Embryonic lead (Pb) contact impairs lipid, oxidative, and behavioral markers in zebrafish across multiple generations.

The heavy metal lead (Pb) is widely accepted as a toxicant that impairs different physiological functions dependent on dose. The central nervous system (CNS) is highly sensitive to Pb especially when exposure occurs during early developmental periods. Moreover, even low Pb exposures during development can be detrimental and have long-lasting effects on the individual. Pb has also been implicated to exert changes across generations, impairing physiological traits as well as behavioral markers exerting an impairment in the health span. In this study, the developmental effect of environmental-relevant concentrations of Pb (0.01, 0.1, and 1 ppb; μg/L) were assessed in the F1 (multigenerational) and F2 (transgenerational) generations from an F0-exposed zebrafish (Danio rerio). Behavioral, oxidative, and lipid-profiling were assessed for these generations to identify changes inherited from developmental Pb contact. Behavioral assessments revealed an embryonic Pb exposure in the F0 generation led to significant hypolocomotion, anxiolytic- and anxiogenic-like behaviors, impaired social interaction, and reduced decision-making capacity in F1 larvae. On the other hand, minimal effects were observed in the F2 larvae. Lipidomic analysis indicated these behavioral phenotypes were associated with altered levels of sphingomyelins, phosphatidylcholines, and cholesterol esters, suggesting disrupted neuronal signaling and membrane homeostasis. Enzymatic alterations were related to glutathione metabolism and those might be driven by some mechanistic Pb-induced epigenetic modifications. Together, these findings provide evidence that low-level Pb exposure induces multigenerational neurobehavioral toxicity, mediated by lipidomic and redox pathway disruptions, with implications for long-term environmental health risk assessment.