Activation of Inflammation/NF-κB Signaling in Infants Born to Arsenic-Exposed Mothers

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Abstract
The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothers experienced varying levels of arsenic exposure during pregnancy. Through the application of machine learning–based two-class prediction algorithms, we identified expression signatures from babies born to arsenic-unexposed and -exposed mothers that were highly predictive of prenatal arsenic exposure in a subsequent test population. Furthermore, 11 transcripts were identified that captured the maximal predictive capacity to classify prenatal arsenic exposure. Network analysis of the arsenic-modulated transcripts identified the activation of extensive molecular networks that are indicative of stress, inflammation, metal exposure, and apoptosis in the newborn. Exposure to arsenic is an important health hazard both in the United States and around the world, and is associated with increased risk for several types of cancer and other chronic diseases. These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood. Arsenic is an environmental pollutant and known human carcinogen. Chronic exposure to arsenic-contaminated water is an important public health hazard around the world, including the United States, with millions exposed to drinking water with levels that far exceed World Health Organization (WHO) guidelines. Given the implications of prenatal exposure on human health and the known public health hazard of chronic arsenic exposure, this study was aimed at establishing the extent to which maternal arsenic exposure in a human population affects newborn gene expression. The authors show that prenatal arsenic exposure in a human population results in alarming gene expression changes in newborn babies. The gene expression changes monitored in babies born to mothers exposed to arsenic during pregnancy are highly predictive of prenatal arsenic exposure in a subsequent test population. The study establishes a subset of just 11 transcripts that captured maximal predictive capability that could prove promising as genetic biomarkers of prenatal arsenic exposure. Pathway analysis of the genome-wide response in the babies exposed to arsenic in utero indicates robust activation of an integrated network of pathways involving NF-κB, inflammation, cell proliferation, stress, and apoptosis. This study contributes to our understanding of biological responses to arsenic exposure.