Proposed Role of Prenatal Nicotine Exposure Induced TNF-α Signaling as an Upstream Contributor of Neurodegenerative Diseases: A Systematic Review

Background Tumor necrosis factor-alpha (TNF-α) regulates immune responses, neuroinflammatory signaling, and central nervous system (CNS) homeostasis. While physiological TNF-α signaling contributes to normal brain function, dysregulation of this pathway has been implicated in chronic neuroinflammation and neurodegenerative disease progression. Prenatal nicotine exposure (PNE) has been associated with persistent alterations in neuroimmune function, including microglial activationand disruption of TNF-α signaling pathways, potentially contributing to long-term neurological dysfunction.Methods A PubMed literature search was conducted using terms related to prenatal/maternal nicotine exposure, TNF-α, neuroinflammation, microglia, and neurodegenerative disease, following PRISMA guidelines. Peer-reviewed English-language studies published after 1985 that met predefined inclusion criteria were selected, yielding 134 articles.Results Preclinical and clinical studies indicate that PNE alters neuroimmune homeostasis through changes in inflammatory signaling, microglial function, and TNFR1/TNFR2-associated mechanisms. Dysregulated TNF-α signaling emerged as a shared feature across multiple neurodgenerative disorders, contributing to disease progression through distinct yet overlapping mechanisms involving neuroimmune dysfunction and chronic inflammatory signaling. Direct evidence connecting PNE-induced TNF-α dysregulation to the onset of these specific diseases, however, remains limited.Conclusion Current evidence supports a potential link between PNE and TNF-α-mediated neuroinflammation. Further research is needed to clarify the proposed underlying mechanisms connecting early-life nicotine exposure to long-term neurodegenerative risk, as well as their broader clinical and public health implications.