Zinc oxide nanoparticles exposure disrupts brain redox-inflammatory-epigenetic axis and impairs PI3K/Akt survival pathway in male offspring.

Abstract

Widespread use of Zinc Oxide Nanoparticles (ZnO NPs) raises concerns about potential health risks, particularly following maternal exposure during critical developmental windows. The impact of exposure on offspring brain development remains unclear. The work aims to investigate the neurodevelopmental consequences of maternal ZnO NP exposure during gestation, lactation, or both periods in male rat offspring. Pregnant rats were administered ZnO NPs (< 100 nm) or vehicle. Offspring developmental parameters and brain tissues were analyzed at postnatal day 60. Assessments included oxidative stress markers (8-OHdG, MDA, NO), antioxidant (GSH, GST, GPX, SOD, CAT), cholinergic function (AChE), epigenetic markers (DNA methylation, BDNF promoter methylation, miR-34a, miR-29b), neurodegeneration-associated proteins (Aβ1-42, Tau), survival/inflammatory signaling pathways (p-Akt, PI3K mRNA, ERK, Bcl-2, COX2, IL-1β, TNF-α, IL-2, TGF-β), apoptosis (Caspase-3), BDNF mRNA, and brain histology. Maternal ZnO NP exposure significantly reduced offspring brain weight, body weight, and survival index, particularly following combined gestational and lactational exposure. Exposed offspring brains exhibited increased oxidative stress, depleted antioxidant defenses, impaired AChE activity, global DNA hypomethylation with targeted BDNF promoter hypermethylation (correlating with reduced BDNF mRNA), increased Aβ1-42 and Tau accumulation, suppressed PI3K/p-Akt and ERK survival signaling, elevated pro-inflammatory markers (IL-1β, TNF-α, IL-2, COX2, TGF-β), increased apoptosis (Caspase-3) alongside decreased Bcl-2, and dysregulated miRNA expression (increased miR-34a, decreased miR-29b). Histology confirmed duration-dependent neuronal damage. Maternal ZnO NP exposure induces persistent offspring neurotoxicity via oxidative stress, neuroinflammation, apoptosis, and epigenetic dysregulation. This highlights developmental brain vulnerability and the importance of assessing maternal nanoparticle exposure.