Germline and Embryonic Mechanisms in the Epigenetic Inheritance of Neurodevelopmental and Cognitive Traits in Mammals.

Epigenetic mechanisms profoundly regulate gene expression, developmental trajectories, and phenotypic variation, extending biological influence beyond DNA sequence alone. A growing body of evidence suggests that environmental exposures, including pollutants, drugs, stress, and diet, can induce germline and early embryonic epimutations that alter developmental programs with lasting consequences for neurodevelopmental and cognitive outcomes. However, the fields most relevant to these processes have largely developed independently. These include germline epigenetics, early embryonic patterning, neurodevelopment and cognitive regulation, and intergenerational or transgenerational inheritance. Each field has its own conceptual frameworks and mechanistic models. This fragmentation obscures the biological reality that these systems are tightly interconnected: environmentally induced epigenetic perturbations in gametes can reshape the epigenetic landscape of the early embryo, influence lineage allocation during gastrulation, and ultimately modify the molecular architecture of the developing central nervous system. A systems-biology perspective capable of linking germline epimutations and early embryonic epigenetic instability to later neurodevelopmental and cognitive phenotypes and their potential inheritance is therefore required. This review synthesizes current evidence across these traditionally isolated domains and proposes a coherent mechanistic framework linking germ cell epimutations and early embryonic epigenetic instability to the emergence of neurodevelopmental and cognitive phenotypes. By bridging these conceptual gaps, we aim to establish a cohesive foundation for understanding how early epigenetic disruptions generate long-lasting and in some cases heritable effects on brain development and cognitive function.