In recent years, chromium (Cr) has been found to induce neurotoxicity. However, the underlying mechanism remains unclear. This study aimed to investigate the effects of chromium exposure on the metabolome and microbiome that may contribute to neurotoxicity in juvenile zebrafish. Zebrafish embryos were exposed to 1 mg/L Cr (III) and 1 mg/L Cr (VI) for 7 days, respectively. Swimming distance and locomotor behavior was decreased, and acetylcholinesterase activity was reduced in Cr‐exposed groups. Total cholesterol levels were decreased in Cr‐exposed groups. The differential‐expressed metabolites due to Cr exposure were mainly enriched in primary bile acid biosynthesis, which indicated that Cr exposure may promote cholesterol conversion. The abundance of Bacteroidetes decreased and the abundance of Actinomycetes increased in Cr‐exposed groups, as compared with that in the control group. At the genus level, the abundance of Acinetobacter, Acidophorax, Mycobacterium, Aeromonas, Hydrophagophaga, and Brevundimonas increased, whereas Chryseobacterium, Pseudomonas, Delftia, and Ancylobacter decreased in the Cr‐exposed groups. Analysis of the correlation between gut microbiota and bile acid metabolites showed that changes of gut microbial community due to Cr exposure may be related to secondary bile acid metabolism. Collectively, chromium exposure may disturb cholesterol metabolism, including primary bile acid and microbiota‐related secondary bile acid metabolism. This study provides potential mechanism of the effects of chromium on neurotoxicity based on modulation of metabolome and gut microbiota diversity, which needs further verification.

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Background: Epidemiological studies have showed that PAHs may exert its adverse effects on childhood asthma. However, the underlying molecular mechanism remains to be fully elucidated. This study aimed to investigate this process in view of metabolic pathway, especially one carbon metabolism and tryptophan metabolism. Methods: Fifty asthmatic children and fifty control subjects were recruited in this study. Serum IgE and IL-17A was detected by ELISA assay. Serum PAHs concentrations were measured by GC-MS. One carbon-related metabolites and tryptophan metabolites were determined by UPLC-Orbitrap-MS. Blood DNA methylation in long interspersed nucleotide element-1 (LINE-1) was analyzed by bisulfite sequencing PCR. ChIP assays were used to examine H3K4me3 enrichment on IL-17A gene. Multivariable linear regression was performed to evaluate the associates between PAHs and one carbon metabolite and tryptophan metabolites and childhood asthma. HE staining in lung tissue, IgE and IL-17A in BALF, metabolic profiles in urine, and AhR, iL-17a and Cyp1a1 gene expression were determined in PAHs-exposed mice.Results: The asthmatic group presented significantly higher total serum IgE and IL-17A concentrations. Serum Fla was associated with childhood asthma (OR=1.380, 95%CI: 1.063-1.792). The asthmatic group displayed an increasing conversion from SAM to SAH and an elevated capacity of methylation reactions. Fla had a great effect on one carbon metabolites, especially SAH, SAM and Ser, which exerted significant mediation effects between the Fla concentration and asthma. What’s more, Fla had a positive effect on LINE-1 DNA methylation (β=0.395, P=0.000) and H3K4 tri-methylation level in the IL-17A promoter region(β=0.293, P=0.002). We did find significant mediation effect between serum Fla and asthma by LINE-1 DNA methylation and H3K4me3 level in the IL-17A promoter region. The differential Trp metabolites, such as Trp, tryptamine, IA, IAA, Indole, IAld and IAAld indicated the asthmatic children had increased indole-AhR pathway. Mediation analysis failed to show a mediator effect of Trp metabolites in the association between PAHs and childhood asthma. Animal study confirmed that PAHs exposure increased methylation levels, and altered Trp metabolites -AhR-IL-17A axis, which may be influenced by gender.Conclusion: PAHs disturbed one carbon metabolism to influence the methyl group refill of DNA methylation and histone methylation, and disturbed tryptophan metabolism to regulate Th17 cell differentiation, which may elevate serum IL-17A concentration in asthmatic children.

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