Abstract
Cadmium (Cd) is a widespread environmental pollutant that affects millions of individuals worldwide. Cd
exposure in humans occurs most often through Cd’s many industrial applications, or consumption of
contaminated food. Due to its extremely extended biological half-life, Cd persists for decades in tissues, primarily
in the liver and kidneys. Cd exerts numerous deleterious effects, including bone, reproductive,
neurodevelopmental, and pulmonary toxicities, and carcinogenesis. The kidneys are the major target of Cd
toxicity, particularly the proximal tubular epithelial cells, injury to which hampers tubular reabsorption. Despite
the many sequelae associated with Cd exposure in humans, specific molecular mechanisms of Cd toxicity are
poorly understood, and no specific therapies exist to mitigate the effects of Cd exposure. Via unbiased high-
throughput screening, we identified a previously unknown ability of multiple chemically distinct histone
deacetylase inhibitors (HDACi) and Bromodomain and Extra-Terminal motif inhibitors (BETi) to rescue acute
cellular Cd toxicity. The long-term goal of these studies is to elucidate novel aspects of the cellular and
molecular mechanisms of Cd toxicity. The objectives of this application are: i) to evaluate changes in gene
expression and chromatin acetylation (Ac) occurring in response to Cd exposure in cultured cells and the kidney,
and their potential rescue by HDACi or BETi treatment; and ii) to test the ability of HDACi and BETi to mitigate
Cd induced nephrotoxicity. The central hypothesis of this application is that the interplay between histone Ac
and mitochondrial metabolism represents a key functional target of Cd toxicity in mammalian cells. The rationale
for this application is our novel foundational data demonstrating that Cd exposure induces a reduction in
mitochondrial function and histone Ac. Crucially, treatment with HDACi and BETi rescue Cd-induced defects in
mitochondrial respiration, metabolite levels, and cell viability. These findings implying that histone Ac and
mitochondrial function are important functional cellular targets of Cd. The work will take place in the context of
two Specific Aims. First, via RNA-seq and chromatin profiling, functionally important genes and pathways
targeted by Cd, and rescued by an HDACi and a BETi, will be identified in cultured fibroblasts. Second, rescue
of Cd-induced nephrotoxicity by an HDACi and a BETi will be evaluated in vivo in mice. We will compare the
gene expression signatures of Cd-exposed kidney and fibroblasts, to identify core gene expression programs
driving Cd toxicity, particularly focusing on those rescued by HDACi and BETi. The approach is innovative, in
that mechanistic links between epigenetic alterations induced by Cd and its biological effects have yet to be
conclusively established, and the use of small molecules directed against histone Ac or epigenetic perturbations
more generally as treatments for Cd toxicity has not previously been described. The work is significant, since
there is an unmet need for improved, mechanism-treatments for Cd toxicity. These studies may establish histone
Ac as a novel therapeutic target for Cd toxicity.