Developmental exposure to Pb²⁺ induces transgenerational changes to zebrafish brain transcriptome

Lead (Pb²⁺) is a major public health hazard for urban children, with profound and well-characterized developmental and behavioral implications across the lifespan. The ability of early Pb²⁺ exposure to induce epigenetic changes is well-established, suggesting that Pb²⁺-induced neurobehavioral deficits may be heritable across generations. Understanding the long-term and multigenerational repercussions of lead exposure is crucial for clarifying both the genotypic alterations behind these behavioral outcomes and the potential mechanism of heritability. To study this, zebrafish (Danio rerio) embryos (<2 h post fertilization; EK strain) were exposed for 24 h to waterborne Pb²⁺ at a concentration of 10 μM. This exposed F₀ generation was raised to adulthood and spawned to produce the F₁ generation, which was subsequently spawned to produce the F₂ generation. Previous avoidance conditioning studies determined that a 10 μM Pb²⁺ dose resulted in learning impairments persisting through the F₂ generation. RNA was extracted from control- and 10 μM Pb²⁺-lineage F₂ brains, (n = 10 for each group), sequenced, and transcript expression was quantified utilizing Quant-Seq. 648 genes were differentially expressed in the brains of F₂ lead-lineage fish versus F₂ control-lineage fish. Pathway analysis revealed altered genes in processes including synaptic function and plasticity, neurogenesis, endocrine homeostasis, and epigenetic modification, all of which are implicated in lead-induced neurobehavioral deficits and/or their inheritance. These data will inform future investigations to elucidate the mechanism of adult-onset and transgenerational health effects of developmental lead exposure.