Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort

Domenico Franco Merlo; Silvia Agramunt; Lívia Anna; Harrie Besselink; Maria Botsivali; Nigel J Brady; Marcello Ceppi; Leda Chatzi; Bowang Chen; Ilse Decordier; Peter B Farmer; Sarah Fleming; Vincenzo Fontana; Asta Försti; Eleni Fthenou; Fabio Gallo; Panagiotis Georgiadis; Hans Gmuender; Roger W Godschalk; Berit Granum; Laura J Hardie; Kari Hemminki; Kevin Hochstenbach; Lisbeth E Knudsen; Manolis Kogevinas; Katalin Kovács; Soterios A Kyrtopoulos; Martinus Løvik; Jeanette K Nielsen; Unni Cecilie Nygaard; Marie Pedersen; Per Rydberg; Bernadette Schoket; Dan Segerbäck; Rajinder Singh; Jordi Sunyer; Margareta Törnqvist; Henk van Loveren; Frederik J van Schooten; Kim Vande Loock; Hans von Stedingk; Andrew John Wright; Jos C Kleinjans; Micheline Kirsch-Volders; Joost H M van Delft; NewGeneris Consortium

doi:10.1289/ehp.1206324

Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort

Domenico Franco Merlo, Silvia Agramunt, Lívia Anna, Harrie Besselink, Maria Botsivali, Nigel J Brady, Marcello Ceppi, Leda Chatzi, Bowang Chen, Ilse Decordier, Peter B Farmer, Sarah Fleming, Vincenzo Fontana, Asta Försti, Eleni Fthenou, Fabio Gallo, Panagiotis Georgiadis, Hans Gmuender, Roger W Godschalk, Berit GranumLaura J Hardie, Kari Hemminki, Kevin Hochstenbach, Lisbeth E Knudsen, Manolis Kogevinas, Katalin Kovács, Soterios A Kyrtopoulos, Martinus Løvik, Jeanette K Nielsen, Unni Cecilie Nygaard, Marie Pedersen, Per Rydberg, Bernadette Schoket, Dan Segerbäck, Rajinder Singh, Jordi Sunyer, Margareta Törnqvist, Henk van Loveren, Frederik J van Schooten, Kim Vande Loock, Hans von Stedingk, Andrew John Wright, Jos C Kleinjans, Micheline Kirsch-Volders, Joost H M van Delft, NewGeneris Consortium

Section of Environmental Health

22 Citations (Scopus)

Abstract

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 (M₁dG) 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 M₁dG-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® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (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.

Original language	English
Journal	Environmental Health Perspectives
Volume	122
Issue number	2
Pages (from-to)	193-200
Number of pages	8
ISSN	0091-6765
DOIs	https://doi.org/10.1289/ehp.1206324
Publication status	Published - Feb 2014

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Merlo, D. F., Agramunt, S., Anna, L., Besselink, H., Botsivali, M., Brady, N. J., Ceppi, M., Chatzi, L., Chen, B., Decordier, I., Farmer, P. B., Fleming, S., Fontana, V., Försti, A., Fthenou, E., Gallo, F., Georgiadis, P., Gmuender, H., Godschalk, R. W., ... NewGeneris Consortium (2014). Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort. Environmental Health Perspectives, 122(2), 193-200. https://doi.org/10.1289/ehp.1206324

Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression : the NewGeneris cohort. / Merlo, Domenico Franco; Agramunt, Silvia; Anna, Lívia et al.

In: Environmental Health Perspectives, Vol. 122, No. 2, 02.2014, p. 193-200.

Research output: Contribution to journal › Journal article › Research › peer-review

Merlo, DF, Agramunt, S, Anna, L, Besselink, H, Botsivali, M, Brady, NJ, Ceppi, M, Chatzi, L, Chen, B, Decordier, I, Farmer, PB, Fleming, S, Fontana, V, Försti, A, Fthenou, E, Gallo, F, Georgiadis, P, Gmuender, H, Godschalk, RW, Granum, B, Hardie, LJ, Hemminki, K, Hochstenbach, K, Knudsen, LE, Kogevinas, M, Kovács, K, Kyrtopoulos, SA, Løvik, M, Nielsen, JK, Nygaard, UC, Pedersen, M, Rydberg, P, Schoket, B, Segerbäck, D, Singh, R, Sunyer, J, Törnqvist, M, van Loveren, H, van Schooten, FJ, Vande Loock, K, von Stedingk, H, Wright, AJ, Kleinjans, JC, Kirsch-Volders, M, van Delft, JHM & NewGeneris Consortium 2014, 'Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort', Environmental Health Perspectives, vol. 122, no. 2, pp. 193-200. https://doi.org/10.1289/ehp.1206324

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title = "Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort",

abstract = "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 (M1dG) 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 M1dG-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{\textregistered} (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX{\textregistered} (for estrogens) (2 genes), and DR CALUX{\textregistered} (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.",

author = "Merlo, {Domenico Franco} and Silvia Agramunt and L{\'i}via Anna and Harrie Besselink and Maria Botsivali and Brady, {Nigel J} and Marcello Ceppi and Leda Chatzi and Bowang Chen and Ilse Decordier and Farmer, {Peter B} and Sarah Fleming and Vincenzo Fontana and Asta F{\"o}rsti and Eleni Fthenou and Fabio Gallo and Panagiotis Georgiadis and Hans Gmuender and Godschalk, {Roger W} and Berit Granum and Hardie, {Laura J} and Kari Hemminki and Kevin Hochstenbach and Knudsen, {Lisbeth E} and Manolis Kogevinas and Katalin Kov{\'a}cs and Kyrtopoulos, {Soterios A} and Martinus L{\o}vik and Nielsen, {Jeanette K} and Nygaard, {Unni Cecilie} and Marie Pedersen and Per Rydberg and Bernadette Schoket and Dan Segerb{\"a}ck and Rajinder Singh and Jordi Sunyer and Margareta T{\"o}rnqvist and {van Loveren}, Henk and {van Schooten}, {Frederik J} and {Vande Loock}, Kim and {von Stedingk}, Hans and Wright, {Andrew John} and Kleinjans, {Jos C} and Micheline Kirsch-Volders and {van Delft}, {Joost H M} and {NewGeneris Consortium}",

year = "2014",

month = feb,

doi = "10.1289/ehp.1206324",

language = "English",

volume = "122",

pages = "193--200",

journal = "Environmental Health Perspectives",

issn = "0091-6765",

publisher = "National Institute of Environmental Health Sciences",

number = "2",

}

TY - JOUR

T1 - Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression

T2 - the NewGeneris cohort

AU - Merlo, Domenico Franco

AU - Agramunt, Silvia

AU - Anna, Lívia

AU - Besselink, Harrie

AU - Botsivali, Maria

AU - Brady, Nigel J

AU - Ceppi, Marcello

AU - Chatzi, Leda

AU - Chen, Bowang

AU - Decordier, Ilse

AU - Farmer, Peter B

AU - Fleming, Sarah

AU - Fontana, Vincenzo

AU - Försti, Asta

AU - Fthenou, Eleni

AU - Gallo, Fabio

AU - Georgiadis, Panagiotis

AU - Gmuender, Hans

AU - Godschalk, Roger W

AU - Granum, Berit

AU - Hardie, Laura J

AU - Hemminki, Kari

AU - Hochstenbach, Kevin

AU - Knudsen, Lisbeth E

AU - Kogevinas, Manolis

AU - Kovács, Katalin

AU - Kyrtopoulos, Soterios A

AU - Løvik, Martinus

AU - Nielsen, Jeanette K

AU - Nygaard, Unni Cecilie

AU - Pedersen, Marie

AU - Rydberg, Per

AU - Schoket, Bernadette

AU - Segerbäck, Dan

AU - Singh, Rajinder

AU - Sunyer, Jordi

AU - Törnqvist, Margareta

AU - van Loveren, Henk

AU - van Schooten, Frederik J

AU - Vande Loock, Kim

AU - von Stedingk, Hans

AU - Wright, Andrew John

AU - Kleinjans, Jos C

AU - Kirsch-Volders, Micheline

AU - van Delft, Joost H M

AU - NewGeneris Consortium

PY - 2014/2

Y1 - 2014/2

N2 - 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 (M1dG) 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 M1dG-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® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (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.

AB - 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 (M1dG) 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 M1dG-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® (chemically activated luciferase expression for androgens) (8 genes), ERα CALUX® (for estrogens) (2 genes), and DR CALUX® (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.

U2 - 10.1289/ehp.1206324

DO - 10.1289/ehp.1206324

M3 - Journal article

C2 - 24252472

SN - 0091-6765

VL - 122

SP - 193

EP - 200

JO - Environmental Health Perspectives

JF - Environmental Health Perspectives

IS - 2

ER -

Micronuclei in cord blood lymphocytes and associations with biomarkers of exposure to carcinogens and hormonally active factors, gene polymorphisms, and gene expression: the NewGeneris cohort

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