Placental Ferroptosis May Be Involved in Prenatal Arsenic Exposure Induced Cognitive Impairment in Offspring.

Abstract

The association between prenatal arsenic (As) exposure and offspring's cognition is still unclear, and the underlying etiology has also not been elucidated. Based on the Ma'anshan Birth Cohort (MABC) study in China, 1814 mother-child pairs were included in this study, and the association of As levels in cord serum with preschoolers' intelligence scores was explored. To validate the results from population study, in vivo models were adopted to observe the association between prenatal As exposure and spatial learning and memory abilities of mice offsprings. The As-exposure induced ferroptosis in the placenta of human beings as well as C57BL/6 J mice and HTR-8/SVneo cells was explored in order to clarify the potential cause of impairment of offspring's cognition related to As exposure, respectively. In the population study, we observed a significant inverse association between natural logarithm transformed (ln) As levels and preschoolers' intelligence scores, especially for the fluid reasoning index (FRI) [(β (95%CI): - 1.07 (- 1.98, - 0.16)] and working memory index (WMI) [β (95%CI): - 1.51 (- 2.76, - 0.25)]. Meanwhile, the data from in vivo models revealed that the learning and memory abilities of offspring mice decreased after prenatal As exposure. The occurrence of ferroptosis-like characteristics in the placenta and HTR-8/SVneo cells after As exposure was observed, accompanying with evident oxidative stress, iron accumulation, mitochondrial damage, and decreased protein levels of GPX4, xCT, and FTH1 (or FPN1). Notably, the ferroptosis-like alterations induced by NaAsO₂ can be effectively alleviated by N-acetylcysteine (NAC) and ferrostatin-1 (Fer-1) treatment in HTR-8/SVneo cells, respectively. In conclusion, prenatal As exposure associates with impairment of offspring's cognition, and placental ferroptosis may be involved in the association. Further studies are needed to confirm the findings.