Effects of chronic lead acetate exposure on neurobehavior and serum metabolomics in mice / 环境与职业医学

ABSTRACT

Background Chronic low-level exposure to lead can damage the central nervous system and cause anxiety-like behavior. However, whether changes of blood metabolites occur in this process and its relationship with lead-induced neurobehavioral disorder remain unclear. Objective To explore the effects of chronic lead acetate (PbAc) exposure at different concentrations on anxiety-like behavior and serum metabolites and their relationships in mice, as well as the mechanism of lead exposure on neurobehavioral injury in mice from the perspective of metabolomics. Methods A total of 64 healthy 4-week-old C57BL/6J mice, half male and half female, were randomly divided into four groups control group (normal drinking water), 20 mg·L−1 PbAc group, 100 mg·L−1 PbAc group, and 500 mg·L−1 PbAc group. After 10 weeks of free drinking of water containing designed concentrations of PbAc, the mice were tested for anxiety-like behavioral changes by open field experiment. After the mice were anesthetized, blood was collected from the eyes, the serum was separated, and the effects of designed doses of lead exposure on metabolites in the serum of mice were compared by liquid chromatography with tandem mass spectrometry combined with principal component analysis and partial least squares discrimination analysis. Results The results of the open field experiment showed that the reductions in movement time spent in central area in the 100 mg·L−1 and 500 mg·L−1 PbAc groups compared with the control group were of statistical significance (P<0.05); the reduction in crossing times of central region in the 500 mg·L−1 PbAc group was statistically significant compared with the control group (P<0.05); the increases in defecation frequency in the 100 mg·L−1 and 500 mg·L−1 PbAc groups were statistically significant compared to the control group (P<0.05). In both positive and negative ion modes, compared with the control group, 157 differential metabolites were screened out in the 20 mg·L−1 PbAc group, of which 80 were up-regulated and 77 were down-regulated; 172 differential metabolites were screened out in the 100 mg·L−1 PbAc group, of which 57 were up-regulated and 115 were down-regulated; 119 differential metabolites were screened out in the 500 mg·L−1 PbAc group, of which 42 were up-regulated and 77 were down-regulated. The results of the KEGG enrichment analysis on the differential metabolites revealed alterations in metabolic pathways mainly involving primary bile acid biosynthesis, bile secretion, and cholesterol metabolism. Among the differential metabolites, norethisterone was positively correlated with the number of central region crossings (r=0.406, P<0.05); dihydrothymine was negatively correlated with the number of central region crossings (r=−0.346, P<0.05); lysophosphatidylcholine 22∶1 and lysophospholipid 14∶0 were negatively correlated with time spent in central region (r=−0.429, P<0.05; r=−0.374, P<0.05). Conclusion Chronic lead exposure induces anxiety-like behavior in mice, and this altered behavior is associated with altered metabolites in serum, with differential metabolites enriched primarily in the metabolic pathways of primary bile acid biosynthesis, bile acid secretion, and cholesterol metabolism.