Abstract

Many metals in the environment are nephrotoxic. To better understand both similar and dissimilar responses to different metals, we compared RNA sequencing data from primary human proximal tubule epithelial kidney cells treated with arsenic, cadmium, vanadium, or uranium for 6 or 24 h. At 24 h post-treatment, arsenic- or cadmium-treated cells shared processes related to metal stress response and detoxification. Distinct characteristics of arsenic exposure included terms associated with membrane transport, immune/inflammatory signaling, and renal/urogenital development. This was in contrast to cadmium, where proteostasis and protein quality control were the dominant themes. Vanadium and uranium had limited overlaps with either arsenic or cadmium or one another. Response to vanadium revealed solute transport and stimulus detection as well as cell cycle/mitotic regulation and chromosome segregation. Uranium exposure was associated with RNA processing/splicing, proteostasis/ER stress and apoptotic signals, but there were fewer DEGs to define GO terms and themes. The results demonstrate that arsenic and cadmium initiate robust and partially overlapping transcriptional responses as early as 6 h, reflecting shared mechanisms of metal toxicity alongside individual metal-specific signatures. In contrast, uranium and vanadium elicit minimal early (6 h) transcriptional responses but develop more robust signatures by 24 h. These findings demonstrate that environmentally relevant metals act through both shared mechanistic pathways and distinct, metal-specific mechanisms. Understanding their individual and overlapping transcriptional mechanisms is critical for interpreting health risks associated with human exposure.

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