High levels of anti-inflammatory epoxyeicosatrienoic acids may improve neurodevelopment in children prenatally exposed to mercury

A balanced concentration of polyunsaturated fatty acids (PUFA) in the prenatal stage is essential for children¿s neurodevelopment. Also, animal studies showed that high levels of anti-inflammatory PUFA metabolites in the embryonic brain protect against genetic or environmental insults that would otherwise cause cognitive impairment. Here we used liquid chromatography - mass spectrometry to analyze oxylipins, the oxygenated metabolites of PUFA, in the placenta tissue (N=12) and cord blood plasma (N=39) of children from the INMA cohort (Valencia, Spain). Both tissues were characterized for total Hg levels as a reference for developmental neurotoxic MeHg exposure during pregnancy and distributed in low and high Hg groups. Deleterious effects of high Hg were confirmed in the placenta as decreased proteasome activity and inhibitory epigenetic changes. Children¿s neurodevelopment was assessed using the Bayley (14 months) and McCarthy (5 years) scales. Spearman correlation coefficients were calculated between scores and oxylipin levels. We also analyzed cortical brain tissue from wild type and transgenic Alzheimer's disease (5XFAD) mice dosed for 2 months with vehicle or a soluble epoxide hydrolase enzyme (sEH) inhibitor, UB-BJ-02 (5 mg/Kg, N=5/group). Inhibition of sEH increases levels of the potent anti-inflammatory epoxyeicosatrienoic acids (EETs) by inhibiting their hydrolysis to dihydro-EETs (DiHETs). We found that DiHETs were increased in the placenta of high Hg group. Furthermore, the mental and psychomotor development of 14-month-old children correlates positively with DiHETs levels in both placenta and cord blood tissues. Interestingly, cord blood DiEHTs positively correlate with working memory at 5 years. Thus we suggest that higher levels of DiHETs indicate higher synthesis of their anti-inflammatory EETs precursors. Accordingly, placenta levels of EETs correlate with mental development at 14 months of age. Other oxylipin changes also suggested an involvement of