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Assessment of Skeletal Malformations associated with Embryonic Toxicant Exposure


Tobacco use during pregnancy poses many risks to reproductive health and unborn life. Children exposed to tobacco in utero grow up to experience abnormalities ranging from cognitive or developmental deficits to malformations of the skeleton, such as cleft lip and palate, as well as an increased risk of fractures following minor injuries. While numerous studies demonstrate the adverse effects of tobacco-related products towards human health and developing embryos, the molecular underpinnings of embryonic skeletal maldevelopment remain unclear largely due to the inadequacy of existing model systems. Moreover, new tobacco products are still being introduced into the market, despite fervent public health initiatives. One such product is Snus, a non-combustible chewing type of tobacco. Snus received clearance to be advertised as a harm-reduction product, and hence would be an attractive alternative to pregnant smokers unable to quit. Yet here we provide evidence that Snus might not be free of all harm. Our lab has previously found a robust and reproducible hypomineralized phenotype in multiple bones of mice and zebrafish when exposed to smoke extracts of Snus tobacco during development. This phenotype of reduced calcification can also be detected when human embryonic stem cells (hESCs) are exposed during differentiation to bone-forming osteoblasts, thereby providing an adequate human in vitro model to study tobacco-exposure-mediated hypomineralization.This hESC model will serve as the primary relevancy to human health to expose the negative implications of tobacco, primarily Snus, on prenatal bone health and work to negate the changes in the osteogenic molecular framework caused by Snus tobacco exposure. By extension, new insight on the molecular mechanism of tobacco-induced hypomineralization has implications beyond specific Snus exposure. This work could provide a solid framework for future analyses of human genetic traits that increase the risk for congenital skeletal diseases. As a result, new guidelines could be implemented by the American Academy of Pediatrics for pediatricians to conduct well-childcare exams in which pre-visit questionnaires include questions on the type of tobacco the child was/is exposed to. After exposure is confirmed, bone health and quality should be routinely assessed, appropriate parental education executed, and fracture prevention strategies discussed with the family.

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