Micro- and nanoplastics and brain sexual differentiation: An emerging neurodevelopmental threat within the DOHaD framework

Micro- and nanoplastics (MNPs) have been increasingly detected in human tissues, including the placenta and, more recently, the brain. Their capacity to cross biological barriers such as the placenta and the blood-brain barrier raises significant concern for sexually dimorphic neurodevelopment. Brain sexual differentiation, orchestrated by steroid hormones, neuroimmune signaling, and epigenetic programming during early life, represents one of the most hormonally sensitive and developmentally critical targets of environmental disruption. In this narrative review, we synthesize evidence positioning MNPs as potential endocrine and epigenetic disruptors that may reprogram hypothalamic circuits governing reproduction and socioemotional behavior within a DOHaD framework. Evidence is stronger in animal and cellular models, implicating oxidative stress, neuroinflammation, apoptosis, and disrupted neurotransmission as central mechanisms; however, sex-specific endpoints remain underexplored and human data are still limited. This review adds a novel integrative perspective by focusing on sexually dimorphic hypothalamic nuclei and by outlining testable, sex-informed hypotheses. We highlight key methodological priorities for future research, including environmentally relevant exposures, explicit consideration of sex as a biological variable, multi-omics approaches, and longitudinal designs.