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Long non-coding RNAs and environmental health: a role in linking early life phthalate exposure to allergies and asthmaDubourg, Virginie 25 September 2019 (has links)
Allergies and asthma result from immune responses to common environmental antigens. Despite the fact that both diseases have been described as having a strong genetic background, influences by environmental factors are not negligible. In fact, direct exposure to environmental pollutants (e.g tobacco
smoke or chemicals) has already been associated with the development of such diseases and pieces of evidence pile up that early life exposure to these substances is critical. The group of chemicals called 'phthalates' are classified among the incriminated substances. Long non-coding RNAs (lncRNAs) are
part of the cellular elements that can be influenced by such exposure. They have been extensively studied over the last decade, highlighting potential roles in both normal and pathological cell functions, and have been associated with various diseases including some immune-related ones such as allergic reactions. Nevertheless, the role they play in environmental health still requires to be clarified.
Maternal exposure to benzyl butyl phthalate (BzBP), a chemical from the phthalate family present in daily-life products (e.g. vinyl flooring, adhesives), has been associated with allergies and asthma development in cohort studies. The underlying cellular mechanisms remain nonetheless mostly unknown. Because the immune cells T helper (TH) and B cells are key actors in such pathologies, we hypothesized that maternal exposure to BzBP may have an impact on asthma and allergy development by affecting these cells. The present study therefore focused on the effect of maternal exposure to BzBP on TH and B cells, with a particular interest in BzBP-induced changes in lncRNAs expression, motivated by their
cellular functions and their putative responsiveness to chemicals.
Using a murine model and RNA-sequencing, we observed that perinatal (during pregnancy and breastfeeding) and prenatal (pregnancy only) exposure to BzBP led to differential expression in TH cells, including for lncRNAs. With the aim of identifying putative roles of BzBP-regulated lncRNAs, weighted correlation network analysis was performed. The results suggest that some of the non-coding transcripts regulated by prenatal exposure to BzBP may be involved in TH cell-related functions such as cell activation, TH2-cytokines expression and regulation of the inflammatory response.
Differential expression of lncRNAs due to prenatal exposure to BzBP was also observed in mouse B cells. Recently published RNA-sequencing data for B cell development and activation (Brazao et al., 2016) were integrated with our own data for correlation network analysis. The results revealed that some of the BzBP-regulated lncRNAs were correlated with genes involved in B cell-related functions.
In particular, we hypothesized that two of these lncRNAs may play a role in germinal center B cell functions.
Several non-coding transcripts that are regulated by prenatal exposure to BzBP and that may be involved in TH cell-related processes and in germinal center B cell functions were therefore identified. Due to the association of the concerned processes and of this B cell sub-population with the development of allergies and asthma, we suspect these genes to also be actors in such phenomenons after
prenatal exposure to BzBP. We propose models of how these genes are involved in immune-related functions and how their regulation by BzBP may be critical. Taken together, these data thus provide a whole new layer of information of the toxicological effect of prenatal exposure to BzBP and of how this exposure might be associated with allergies and asthma development by providing an insight of underlying cellular mechanisms. Moreover, our study also contributes to filling the gaps in the knowledge concerning the roles of lncRNAs in environmental health by showing that BzBP influences non-coding transcripts that may be involved in pathologies.
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