Prenatal PM exposure contributes to neuronal tau lesion in male offspring mice through mitochondrial dysfunction-mediated insulin resistance.

The epidemiological evidence has linked prenatal exposure to fine particulate matter (PM) pollution with neurological diseases in offspring. However, the biological process and toxicological mechanisms remain unclear. Tau protein is a neuronal microtubule-associated protein expressed in fetal brain and plays a critical role in mediating neuronal development. Aberrant expression of tau is associated with adverse neurodevelopmental outcomes. To study whether prenatal exposure to PM pollution induce tau lesion in mice offspring and elucidate the underlying pathogenic mechanism, we exposed pregnant mice to PM (3 mg/kg b.w.) by oropharyngeal aspiration every other day. The results indicate that prenatal PM exposure induced hyperphosphorylation of tau in the cortex of postnatal male offspring, which was accompanied by insulin resistance through the IRS-1/PI3K/AKT signaling pathway. Importantly, we further found that prenatal PM exposure induced mitochondrial dysfunction by disrupting mitochondrial ultrastructure and decreasing the expression of rate-limiting enzymes (CS, IDH2 and FH) in the Krebs cycle and the subunits of mitochondrial complex IV and V (CO1, CO4, ATP6, and ATP8) during postnatal neurodevelopment. The findings suggest that prenatal PM exposure could induce tauopathy-like changes in male offspring, in which mitochondrial dysfunction-induced insulin resistance might play an important role.