Prenatal arsenic exposure alters EZH2/H3K27me3 to induce RKIP/NF-kB/ERK1/2-mediated early-onset kidney disease in mouse offspring.

Abstract

The rising incidences of chronic kidney disease (CKD) and renal failure are a major public health concern. Arsenic, a widespread water contaminant and environmental toxicant, is well-known to contribute to kidney disease in adults. However, its long-term effects on kidney health following early-life exposure remain poorly understood. Therefore, we investigated the impact of prenatal arsenic exposure on kidney health in offspring using a BALB/c mouse model. 0.4 ppm arsenic, an environmentally relevant dose, was orally administered to female mice from 15 days before mating until delivery. Structural and ultrastructural changes in the kidney were assessed using histopathology and transmission electron microscopy, while markers of inflammation, kidney injury, and function were evaluated through Luminex assays, FITC-sinistrin-based glomerular filtration rate (GFR), real-time PCR, immunohistochemistry, and immunoblotting. Notably, arsenic-exposed offspring showed reduced body weight, crown-to-rump length, inflammation, and early signs of kidney injury on postnatal day 2 (PND-2). By 6 weeks, examination showed tubular dilation, mitochondrial damage, vacuolated cytoplasm, and basement membrane disruption were more evident in the kidneys. Furthermore, elevated levels of kidney injury markers, including kidney injury molecule-1, beta-2 microglobulin, cystatin C, and tissue inhibitor of metalloproteinase 1, were detected in urine. These changes were accompanied by increased serum creatinine and a decline in kidney function, as evidenced by reduced GFR levels. Proinflammatory cytokines (TNF-α, IL-6) and NF-κB were significantly elevated along with an increased immune cell infiltration in the kidneys of arsenic-exposed offspring. Further analysis showed increased mesenchymal markers fibronectin and alpha-smooth muscle actin and reduced epithelial marker E-cadherin in the kidneys, indicating fibrosis and epithelial-to-mesenchymal transition. Mechanistic studies revealed that arsenic exposure leads to increased levels of epigenetic regulators enhancer of zeste homolog 2 (EZH2) and histone H3 lysine 27 trimethylation (H3K27me3), which were associated with the activation of inflammatory pathways, fibrosis, and impaired kidney function. Overall, our findings demonstrate that only developmental exposure to arsenic can cause dysregulation of EZH2 and H3K27me3, driving inflammation and renal fibrosis. These changes ultimately lead to chronic kidney disease in offspring, highlighting a critical window of vulnerability for arsenic toxicity with significant implications for long-term kidney health.