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Journal of Inorganic Biochemistry – 2017
Highlights
• Mechanisms underlying aluminum adjuvant neurotoxicity have been investigated.
• Key proinflammatory factors were found elevated in the brains of aluminum-injected mice.
• Male mice were more susceptible to aluminum’s neuroinflammatory effects than females.
• Frontal cortex was the most affected area in males.
• Frontal cortex is involved in emotional and social functions which are impaired in autism.
Abstract
Autism is a neurobehavioral disorder characterized by immune dysfunction. It is manifested in early childhood, during a window of early developmental vulnerability where the normal developmental trajectory is most susceptible to xenobiotic insults. Aluminum (Al) vaccine adjuvants are xenobiotics with immunostimulating and neurotoxic properties to which infants worldwide are routinely exposed. To investigate Al′s immune and neurotoxic impact in vivo, we tested the expression of 17 genes which are implicated in both autism and innate immune response in brain samples of Al-injected mice in comparison to control mice. Several key players of innate immunity, such as cytokines CCL2, IFNG and TNFA, were significantly upregulated, while the nuclear factor-kappa beta (NF-κB) inhibitor NFKBIB, and the enzyme controlling the degradation of the neurotransmitter acetylcholine (ACHE), were downregulated in Al-injected male mice. Further, the decrease of the NF-κB inhibitor and the consequent increase in inflammatory signals, led to the activation of the NF-κB signaling pathway resulting in the release of chemokine MIP-1A and cytokines IL-4 and IL-6. It thus appears that Al triggered innate immune system activation and altered cholinergic activity in male mice, observations which are consistent with those in autism. Female mice were less susceptible to Al exposure as only the expression levels of NF-κB inhibitor and TNFA were altered. Regional patterns of gene expression alterations also exhibited gender differences, as frontal cortex was the most affected area in males and cerebellum in females. Thus, Al adjuvant promotes brain inflammation and males appear to be more susceptible to Al′s toxic effects.
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