Nanoplastics Impair GnRH Neuron Migration and Neuroendocrine Function: Emerging Players in the Pathogenesis of...

Nanoplastics (NPs) pose an emerging threat to environmental and human health. Still, the impacts of NPs on the endocrine control of reproduction remain poorly understood, despite increasing trends of infertility worldwide. In mammals, reproductive function relies on the hypothalamus-pituitary-gonadal axis, centrally regulated by gonadotropin-releasing hormone (GnRH) neurons. Disruption in GnRH neuron development or function leads to GnRH deficiency (GD), a genetic condition presenting delayed puberty and infertility. Yet, genetic causes explain only ∼50% of GD cases, suggesting a role for environmental factors in disease etiology. Here, we investigate NP effects on GnRH neuron biology by applying two established in vitro models: hormone-secreting GT1-7 cells and migrating GN11 cells. We show that NPs enter cells via non-classical endocytosis, alter neuroendocrine function in GT1-7 cells, and impair migration in GN11 cells. Transcriptomic analysis of NP-exposed GN11 cells reveals differential expression of key genes linked to GnRH neuron development. Moreover, integrating these findings with exome sequencing data from patients with GD identifies rare NPAS2 variants in two males with severe pubertal delay. These results suggest that PS-NPs disrupt key physiological functions of GnRH neurons and may act as novel endocrine disruptors, contributing to the pathogenesis of reproductive disorders.