Transgenerational Inheritance of Cognitive Deficits Induced by Ancestral Arsenic Exposure in Zebrafish (Danio rerio) via Maternal and Paternal Lineages

Exposure to arsenic is known to impair learning and memory functions in animal models and humans. However, the transgenerational inheritance of these cognitive deficits and the underlying epigenetic mechanisms remain poorly understood. The present study investigated the inter- and transgenerational effects of ancestral arsenic exposure on the cognitive performance (latent learning) of zebrafish via maternal and paternal lineages and the underlying biochemical and molecular alterations in the brain, including the DNA methylation patterns of cognition-related genes. Adult male zebrafish exposed to dietary arsenic [30, 60, or 100 μg/g as arsenite for 90 days; F0 generation] were crossed with unexposed (control) females and vice versa to generate F1 progeny of maternal and paternal arsenic exposure, respectively. Subsequently, F1 males and females of the same treatments were crossed to generate the F2 progeny of the respective maternal and paternal lineages of ancestral arsenic exposure. It was found that ancestral arsenic exposure induced cognitive dysfunction in F1 and F2 generations of both maternal and paternal lineages. However, the effects occurred at relatively lower levels of ancestral arsenic exposure (30 and 60 μg/g) in the former treatment relative to those (100 μg/g) in the latter. Inter (F1) and transgenerational (F2) cognitive effects of arsenic were associated with concomitant elevated oxidative stress and dopaminergic dysregulation, including repressed expression of cognition-related genes such as genes involved in dopamine signaling and metabolism (Drd1 and MAO) and the brain-derived neurotrophic factor (BDNF). Furthermore, DNA methylation analyses revealed that the downregulation of these genes across three generations (F0 to F2) resulted from the hypermethylation in their promotor regions (Drd1, MAO, BDNF). Collectively, these observations provide novel insights into the epigenetic mechanisms of the transgenerational inheritance of arsenic neurotoxicity.