Cellular
responses to nanoparticles (NPs) have been largely studied
in cell populations, providing averaged values that often misrepresent
the true molecular processes that occur in the individual cell. To
understand how a cell redistributes limited molecular resources to
achieve optimal response and survival requires single-cell analysis.
Here we applied multiplex single molecule-based fluorescence
in situ
hybridization (fliFISH) to quantify the expression
of 10 genes simultaneously in individual intact cells, including glycolysis
and glucose transporter genes, which are critical for restoring and
maintaining energy balance. We focused on individual gill epithelial
cell responses to lithium cobalt oxide (LCO) NPs, which are actively
pursued as cathode materials in lithium-ion batteries, raising concerns
about their impact on the environment and human health. We found large
variabilities in the expression levels of all genes between neighboring
cells under the same exposure conditions, from only a few transcripts
to over 100 copies in individual cells. Gene expression ratios among
the 10 genes in each cell uncovered shifts in favor of genes that
play key roles in restoring and maintaining energy balance. Among
these genes are isoforms that can secure and increase glycolysis rates
more efficiently, as well as genes with multiple cellular functions,
in addition to glycolysis, including DNA repair, regulation of gene
expression, cell cycle progression, and proliferation. Our study uncovered
prioritization of gene expression in individual cells for restoring
energy balance under LCO NP exposures. Broadly, our study gained insight
into single-cell strategies for redistributing limited resources to
achieve optimal response and survival under stress.