Early developmental exposure to lead (Pb) as a risk factor for stress-related disorders investigated in larval zebrafish (<i>Danio rerio</i>)

Lead (Pb) is a prevalent environmental contaminant and developmental neurotoxin associated with neurological, cognitive, and mental dysfunctions, including anxiety and depressive disorders. However, significant gaps remain in our understanding of its precise effects, the underlying mechanisms, and actionable levels of exposure. This study investigates the effects of exposure to environmentally relevant levels of Pb during a period of heightened nervous system development, focusing on alterations to acute behavioral stress responses and the molecular pathways regulating them. Altered acute stress responses indicate disruptions in the stress circuitry, creating a path to prioritizing chemical risk factors and understanding underlying mechanisms. We exposed enzymatically dechorionated zebrafish embryos to lead (II) acetate from 6 to 120 h post-fertilization (hpf). Our target concentrations folded from the actionable contaminant level in drinking water as set by the US Environmental Protection Agency (US EPA). At 120 hpf, we evaluated Pb-induced effects on survival, development, activity, and behavioral responses to acute visual and acoustic stressors, as well as to peripheral irritants. We also assessed changes in the transcript levels of molecular biomarkers for developmental neurotoxicity and anxiety-related disorders (AD). These exposures led to significant developmental defects, stress behavioral alterations, and abnormalities in pertinent gene expression. The stress behavioral alterations showed a first report of bimodal phenotypes in response to different stimuli and at regulatory levels. These phenotypes were not linked to locomotor deficits or morphological abnormalities. Environmental contamination as a risk factor for stress-related disorders remains an inadequately explored domain within toxicology. This study provides insights into the effects of early-life Pb exposure on behaviors regulated by the stress circuitry and genes associated with stress-related disorders. These findings provide further evidence of the association between Pb exposure and these debilitating conditions, highlighting the need for further in-depth molecular and neurophysiological studies.