Wednesday’s Symposium Session during the SOT 61st Annual Meeting and ToxExpo entitled “Applications of Single Cell Profiling Methods to Enhance Mechanistic Understanding of Toxicological Responses” showed how tissue heterogeneity was increasingly recognized in toxicological studies to unravel the mechanisms involved.
The first speaker was Dr. David Gallegos. He, upon the start of his session, gave credit to the previous bulk tissue/cell-based high-throughput sequencing methods that attempted unravel the complex mechanisms in toxicology. However, these bulk-based techniques inevitably downplayed how the heterogeneity of samples can contribute to the explanation of toxicological mechanisms. Recent revolutions in single cell profiling technologies, such as single cell/nucleus RNA-seq, ATAC-seq, and spatial sequencing, have advanced our ability to overcome these limitations to resolve cell type and response heterogeneity in toxicological research.
Following Dr. Gallegos’s introduction was Dr. Kelly Bakulski’s presentation, which demonstrated how the single cell profiling technique provided evidence for perinatal lead (Pb) exposure–induced alterations in offsprings’ brain hippocampus. In mice perinatally exposed to water (control) or a human physiologically relevant Pb (32 ppm in maternal drinking water; two weeks prior to mating through weaning), the Bakulski lab analyzed 5,258 hippocampal cells in offspring mice at five months of age. With the power of single cell profiling techniques, they were able to understand how perinatal Pb treatment can alter (1) gene expression differences across all cell types/clusters, (2) the cell types’/clusters’ composition, and (3) gene expression and pathway differences within cell types/clusters. For example, their analyses revealed that the perinatal Pb exposure led to more oligodendrocytes, which are supporting cells that ensheath axons of neurons, in the offspring hippocampus. Deep into certain cell types/clusters, they discovered that in response to perinatal Pb exposure, protein folding pathway, inflammatory responses, and DNA damage are significantly altered in microglial cells, oligodendrocytes, and pericytes, respectively. However, such in-depth understanding of perinatal Pb toxicity will not be possible through the traditional gene expression analysis using bulk tissues (hippocampus).
Indeed, multiple procedures through single cell profiling need further optimization. For example, fewer numbers of neuronal cells were detected in hippocampal tissues in Dr. Bakulski’s assays than expected. This may be due to the tissue dissociation step that has yet to be perfected and thus did not favor the neurons dissociated from tissue for downstream analysis. With the fantastic power of single cell profiling techniques and huge interest among researchers, we have reason to believe the workflow will be further improved to yield more reliable “high-resolution” data.
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