Maternal Metabolic Syndrome Impairs Offspring Neurodevelopment, Behavior and Metabolism with Sexual Dimorphism

Introduction: Maternal metabolic syndrome (MetS) can profoundly impact offspring development. This study aimed to evaluate the effects of maternal MetS on somatic growth, developmental milestones, neurochemical and metabolic alterations, and behavior using an animal model.

Methods: Female Wistar rats were given 20% fructose in drinking water before and during pregnancy to induce MetS, while the control group consumed only water. Offspring were assessed for biochemical markers in whole-brain tissue at postnatal day (PN) 1 and for somatic development and developmental milestones from birth to PN21. Behavioral tests evaluating anxiety-like behavior, cognition, nociception, and social interactions were conducted in adolescence and early adulthood. Metabolic status was assessed at PN100.

Results: At PN1, female MetS offspring exhibited increased lipid peroxidation (TBARS levels), heightened antioxidant enzyme activity (catalase) and expression (superoxide dismutase), and elevated pro-inflammatory COX-2 expression in whole-brain tissue. Neurodevelopmental delays were observed in females (delayed grasp reflexes, cliff aversion, plantar reflex, and righting reflex) and males (delayed forelimb grasp and plantar reflex). Behaviorally, female MetS offspring displayed increased anxiety-like behavior, impaired social interactions, heightened neophobia, and altered nociception, while males exhibited cognitive deficits and social interaction impairments. Additionally, female MetS offspring showed prolonged latency in the nocifensive tail flick response to thermal stimuli, indicating altered pain sensitivity. At PN100, female MetS offspring exhibited increased visceral fat accumulation and elevated triglyceride levels, suggesting long-term metabolic disturbances.

Conclusion: Maternal MetS disrupts offspring development, leading to early biochemical imbalances, neurodevelopmental delays, and long-term metabolic dysfunction. These effects were sex-dependent, with females showing greater oxidative stress, inflammation, anxiety, and metabolic alterations, while males exhibited milder but significant neurodevelopmental and cognitive impairments. These findings underscore the long-lasting impact of maternal MetS on offspring health and highlight the need for early interventions to mitigate neurodevelopmental and metabolic risks.