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DNA-aldehyde adducts as biomarker of air pollution exposure

Grant number: 19/14090-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2019
Effective date (End): September 30, 2021
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Marisa Helena Gennari de Medeiros
Grantee:Pablo Victor Mendes dos Reis
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

Outdoor air pollution is classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans (IARC, 2016). A study based on 3-D atmospheric models shows the overall increase in the concentration of acetaldehyde in the coming years due to the increasing use of fuels such as ethanol and gasoline (Millet et al, 2010). Acetaldehyde reacts with 2'-deoxyguanosine (dGuo) in DNA to primarily form N2-ethylidene-2'-deoxyguanosine (N2-ethylidenedGuo), an unstable Schiff base. The subsequent reaction of N2-ethylidenedGuo with a second molecule of acetaldehyde leads to the formation of the (6S, 8S) and (6R, 8R) diastereoisomers of 1,N2-propano-2'-deoxyguanosine (1,N2-propanodGuo) adducts (Hecht et al, 2001). The 1,N2-propanodGuo adduct is also formed by the reaction of crotonaldehyde with 2'-deoxyguanosine. Crotonaldehyde is an important industrial chemical aldehyde and environmental pollutant. Crotonaldehyde can be endogenously generated by the oxidative degradation of unsaturated lipids and is a metabolite of N-nitrosopyrrolidine (Wang et al, 1992). 1,N2-PropanodGuo is mutagenic; it primarily promotes DNA miscoding in human cells through G para T transversions and can inhibit DNA replication (Stein et al, 2003). Several repair mechanisms appear to be involved in the removal of exocyclic DNA adducts (ObtuBowicz et al, 2010). DNA adducts formed by acetaldehyde are likely repaired through homologous recombination and NER (nucleotide excision repair) (Mechilli et al, 2008). The accurate quantification of 1,N2-propanodGuo in human urinary samples collected from residents of a polluted city (SP) and an unpolluted region showed significantly higher 1,N2-propanodGuo levels in the samples from SP donors than in samples from donors of the unpolluted region (Garcia et al, 2013). The presence of nucleoside adducts in urine has been attributed to the occurrence of DNA repair, apoptosis, and reactions with deoxynucleoside pools (Nair et al, 2010). This result provided evidence that elevated levels of 1,N2-propanodGuo in urinary samples may be correlated with urban air pollution (Garcia et al, 2013). Here, the formation of DNA-aldehyde adducts (adductome) and lipidomic in individuals exposed to urban air pollution will be investigated in order to elucidate the mechanisms by which these adducts are formed and to contribute to a better understanding of the mutagenic effects associated with air-pollution exposure. We will also compare DNA adduct formation in different tissues of mice exposed to formaldehyde, acetaldehyde and acrolein in the LAMP-IQUSP laboratory.