Epigenetic and metabolic mechanisms of cadmium cytotoxicity

Background and Innovation: Cadmium (Cd) is a widespread toxic pollutant that represents a major occupational and environmental hazard worldwide. Cd readily accumulates in human tissues, especially the kidney, and once present, persists for decades. Cd exerts severe deleterious effects, including carcinogenesis in multiple tissues, as well as more general renal, liver, lung, bone, reproductive, neurodevelopmental, and cognitive toxicities. Specific pathogenic mechanisms of Cd cytotoxicity are poorly understood, and no mechanism-based therapies currently exist for Cd poisoning. Via small molecule screening, we identified the ability of certain epigenetically-targeted drugs to mitigate acute Cd cytotoxicity1. BET (Bromodomain and Extra- Terminal motif) proteins regulate gene expression by interacting with acetylated histones; the best characterized member of the BET family is BRD42. We have shown that multiple chemically distinct BET inhibitors (BETi) suppress Cd-induced cytotoxicity, as well as impaired mitochondrial respiration, and associated metabolite changes. In vivo studies reveal that the prototypical BETi JQ1 can mitigate acute Cd-induced kidney injury. Biochemical, immunofluorescence, and ChIP-seq studies indicate that Cd induces accumulation of BRD4 at chromatin. By small molecule and epigenetic approaches, we nominated Succinate Dehydrogenase (SDH) as a likely key target of BRD4 and Cd. Based on a large body of supporting evidence, we hypothesize that Cd induces increased BRD4 activity, thereby leading to misregulation of SDH subunits and other key metabolic genes. In this proposal, we will provide new mechanistic insights into the interaction between gene expression, metabolism, and Cd exposure, focusing on BRD4, and develop an improved mouse model for chronic Cd exposure to evaluate the significance of our findings in vivo. Significance and Impact to Veteran’s Healthcare: Service Members, and by extension, Veterans, are exposed to Cd in the context of exposures relevant to the general US population (smoking and diet), as well as more military-specific exposures: e.g. anti-corrosion coating on military equipment, retained shrapnel, and contaminated environments. One recent study examined the presence of multiple heavy metals in the lungs of Service Members deployed to Iraq and Afghanistan suffering from constrictive bronchiolitis, and found that Cd levels were higher in the lungs of affected individuals than in controls3. Cd is among the metals included in the routine urine biomonitoring panel for Veterans with retained embedded metal fragments4. On Vieques, a part of Puerto Rico used for many years as a bombing range, residents had elevated urinary Cd levels compared to individuals from Main Island Puerto Rico5. Similarly, high soil Cd levels have been observed at military shooting ranges6. In Croatia, civilians from areas experiencing heavy fighting had higher levels of urinary and hair Cd than those exposed to moderate levels of fighting6. In the US, elevated Cd levels have been observed at multiple military-connected sites, contributing to their designations as EPA Superfund sites: Fort Devens, Concord Naval Weapons Station, Portsmouth Navy Shipyard, and the Twin Cities Reserve Air Force Base small arms range landfill. The incidence of Amyotrophic Lateral Sclerosis (ALS) is higher in Veterans, particularly those who fought in the Gulf War, and this may be linked to exposure to Cd and other heavy metals7. Path to translation/implementation: This work will uncover novel, previously unknown mechanistic aspects of the interplay between Cd exposure, epigenetics, and metabolism, as well as evaluate their roles in a translationally relevant animal model. If successful, this work could lead to clinical trials to evaluate the efficacy of BETi treatment in Veterans suffering sequelae of Cd exposure. Project Number: 1I01BX006593-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: David Lombard | Institution: MIAMI VA HEALTH CARE SYSTEM, MIAMI, FL | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 CAMM-P (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11187370