Ferulic acid exerts Nrf2-dependent protection against prenatal lead exposure-induced cognitive impairment in offspring mice

Prenatal and/or early postnatal exposure to lead (Pb) may be associated with deficits in cognitive function in the toddler offspring, and oxidative stress likely play a central role in mediating these adverse effects. Here, we tested the hypothesis that ameliorative effect of ferulic acid (FA) on lead-induced cognitive deficits attributed to its antioxidant properties in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent manner in the context of prenatal Pb exposure. To test this hypothesis, Nrf2 knockout and C57BL/6 wild type mouse dams were exposed/unexposed to PbAc (250 ppm) during gestation day 5 to postnatal day 14 via drinking water, and FA (50 mg/kg)/vehicle was administered orally to dams for 31 d. Spatial learning and memory in pups was assessed by Morris water maze. Biochemical assays, real-time PCR, western blot techniques were employed to evaluate oxidative stress and signaling pathways in the brain of pups. We report that lead acetate (PbAc) leads to deficits in cognitive functions in offspring, which were partially attenuated by FA (P<.05). In parallel, pretreatment with FA also significantly inhibited the PbAc-induced oxidative stress, as indicated by a change in NAD+/NADH ratio, glutathione (GSH) and malondialdehyde contents (all P<.05). Interestingly, FA significantly elevated the glutamate cysteine ligase and heme oxygenase 1 at levels of transcription and translation in both mice exposed and unexposed to Pb, increasing de novo synthesis of GSH (all P<.05). Furthermore, maternal FA administration activates extracellular signal-regulated kinases 1 and 2 and promotes more Nrf2 nuclear accumulation by increasing the Nrf2 total protein in brain of offspring mice (all P<.05). Conversely, FA failed to influence Pb-induced both memory deficits and oxidative stress in offspring of Nrf2 knockout mice (all P≥.05), suggesting that Nrf2 is essential in mediating the cognition-enhancing and antioxidant effects of FA. Overall, our results demonstrate that FA protects against Pb-induced offspring's cognitive deficits, suggesting that it is a promising candidate for the treatment of Pb toxicity.