Beyond Infections: Exploring Immune-Mediated Pathways Linking Cannabis and Emerging Environmental Contaminants to Neurodevelopmental Outcomes.

The development of the brain is a highly coordinated process that begins early in gestation and relies on intricate interactions between maternal and fetal immune systems. Disruptions to this delicate prenatal immune environment can significantly impact fetal brain development, increasing the risk of a spectrum of neurological and behavioral disorders, including autism spectrum disorder (ASD), schizophrenia, depression, and anxiety. While maternal exposure to viral and bacterial infections has been extensively studied as a driver of these disruptions, emerging research highlights the potential role of non-infectious exposures-such as drugs of abuse and environmental contaminants-in shaping neurodevelopmental outcomes. This issue has gained urgency with the rising prevalence of neurodevelopmental disorders; in the United States, for instance, ASD diagnoses have surged from 1 in 150 children in the early 2000s to 1 in 36 by 2020. Within this context, the increasing detection of cannabis, micro- and nanoplastics (MPs/NPs), and flame retardants in maternal and fetal tissues warrants close scrutiny. These substances, which are growing in prevalence due to changing societal norms, widespread environmental pollution, and industrial practices, may disrupt neurodevelopment through immune-mediated mechanisms. Cannabis use during pregnancy, for example, has increased significantly with legalization, while MPs/NPs and flame retardants are now frequently detected in maternal blood, placenta, and breast milk, raising concerns about their impacts on fetal health. In this chapter, we summarize human and preclinical evidence to explore how perinatal exposure to these substances may alter neurodevelopment by disrupting maternal and/or fetal immunity. We begin with an overview of central nervous system development and the critical role of immune interactions in ensuring a healthy pregnancy. We then review evidence linking perinatal exposure to cannabis, MPs/NPs, and flame retardants to neurodevelopmental outcomes, emphasizing immune-mediated pathways such as alterations in cytokine production, microglial activation, and adaptive immune cell function. Finally, we identify key gaps in the literature and propose future research directions to better understand the complex interplay between environmental exposures, immune dysregulation, and neurodevelopmental outcomes.