Abstract
Maternal smoking during pregnancy (MSDP) has been linked to adverse effects on offspring brain health. However, the underlying mechanisms remain unclear. Given that offspring exposed to MSDP exhibit shortened leukocyte telomere length (LTL)-a potential biomarker of accelerated biological ageing-we hypothesized that LTL may mediate the association between MSDP and long-term brain health consequences in adult offspring. Using data from the UK Biobank cohort, we performed association analyses to assess the effects of MSDP (almost 100 000 patients) on LTL, 363 imaging derived phenotypes (IDPs) from structural MRI, 11 kinds of cognitive performances, and 4 mental health outcomes in adult offspring. Mediation analysis was further conducted to evaluate whether LTL mediates the relationship between MSDP and these brain health outcomes. Offspring exposed to MSDP exhibited significantly shorter LTL, greater atrophy in 30 IDPs, poorer performance on 3 cognitive tests, and higher scores on 4 mental health questionnaires compared to unexposed offspring. Mediation analysis revealed that shortened LTL partially mediated the association between MSDP and atrophy in 11 IDPs-particularly in the hippocampus and its subregions-as well as reduced fluid intelligence performance and increased depressive symptoms. In conclusion, this study demonstrates that MSDP may contribute to long-term adverse brain health outcomes in adult offspring. Crucially, we identify accelerated telomere shortening as a partial mediator reflecting cumulative aging that partially explains the link between MSDP and specific adverse outcomes in adult offspring, particularly hippocampal atrophy, declines in fluid intelligence, and increased depressive symptoms. These results underscore the importance of reducing prenatal tobacco exposure to improve population-level brain health.