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.
Highlights
Accumulated epidemiological evidence has suggested that the changing environment and modern life style influence the fetal immune development and may contribute to the recent epidemic rise of allergic diseases, including asthma, and other immunological diseases as well
Allergic asthma is mediated by T helper type 2 (Th2)dominant immune response, leading to lung inflammation and remodeling [13], and emerging evidence from various animal models has suggested that environmental risk factors may modify the epigenome and influence the disease susceptibility [14, 15], where neonatal dendritic cells (DCs) and T cells could be the target for the maternal transmission of allergic phenotypes [16, 17], furthering the support for the importance of maternal phthalate exposure on the development of allergic diseases
To test for the transgenerational impact of di-(2-ethylhexyl) phthalate (DEHP) exposure, F0 dams were daily exposed to human tolerable daily intake (TDI) dose of DEHP ten days prior to mating and during the periods of pregnancy and breastfeeding, and the offspring were subjected to a wellestablished OVA–induced asthma mouse model without being further exposed to DEHP (Supplementary Figure 1)
Summary
Accumulated epidemiological evidence has suggested that the changing environment and modern life style influence the fetal immune development and may contribute to the recent epidemic rise of allergic diseases, including asthma, and other immunological diseases as well. Maternal exposure to environmental pollutants, such as allergens [4], air pollution [5], and tobacco smoke [6, 7], increases the disease risk via its potential impact on neonatal immune system. Allergic asthma is mediated by T helper type 2 (Th2)dominant immune response, leading to lung inflammation and remodeling [13], and emerging evidence from various animal models has suggested that environmental risk factors may modify the epigenome and influence the disease susceptibility [14, 15], where neonatal dendritic cells (DCs) and T cells could be the target for the maternal transmission of allergic phenotypes [16, 17], furthering the support for the importance of maternal phthalate exposure on the development of allergic diseases. The impact of environmental exposure at physiological dosage relevant to the human exposure level has rarely been evaluated and the functional relevance of epigenetically modified genes remains to be defined, as well as the issue regarding whether it is merely an inter-generational (parental) effect or a bona fide transgenerational epigenetic inheritance remains unresolved
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