Arsenik

i mat och dricksva1en –

en global förgi8ning
Professor Karin Broberg, Assistant Professor
Maria Kippler
Metaller och Hälsa, InsBtutet för miljömedicin
Karolinska InsBtutet


As
- element with
many different
forms

Water and food Algea and

Inorg. AsIII, AsV Fish, seafood bivalves
Arsenobetaine Arsenosugars
Metabolism

Arseno-
Inorg.As MMA DMA betaine
- 1,000 µg/l DMA
1-10 µg/l 5-100 µg/L
in urine
 Modified from BGS, 2001

Occurrence of inorganic arsenic in drinking water

WHO standard <10 microg/L
>100 million people affected, eastern USA new hot spot
Foodstuff – rice products
Sweden, some wells elevated levels, food stuff! 3
 Potent poison – many and different health
effects of arsenic in humans

§  Cancer: skin, lung, bladder (NRC 2001, IARC 2012)
§  Skin pigmentaBon, hyperkeratosis
§  Chronic cough
§  Diabetes
§  Cardiovascular system
§  Peripheral nerves/CNS
§  Liver, kidney toxicity
§  Reduced immune defense
§  Children mortality and morbidity

Individual differences in suscepBbility!

 Mechanisms of arsenic toxicity
- targets many systems in the body!
•  Binds –SH, inhibits numerous enzymes; DNA repair
•  OxidaBv stress ROS, NO
•  AnBoxidant inhibiBon,
–  e.g. thioredoxin reductase,
–  consumpBon of glutathione
•  Affects folate/homocysteine biochemistry
•  EpigeneBc effects; affects DNA methylaBon;
–  hypomethylaBon CpG,
–  hypermethylaBon specific genes
•  Hormone receptors, metabolism (ER, GR, AR)

Vahter 2016
EsBmated cancer risk: incidence per 10,000 people

U.S. NaBonal Academy of Sciences:

Arsenic in Drinking Water: 2001 Update. New update ongoing.
Vahter 2016
 Individual differences role of arsenic
metabolism?
– methylaBon to increase excreBon
Food and water MMA=monomethylated arsenic
Inorganic AsIII, AsV
DMA=dimethylated arsenic
Metabolism

More DMA – faster excreMon
in urine
Inorg.As MMA DMA
MMA trivalent – the most toxic
metabolite
Secreted in
urine
Arsenic metabolism ma1ers for suscepBbility

Examples:

•  High %MMA in urine - increased risk for skin lesions and

basal cell carcinoma (Pierce et al. Int. J. Epidemiol. 2013;
Lindberg et al., EHP 2010; Engström et al. Environ Mol Mutagen
2015)

•  High %MMA – stronger effect of arsenic on plasma
insulin-like growth factor 1 (IGF-1) (Ahmed et al. Plos One
2013)

•  High %MMA – increased risk of cardiovascular toxicity
(Wu et al. Toxicol. Appl. Pharmacol. 2014)

From Antonelli Env Res, 2014

 Sex influences arsenic metabolism:
men more %MMA in urine than women
16
14
12
10
%MA

male
8
female
6
4
2
0
≤ 12 12-20 20-55 > 55

Age (years)
Lindberg et al. 2011
 Men higher risk for As-related skin
lesions than women
OR adj.
12

10 Men
Women
8

0
9 60 125 200 350

Life-Bme avg. water-As, µg/L (quinBles)

Rahman et al. 2006
 PopulaBon differences in arsenic metabolism

80
% As metabolites

iAs
60 MMA
DMA

40

20

0
Most pop. Andes Taiwan Matlab

Role of geneBcs? from M. Vahter

 AS3MT
Genome-wide
associaBon
study on
arsenic
metabolism

AS3MT

AS3MT AS3MT
 GeneBcs ma1ers for arsenic metabolism and in turn for toxicity

AS3MT on
chromosome
10 showed
significant
associaBons
with %MMA
and %DMA,


IdenMfies
AS3MT as
the major
gene for
arsenic
metabolism

Schlebusch et al. 2015

Timing of exposure ma1ers for suscepBbility
 Summary
•  Arsenic poisoning affects millions world-wide
•  SuscepBbility factors – sex, geneBcs, Bming of
exposure (”Bme of exposure makes the
poison”)
•  Early-life exposure to arsenic mediated by
epigeneBc mechanisms - memory of toxicity