Developmental nephrotoxicity of per- and polyfluoroalkyl substances: Mechanistic insights and epidemiological evidence from prenatal and early-life exposure.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals with widespread environmental distribution and near-universal human exposure. Increasing evidence indicates that prenatal and early-childhood periods represent critical windows of susceptibility during which PFAS can disrupt kidney development and impair renal function with potential long-term consequences. This review provides a comprehensive synthesis focusing specifically on PFAS-related nephrotoxicity during early life, integrating mechanistic, toxicological, and epidemiological data to elucidate how developmental exposure may influence lifelong renal health. PFAS readily cross the placenta, accumulate in fetal and neonatal tissues, and exhibit limited clearance in infancy due to immature renal filtration and metabolic pathways. Mechanistic studies demonstrate that PFAS induce developmental nephrotoxicity through multiple pathways, including oxidative stress, mitochondrial dysfunction, PPAR signaling disruption, dysregulated glucocorticoid metabolism, inflammatory activation, and altered nephrogenesis. In vitro and in vivo models further show histopathological changes, metabolic shifts, impaired tubular transport, and activation of apoptotic pathways following developmental exposure, suggesting direct structural and toxicological injury to the maturing kidney. Human cohort studies consistently report associations between early-life PFAS exposure and alterations in renal biomarkers, including reduced estimated glomerular filtration rate (eGFR), elevated serum creatinine and cystatin C, and increased tubular injury markers such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), even when clinical function appears within reference ranges. As a key interpretive consideration, these associations must be viewed in light of ongoing discussion regarding the role of renal clearance in shaping circulating PFAS concentrations, which may influence epidemiological findings. These subtle but quantifiable shifts nevertheless support a life-course hypothesis in which early molecular and functional disturbances may increase vulnerability to chronic kidney disease (CKD) later in life. Substantial gaps remain, including limited longitudinal follow-up, underutilization of mixture-based analytical approaches, and inadequate characterization of emerging PFAS compounds. Overall, this review underscores the growing evidence that early-life PFAS exposure may impair renal development and function through combined toxicokinetic, molecular, and structural mechanisms, while highlighting the need for improved exposure mitigation, expanded biomonitoring in maternal and pediatric populations, and integrative translational research to support evidence-based public health and regulatory decision-making.