Metals and epigenetics COPHES March 12, 2012 Karin Broberg Palmgren

- Occupational and Environmental Medicine, Lund University - Institute of Environmental Medicine Karolinska Institutet

Why Genetics and Metals? 

Clear susceptibility to toxic effects of several toxic metals. Genetic mechanisms ?

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Beryllium Lead (Pawlas 2011; Rentschler 2011; Zheng 2011) Mercury (Custodio 2004, 2005; Engström 2008, 2012; Harari 2011) Cadmium (Rentschler, manuscript) Arsenic (Engström 2007, 2008, 2011; Gardner 2012, Schlebusch subm.) Manganese (Rentschler 2012)

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Ideal for studies of gene-environment interaction - good biomarkers of exposure - well-characterized and fairly simple metabolism - probably the metabolism is a susceptibility factor for several of the metals -> i.e., a slower metabolism, more toxic effects

23 March, 2012

2

Arsenic

Bangladesh

Argentina, Andes Mountains

Occurrence of arsenic in drinking water WHO standard 100 million people affected 3

Arsenic metabolism Water: Inorganic arsenic

DMA=dimethylated arsenic

Metabolism Inorg.As MMA

1-10 µg/l in urine

MMA=monomethylated arsenic

DMA

More DMA – faster excretion in urine MMA trivalent – considered most toxic metabolite

Metabolism differs for arsenic - The fractions inorganic arsenic /MMA /DMA differs between individuals/populations/species From Vahter

Genetic factors?

Argentina

Bangladesh 5

E.g. DNA-methylation

6

AS3MT arsenic +3 oxidation state methyltransferase E.g. DNA-methylation

AS3MT

7

*

AS3MT gene – arrows depict single nucleotide polymorphisms, e.g. at * a C/T exchange

(individual combinations: CC, CT, TT) 8

AS3MT genotype and MMA in urine Argentina: N=172 women Average arsenic 200 microg/L

Bangladesh: N=384 pregnant women Average arsenic 100 microg/L

C-variant=38%

C-variant=71%

Low MMA and high DMA= fast and less toxic metabolism

AA

AC

AS3MT rs3740400

CC

AA

AC

CC

AS3MT rs3740400

Six AS3MT polymorphisms gave a similar pattern in both populations (p