Life-long epigenetic programming of cortical architecture by maternal ‘Western’ diet during pregnancy

Female C57BL/6J mice, ~6 weeks old, randomly assigned to ω-6 PUFA-enriched hypercaloric diet or standard chow; timed matings; embryos collected at embryonic day 18.5; adult offspring tested at postnatal day 75; transgenic CCKBAC/DsRed mice used to label interneurons; EdU labeling used in programming protocol; not blinded; n ≥ 5 pregnancies per group.

Hypercaloric diet enriched ~15-fold in ω-6 PUFAs (linoleic acid and arachidonic acid), with ~31% of total fatty acids and ω-3:ω-6 ratio of 1:8; started 2 weeks before conception or 8 weeks before conception and continued through pregnancy; delivered ad libitum via feed.

Excess maternal ω-6 PUFA intake during pregnancy reprograms fetal cortical development via endocannabinoid signaling, desensitizing CB1 receptors and epigenetically repressing transcriptional networks that drive neuronal differentiation. This causes misplacement of cortical neurons, altered axon organization, and downregulation of IgCAMs (e.g., LSAMP, L1CAM, NCAM, neurotrimin). Epigenetic changes include DNA methylation increases and reduced chromatin accessibility at STAT3, MYB, and CEBPB target regions; 1,423 differential chromatin-accessible regions identified. In adulthood, offspring show sustained increases in brain 2-AG, reduced CB1 receptor density, persistent LSAMP mislocalization, and anxiety- and depression-like behaviors. Authors conclude maternal diet can causally shape lifelong brain function through endocannabinoid-mediated epigenetic reprogramming and advocate balancing ω-3 and ω-6 PUFA intake during pregnancy to mitigate neurodevelopmental and emotional disorder risk.

Not blinded; some analyses relied on male offspring and a single mouse strain (C57BL/6J); relatively small sample sizes for certain measurements; timing and duration of ω-6 PUFA exposure not pinpointed to a precise developmental window; translational relevance to humans remains to be established.