Environmental Factor-Mediated Transgenerational Inheritance of Igf2r Hypomethylation and Pulmonary Allergic Response via Targeting Dendritic Cells

Abstract

The developmental origin of allergic diseases has been suggested, but the molecular basis remains enigmatic. Exposure to environmental factors, such as di-(2-ethylhexyl) phthalate (DEHP; a common plasticizer), is suggested to be associated with increased childhood allergic asthma, but the causal relationship and its underlying mechanism remain unknown. This study explored the transgenerational mechanism of DEHP on allergic asthma and dendritic cell (DC) homeostasis through epigenetic modification. In a murine model, ancestral exposure of C57BL/6 mice to low-dose DEHP led to trans-generational promoter hypomethylation of the insulin-like growth factor 2 receptor (Igf2r), concomitant with enhanced Igf2r expression and increased apoptosis prominently in CD8α+ DCs upon ligand stimulation, with consequent reduction in their IL-12 secretion and subsequent T cell-derived IFN-γ, thereby promoting a default Th2-associated pulmonary allergic response. Increased apoptosis was also noted in circulating IGF2Rhigh human DCs. Further, in human placenta, the methylation level at the orthologous IGF2R promoter region was shown to be inversely correlated with the level of maternal DEHP intake. These results support the importance of ancestral phthalate exposure in conferring the trans-generational risk of allergic phenotypes, featuring hypo-methylation of the IGF2R gene and dysregulated DC homeostasis.

Phthalate Exposure Pattern in Breast Milk within a Six-Month Postpartum Time in Southern Taiwan

“…It seems that the fetus is most sensitive to the anti-androgenic effect of phthalates during development [ 52 ]. In addition, our recent study showed that chronic exposure to low-dose DEHP in pregnant dams significantly enhanced allergic lung inflammation in young offspring through at least four generations [ 53 ]. Taken together, considering the potential MEHP modulatory effect on neonates, the DEHP daily intake of newborns should be considered.…”

Corylin Ameliorates LPS-Induced Acute Lung Injury via Suppressing the MAPKs and IL-6/STAT3 Signaling Pathways

“…The staining panel for immune cell subsets in BALF was designed according to previous studies [44,45]. Briefly, the BALF cells were stained with fluorochrome-conjugated monoclonal antibodies at 4 • C for 30 min.…”

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

“…The exact mechanism(s) of how epigenetics makes the lungs more vulnerable to develop chronic inflammatory diseases later in life remains to be identified. Importantly, some of these epigenetic events can be handed down over several generations and seem to mimic genetic inheritance [106][107][108] (Figure 3).…”

“…The exact mechanism(s) of how epigenetics makes the lungs more vulnerable to develop chronic inflammatory diseases later in life remains to be identified. Importantly, some of these epigenetic events can be handed down over several generations and seem to mimic genetic inheritance [106][107][108] (Figure 3). Parental asthma, especially of mothers, is a well-recognized risk factor for childhood asthma, which cannot be fully explained by genetics or the shared environmental factors [109,110].…”