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Lead is a known neurotoxicant with many detrimental health effects, including neurocognitive deficits and cardiovascular and metabolic disorders. However, few studies have tested the association between lead exposure and the physiological stress response, which in and of itself may act as a precursor to and/or underlying mechanism of detrimental health outcomes. The purpose of this study was to examine the influence of early childhood and early adolescent low-level lead exposure on early adolescent heart rate variability, a widely-used measure of physiological stress. Participants were 408 children from Jintan, China for whom blood lead levels were measured between 3 and 5 years (early childhood) and again at 12 years (early adolescence). Heart rate variability was assessed at 12 years while participants underwent an induced stress task utilizing the ratio of low to high frequency (LF/HF) ECG measures. Mean blood lead levels in the cohort were 6.63 mcg/dl and 3.10 mcg/dl at 3–5 years and 12 years, respectively. Blood lead levels at 3–5 years of age (β 0.06, p = 0.027), but not at age 12 (β −0.05, p = 0.465), were significantly associated with LF/HF measures while controlling for multiple sociodemographic variables, potentially reflecting a dysregulated stress response with a shift towards sympathetic dominance. These findings suggest that early childhood lead exposure may have a detrimental influence on early adolescent autonomic responses to acute stress, which holds implications for cardiovascular health and overall growth and development. [ABSTRACT FROM AUTHOR]