Early-life Exposure to Arsenic Primes the Offspring to Increased Asthma Risk: Transcriptome and Epigenome Analysis
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Inorganic arsenic (iAs) in drinking water is a global health concern. This study tests whether maternal exposure to iAs in drinking water at the WHO provisional level (10µg/L) increases offspring asthma risk via epigenetic reprogramming. F1 mice prenatally exposed to iAs were analyzed at 5 months for blood transcriptome and methylome changes and challenged with house allergens before lung function testing. Prenatal iAs exposure led to increased airway hyperresponsiveness (AHR) and altered inflammation gene expression and DNA methylation changes. Notably, miR-101c was epigenetically reprogrammed early in development, with persistent downregulation in both target (fetal and adult lungs) and surrogate (amniotic fluid and blood) tissues. These changes correlated with increased allergic AHR and TGFβ pathway dysregulation. Findings suggest that maternal iAs exposure primes offspring for asthma risk through epigenetic alterations and may inform risk assessment and biomarker development in affected communities.
KEY FINDINGS
In utero exposure to 10 part per billion (or 10 µg/L, the current WHO and EPA provisional level in drinking water) inorganic arsenic (iAs) increases offspring asthma risk. These results raise concerns about the current safety thresholds for iAs in drinking water (Fig. 1).
Transcriptomic and methylome analyses of blood leukocytes from 5-month-old F1 mice revealed that maternal iAs exposure induces transcriptional changes in genes related to allergic airway responses. Pathway analysis highlighted the involvement of miR-101c and its connection with TGFβ downstream targets in regulating extracellular matrix signaling, embryonic development, and inflammatory (Figs. 2 and 3).
Transcriptional changes in c ol3a1 and miR-101c in blood were strongly correlated with allergen-induced airway hyperresponsiveness (AHR), with similar alterations detected in plasma samples. These findings provide new insights into respiratory health in affected communities and support the development of biomarkers for iAs risk assessment (Figs. 4 and 5).
Several gene-specific epigenetic alterations induced by early-life iAs exposure were consistently observed in both surrogate (blood) and target (lung) tissues across developmental stages, offering new panels of easily accessible markers for early detection and monitoring of lung disease risk in offspring. The persistence of these markers over time makes them valuable for predictive modeling and life course studies. (Fig. 6).
Downregulation of miR-101c was validated in fetal lung and amniotic fluid of the iAs-exposed group, suggesting that epigenetic reprogramming of miR-101c is initiated early in gestation (Fig. 7). These findings help uncover causal pathways linking environmental exposures to asthma pathogenesis.
Distinct sex-specific patterns in blood transcriptome and methylome alterations in respond to early-life iAs exposure underscore the importance of considering sex as a biological variable in omics research.
GRAPHIC ABSTRACT
Description: F1 progeny prenatally exposed to iAs were assessed for blood transcriptomic and DNA methylome analysis at 5 months of age. Correlation analysis between transcriptional changes and allergen-induced airway hyperresponsiveness (AHR) was conducted to examine the epigenetic impact of maternal iAs exposure on offspring asthma risk.
