Activation of anti-inflammatory pathways by polyunsaturated fatty acid signaling may protect neurodevelopment in children prenatally exposed to methylmercury

Abstract Background Mercury is ubiquitous in the environment. Substantial levels of its organic form, methylmercury, pose a risk to fetal neurodevelopment through the maternal diet. Conversely, nutrients such as the polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) promote neurodevelopment. We aimed to elucidate the neuroprotective role of PUFA signaling against prenatal methylmercury exposure in a Mediterranean fish-consuming area, addressing a critical gap in understanding nutritional modulation of neurotoxicity. Methods Associations between levels of oxidized PUFA metabolites (oxylipins) in placental tissue ( N = 12) or cord blood plasma ( N = 39) and postnatal neurodevelopment in children were evaluated at two levels of prenatal mercury exposure. Low and moderate exposure groups were defined by total mercury concentrations in whole cord blood of 1.4–6.6 µg/L and 20–66 µg/L, respectively. Oxylipins were measured using liquid chromatography ­ mass spectrometry. Neurodevelopment was assessed at 14 months and 5 years using Bayley and McCarthy scales, respectively. Oxylipins were also analyzed in mouse brain tissue after treatment with a soluble epoxide hydrolase inhibitor to increase AA epoxide levels. Results Under low mercury exposure, EPA-, DHA- and AA-derived placental oxylipins showed positive Spearman correlations with 14-month scores. In cord blood plasma, AA epoxides correlated positively with cognitive parameters at both ages under moderate exposure. Multivariate linear regression revealed positive associations between anti-inflammatory AA-derived epoxides and neurodevelopmental scores across tissues and ages, and between a DHA oxylipin in cord blood plasma and 14-month scores. No neurodevelopmental delays were observed in the moderate exposure group compared to the low exposure group. Oxylipin levels exhibited a more anti-inflammatory profile in samples from the moderate exposure group. Additionally, the brain oxylipin profile of mice treated with an AA epoxide enhancer indicated reduced inflammation. Conclusions PUFA signaling dynamics revealed potential protective pathways against methylmercury-induced neurodevelopmental toxicity. Differential oxylipin modulation, together with the absence of neurodevelopmental delays, underscores the importance of a maternal diet rich in anti-inflammatory PUFAs for children at risk of cognitive impairment due to prenatal methylmercury exposure.