Chronic Low-Dose Cadmium Exposure Impairs Adult Hippocampal Neurogenesis by Suppressing Noncanonical Wnt5a Signaling

Cadmium (Cd) is a pervasive environmental heavy metal associated with impaired hippocampal neurogenesis, yet the molecular mechanisms linking chronic low-dose exposure to disrupted neuronal differentiation remain incompletely understood. In particular, whether noncanonical Wnt5a signaling, a pathway implicated in neural stem cell (NSC) lineage commitment and neuronal maturation, contributes to Cd-induced neurogenic deficits remains not fully elucidated. Here, using primary mouse NSCs derived from the subgranular zone (SGZ) and a chronic low-dose Cd-exposed mouse model, we investigated the effects of Cd on noncanonical Wnt5a signaling and adult hippocampal neurogenesis (AHN). We found that long-term Cd exposure suppresses multiple components of the noncanonical Wnt5a signaling cascade, including Wnt5a, its receptors Fzd2/3, the coreceptor Ror2, and downstream effectors RhoA, PKC, and JNK. This suppression was accompanied by reduced differentiation of NSCs into DCX⁺ immature neurons and decreased neuronal structural complexity both in vitro and in vivo. Functional rescue experiments further demonstrated that recombinant Wnt5a treatment partially restored neuronal differentiation and morphological complexity, whereas lentiviral-mediated Wnt5a overexpression more effectively reversed Cd-induced deficits and reactivated downstream signaling. Together, these results provide converging evidence that disruption of noncanonical Wnt5a signaling contributes to impaired SGZ-derived NSC differentiation under chronic Cd exposure. This study offers mechanistic insight into Cd-induced neurotoxicity and identifies Wnt5a signaling as a potential molecular target for mitigating environmentally relevant Cd-associated neurogenic dysfunction.