Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs.

Autism Spectrum Disorders (ASD) comprise a group of heterogeneous and complex neurodevelopmental disorders. Genetic and environmental factors contribute to ASD etiology. DNA methylation is particularly relevant for ASD due to its mediating role in the complex interaction between genotype and environment and has been implicated in ASD pathophysiology. The lack of diversity in DNA methylation studies in ASD individuals is remarkable. Since genetic and environmental factors are likely to vary across populations, the study of underrepresented populations is necessary to understand the molecular alterations involved in ASD and the risk factors underlying these changes. This study explored genome-wide differences in DNA methylation patterns in buccal epithelium cells between Mexican ASD patients (n = 27) and age-matched typically developing (TD: n = 15) children. DNA methylation profiles were evaluated with the Illumina 450k array. We evaluated the interaction between sex and ASD and found a differentially methylated region (DMR) over the 5′UTR region of ZFP57 and one of its targets, RASGRF2. These results match previous findings in brain tissue, which may indicate that ZFP57 could be used as a proxy for DNA methylation in different tissues. This is the first study performed in a Mexican, and subsequently, Latin American, population that evaluates DNA methylation in ASD patients.

The etiology of Autism Spectrum Disorders (ASD) is a result of the interaction between genes and the environment. The study of epigenetic factors that affect gene expression, such as DNA methylation, has become an important area of research in ASD. In recent years, there has been an increasing body of evidence pointing to epigenetic mechanisms that influence brain development, as in the case of ASD, when gene methylation dysregulation is present. Our analysis revealed 853 differentially methylated CpG in ASD patients, affecting 509 genes across the genome. Enrichment analysis showed five related diseases, including autistic disorder and mental disorders, which are particularly significant. In this work, we identified 64 genes that were previously reported in the SFARI gene database, classified according to their impact index. Additionally, we identified new genes that have not been previously reported as candidates with differences in the methylation patterns of Mexican children with ASD.