Correction: Angrand et al. Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants. Toxics 2022, 10, 518.

There was an error in the original publication [...].

Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants.

Autism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)-containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a "scientific gap". We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools.

Physico-chemical properties of aluminum adjuvants in vaccines: Implications for toxicological evaluation.

Aluminum salts have been used as adjuvants in human vaccines since 1932. The most used adjuvants are Al oxyhydroxide (AlOOH) and Al hydroxyphosphate (AlOHPO4). Al adjuvants have different physico-chemical properties. The differences in these properties are not well documented and not considered by the Food and Drug Administration (FDA), though they can largely influence biological effects of the adjuvants which are particulate components. In this study, different physico-chemical properties including the shape, size and charge of particles have been evaluated under different conditions in three Al adjuvants containing-vaccines and two corresponding commercial adjuvants suspensions. The results showed that the two Al adjuvants have different shapes, sizes and charges but both form aggregates. In addition, a clear effect of dilution on the size of the aggregates was observed. Moreover, different sizes of Al particles were measured for both Al oxyhydroxide adjuvant alone or in the vaccine, at identical concentrations, displaying the impact of adsorbed proteins on the size of aggregates in the case of the vaccine. Taken together, this paper suggests the importance to evaluate, before any biological and especially toxicological impact study, the whole physico-chemical properties of Al particle without restricting to the sole evaluation of the injected concentration. Furthermore, any modification of these mentioned parameters during manipulation, before animal or cell exposure, should be considered. In a more global way, the fixed "safe dose" of Al adjuvants should be specific for each type of Al adjuvant independently or for a mix of the two compounds, due to their different properties.

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation.

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens. 312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman's correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method. We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05). Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.

Persistent brainwave disruption and cognitive impairment induced by acute sarin surrogate sub-lethal dose exposure.

Warfare neurotoxicants such as sarin, soman or VX, are organophosphorus compounds which irreversibly inhibit cholinesterase. High-dose exposure with nerve agents (NA) is known to produce seizure activity and related brain damage, while less is known about the effects of acute sub-lethal dose exposure. The aim of this study was to characterize behavioral, brain activity and neuroinflammatory modifications at different time points after exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. In order to decipher the impacts of sub-lethal exposure, we chose 4 different doses of NIMP each corresponding to a fraction of the median lethal dose (LD50). First, we conducted a behavioral analysis of symptoms during the first hour following NIMP challenge and established a specific scoring scale for the intoxication severity. The intensity of intoxication signs was dose-dependent and proportional to the cholinesterase activity inhibition evaluated in mice brain. The lowest dose (0.3 LD50) did not induce significant behavioral, electrocorticographic (ECoG) nor cholinesterase activity changes. Animals exposed to one of the other doses (0.5, 0.7 and 0.9 LD50) exhibited substantial changes in behavior, significant cholinesterase activity inhibition, and a disruption of brainwave distribution that persisted in a dose-dependent manner. To evaluate long lasting changes, we conducted ECoG recording for 30 days on mice exposed to 0.5 or 0.9 LD50 of NIMP. Mice in both groups showed long-lasting impairment of theta rhythms, and a lack of restoration in hippocampal ChE activity after 1-month post-exposure. In addition, an increase in neuroinflammatory markers (IBA-1, TNF-α, NF-κB) and edema were transiently observed in mice hippocampus. Furthermore, a novel object recognition test showed an alteration of short-term memory in both groups, 1-month post-NIMP intoxication. Our findings identified both transient and long-term ECoG alterations and some long term cognitive impairments following exposure to sub-lethal doses of NIMP. These may further impact morphopathological alterations in the brain.