Sex Differences in Oxidative Stress and Depression-Like Behavior Following Chronic Lead Exposure from Pregnancy to Adulthood

Abstract

Abstract Lead (Pb) is a neurotoxic heavy metal that crosses the placental barrier and may affect fetal development. However, the effects of chronic developmental Pb exposure on oxidative stress, stress-related endocrine responses, and depression-like behavior, particularly regarding sex differences, remain unclear. This study evaluated the effects of chronic Pb exposure from gestation to adulthood on redox balance, corticosterone responses, and depression-like behavior in male and female mice. Pregnant C57BL/6J mice received 250 ppm lead acetate in drinking water from gestational day 0 until offspring reached adulthood. Depression-like behavior was assessed using the forced swimming and tail suspension tests. Reactive oxygen species and lipid peroxidation were measured in the prefrontal cortex and hippocampus, and plasma corticosterone was quantified following behavioral stress. Chronic Pb exposure increased immobility in both behavioral tests and increased oxidative stress markers in the prefrontal cortex and hippocampus, with sex- and region-dependent differences. Pb exposure also altered corticosterone dynamics in both sexes: males showed a delayed corticosterone peak, whereas females exhibited a prolonged response that remained elevated 24 h after stress. Overall, chronic developmental Pb exposure was associated with depression-like behavior, oxidative imbalance, and altered corticosterone responses in a sex-dependent manner. These findings highlight biological sex as an important factor influencing the neurobehavioral, redox, and stress-related endocrine consequences of chronic developmental Pb exposure.