Developmental Exposure to PM Causes Feminization of Liver in Male Mice Later in Life

Abstract

Rationale: Particulate matter (PM) air pollution is a global health problem estimated to cause 4.2 million premature deaths worldwide annually. The morbidity and mortality associated with PM is largely due to cardiopulmonary disease. Exposure to PM has also been associated with metabolic changes likely through effects on the liver. Early childhood may represent a vulnerable period during which exposure to PM may have long-term consequences. Here we sought to determine the how the developmental exposure to PM affects the transcriptome in liver later in life.Methods: We exposed C57BL/6J mice in utero and until 3 weeks old to PM2.5 concentrated from ambient Chicago air for 8 h per day for 5 days a week in a chamber connected to a Versatile Aerosol Concentration Enrichment System (VACES). Control mice were also connected to VACES with Teflon filter to remove all particles and received filtered air (FA). Liver tissues were harvested from mice at 3 weeks and 5 months of age. RNA was isolated from liver tissue and sequenced. Analysis of raw RNA-seq data included quality control, read alignment, quantification of gene and transcript levels, as well as visualization, and identification of differentially expressed genes (DEGs). Results: Weights of male mice exposed to PM were higher compared to FA group. There was no weight difference between PM and FA in female mice. PC plots showed similar changes in response to PM with no effect of sex at 3 weeks of age. However, at 5 months of age, PC plot showed sex-related differences in addition to PMrelated differences. We identified 19 DEGs between FA and PM in female mice. In contrast, there were 260 DEGs between FA and PM groups in male mice. Analysis of these DEGs in male mice showed increased expression of genes that can be affected by estrogen. Conclusions: Developmental exposure to PM in utero and during the first three weeks of life causes transcriptomic changes in the liver at 3 weeks and 5 months. The transcriptomic changes at 3 weeks of age are predominantly due to PM exposure with no effect of sex whereas at 5 months of age, both sex and PM affect the liver transcriptome. The effect of PM on liver transcriptome at 5 months is greater in males compared to females. Developmental exposure to PM causes feminization of liver in male mice at 5 months. Further studies are needed to understand the mechanisms behind these changes.