Περίληψη:
Background: Leukemia incidence has increased in recent decades among
European children, -suggesting that early-life environmental exposures
play an important role in disease development.
Objectives: We investigated the hypothesis that childhood susceptibility
may increase as a result of in utero exposure to carcinogens and
hormonally acting factors. Using cord blood samples from the NewGeneris
cohort, we examined associations between a range of biomarkers of
carcinogen exposure and hormonally acting factors with micronuclei (MN)
frequency as a proxy measure of cancer risk. Associations with gene
expression and genotype were also explored.
Methods: DNA and protein adducts, gene expression profiles, circulating
hormonally acting factors, and GWAS (genome-wide association study) data
were investigated in relation to genomic damage measured by MN frequency
in lymphocytes from 623 newborns enrolled between 2006 and 2010 across
Europe.
Results: Malondialdehyde DNA adducts (M(1)dG) were associated with
increased MN frequency in binucleated lymphocytes (MNBN), and exposure
to androgenic, estrogenic, and dioxin-like compounds was associated with
MN frequency in mononucleated lymphocytes (MNMONO), although no
monotonic exposure-outcome relationship was observed. Lower frequencies
of MNBN were associated with a 1-unit increase expression of PDCD11,
LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was
significantly higher in association with the highest versus lowest
category of bulky and M(1)dG-DNA adducts for five and six genes,
respectively. Gene expression levels were significantly lower for 11
genes in association with the highest versus lowest category of plasma
AR CALUX (R) (chemically activated luciferase expression for androgens)
(8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX
(R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on
chromosome 11 near FOLH1 significantly modified associations between
androgen activity and MNBN frequency. Polymorphisms in EPHX1/ 2 and
CYP2E1 were associated with MNBN.
Conclusion: We measured in utero exposure to selected environmental
carcinogens and circulating hormonally acting factors and detected
associations with MN frequency in newborns circulating T lymphocytes.
The results highlight mechanisms that may contribute to
carcinogen-induced leukemia and require further research.
Συγγραφείς:
Merlo, Domenico Franco
Agramunt, Silvia
Anna, Livia and
Besselink, Harrie
Botsivali, Maria
Brady, Nigel J.
Ceppi,
Marcello
Chatzi, Leda
Chen, Bowang
Decordier, Ilse and
Farmer, Peter B.
Fleming, Sarah
Fontana, Vincenzo
Foersti,
Asta
Fthenou, Eleni
Gallo, Fabio
Georgiadis, Panagiotis and
Gmuender, Hans
Godschalk, Roger W.
Granum, Berit
Hardie,
Laura J.
Hemminki, Kari
Hochstenbach, Kevin
Knudsen, Lisbeth
E.
Kogevinas, Manolis
Kovacs, Katalin
Kyrtopoulos, Soterios
A.
Lovik, Martinus
Nielsen, Jeanette K.
Nygaard, Unni
Cecilie
Pedersen, Marie
Rydberg, Per
Schoket, Bernadette and
Segerback, Dan
Singh, Rajinder
Sunyer, Jordi
Tornqvist,
Margareta
van Loveren, Henk
van Schooten, Frederik J.
vande
Loock, Kim
von Stedingk, Hans
Wright, John
Kleinjans, Jos C.
and Kirsch-Volders, Micheline
van Delft, Joost H. M.
NewGeneris
Consortium
