Comparative and combined neurotoxic effects of lithium carbonate and lead acetate in rats: From clinical alterations to molecular insights

Heavy metal contamination in soil and water is a global concern with significant ecological and health implications. Lithium (Li), increasingly used in electric vehicles, and lead (Pb), a well-established pollutant, poses neurotoxic risks to animals and humans. This study evaluated the individual and combined effects of lithium carbonate (Li; 20 mg/kg) and lead acetate (Pb; 20 mg/kg) administered orally for 28 days in adult rats. Forty-eight rats were divided into four groups: control, Li, Pb, and Li + Pb. Clinical signs included hair loss, diarrhoea, dehydration, dullness, and foul-smelling faeces, with Li + Pb rats showing greater feed reduction and weight loss than single-exposure groups. Behavioural assessments revealed impaired motor coordination, anxiety-like behaviour, and significantly increased grip strength in Li + Pb as compared to the control group. Oxidative stress markers demonstrated significantly reduced Superoxide Dismutase (SOD), catalase, glutathione, and total antioxidant capacity, along with significantly elevated Malondialdehyde (MDA) and Nitric Oxide (NO) levels in the Li + Pb group compared with the control group. Brain AChE activity was significantly reduced in the Pb and Li + Pb groups compared with the control group. Gene expression analysis revealed significant downregulation of apoe (3.93-fold), app (6.15-fold), and ache (4.75-fold) genes, alongside bax (4.98-fold) upregulation in the Li + Pb group compared with the control group, indicating enhanced apoptosis, impaired antioxidant defense, and Alzheimer’s-like neurodegeneration. Gross pathology revealed mild cerebral congestion in the Li and Pb alone groups, and marked congestion in the Li + Pb rats. Histopathology confirmed neuronal degeneration, Purkinje cell loss, perineuronal space widening, and astrocytic proliferation, with the Li + Pb group exhibiting the most severe lesions. Collectively, these findings suggest that co-exposure to lithium and lead exerts more pronounced neurotoxic effects, mediated by oxidative stress, apoptosis, and gene alterations linked to neurodegeneration.