Chlorogenic Acid Alleviates Early-Life GenX Exposure-Induced Neurotoxicity via Decreasing Lipopolysaccharide-Induced Pyroptosis by the Systemic Translocation and Suppressing the PI3K/AKT/NF-κB Pathway

Abstract

Ammonium perfluoro (2-methyl-3-oxahexanoate) (GenX), a substitute for perfluorooctanoic acid, disrupts early-life intestinal homeostasis and impacts neurodevelopment. However, the mechanisms are unclear, and interventions are limited. In this study, pregnant mice were exposed to GenX (2 mg/kg/day) and chlorogenic acid (CGA, 30 mg/kg/day) from gestation day 0 to postnatal day 21. GenX exposure resulted in a significant reduction in birth length, body weight, and colon length in the pups as well as an infiltration of inflammatory cells, glandular atrophy, and a decrease in the number of goblet cells within the colon. Moreover, the expression of ZO-1, occludin, and claudin-5 decreased in the colon, indicating that exposure to GenX may have compromised intestinal barrier function. The GenX group exhibited increased levels of lipopolysaccharide (LPS) in both the serum and cortex, along with increased expression of NLRP3, GSDMD, GSDMD-N, IL-1β, IL-18, and Caspase-1 p10 in the colon and cortex, indicating pyroptosis activation. The elevated protein expression levels of inflammatory factors, including TNF-α, IFN-γ, COX-2, iNOS, p-PI3K, p-AKT, and p-NF-κB in the cortex, indicated the activation of the PI3K/AKT/NF-κB signaling pathway, contributing to the developmental neurotoxicity. CGA treatment improved intestinal barrier function and reduced LPS leakage and inflammation in the cortex, possibly by decreasing LPS translocation and pyroptosis. Taken together, CGA treatment effectively alleviated perinatal GenX exposure-induced intestinal homeostasis disruption and developmental neurotoxicity due to the LPS translocation and activation of pyroptosis.