Heavy metal mixture induced hippocampal toxicity involve biometal accumulation, increase in oxidative stress, inflammation, and caspase-3 activation in rats via Nrf-2/HO-1/BDNF pathway.

Exposure to heavy metal mixtures HMM can elicit significant health risks due to their combined toxic effects. This study investigates the mechanisms of hippocampal toxicity associated with HMM exposure. Rats were exposed to lead (Pb) 20, aluminum (Al) 35 and manganese (Mn) 0.564 mg/kg body weight alone or in combination for 90 days. The rats exposed to Pb-Al-Mn mixture spent least time exploring the open arms and had longer latency to find the hidden platform than the control and individual metal exposure groups in the Elevated Plus Maze test. Bioaccumulation of Pb, Al and Mn in the hippocampus was measured, oxido-inflammatory, markers, caspase-3, Nrf-2, Aβ40, Aβ42, occludin, BDNF were evaluated. Al, Pb and Mn exposure individually significantly (p ≤ 0.05) decreased the hippocampal antioxidant enzymes activities, glutathione level and increased oxidative stress and neuroinflammation biomarkers. HMM significantly increased caspase-3, Nrf-2, Aβ40 and Aβ42 and significantly decreased occludin, BDNF, HO-1 when compared with the control. HMM significantly (p ≤ 0.05) exacerbated hippocampal in comparison to individual Al, Pb or Mn. HMM induced hippocampal toxicity via multiple targets, namely biometal accumulation, increase in oxidative stress, inflammation, and caspase-3 activation in rats via Nrf-2/HO-1/BDNF. All in all, this study has shown that exposure to Pb-Al-Mn tertiary mixture, even at lower doses than individual heavy metals, significantly amplified anxiety-like behavior in comparison to exposure to individual heavy metals, which were associated with the alternations in Nrf-2, HO-1, Aβ-40, Aβ-42, BDNF, occludin levels, COX-2 and Caspase-3 activities in the hippocampus.