (p < 0.05) in the cerebellum relative to controls. These biochemical alterations were more pronounced in the mixture-exposed group than in animals treated with individual metals. Overall, chronic low-dose exposure to an environmentally relevant heavy metal mixture induces cerebellar neurotoxicity through enhanced amyloid-β accumulation and downregulation of occludin, a key tight junction protein, in adult male Wistar rats. These findings underscore the role of mixed metal exposure in amyloid-β dysregulation, tight junction disruption, and cerebellar dysfunction.