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Genetic variability and cadmium metabolism and toxicity

Rentschler, Gerda LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:29.
Abstract (Swedish)
Popular Abstract in Swedish

POPULÄRVETENSKAPLIG SAMMANFATTNING PÅ SVENSKA



Kadmium är en giftig metall vilken finns i mat som vi rekommenderas äta mycket av, exempelvis sädesprodukter, grönsaker och skaldjur. Våra matjordar är kontaminerade med kadmium och föroreningen kommer att kvarstå under mycket lång tid framöver. Kadmium skadar framförallt njurarna och skelettet och kan antagligen även orsaka vissa typer av cancer. Människor är olika känsliga för toxiska effekter av kadmium, och resultat tyder på en ärftlig orsak till denna skillnad i känslighet, men bakgrunden är oklar.



Detta arbete vill identifiera ärftliga faktorer hos människa vilka påverkar upptag och omsättning av kadmium i... (More)
Popular Abstract in Swedish

POPULÄRVETENSKAPLIG SAMMANFATTNING PÅ SVENSKA



Kadmium är en giftig metall vilken finns i mat som vi rekommenderas äta mycket av, exempelvis sädesprodukter, grönsaker och skaldjur. Våra matjordar är kontaminerade med kadmium och föroreningen kommer att kvarstå under mycket lång tid framöver. Kadmium skadar framförallt njurarna och skelettet och kan antagligen även orsaka vissa typer av cancer. Människor är olika känsliga för toxiska effekter av kadmium, och resultat tyder på en ärftlig orsak till denna skillnad i känslighet, men bakgrunden är oklar.



Detta arbete vill identifiera ärftliga faktorer hos människa vilka påverkar upptag och omsättning av kadmium i kroppen samt dess toxicitet.



Kadmium är ett främmande ämne och därför finns det inga speciella gener eller proteiner som reglerar dess omsättning. Man vet att proteiner som omsätter de essentiella näringsämnena zink och järn inte är hel specifika, och därmed också kan påverka omsättningen av kadmium. Hos kvinnor med lågt järnvärde, vilket kan förekomma t.ex. under graviditet, har det uppmätts förhöjda kadmiumkoncentrationer. Dessutom vet man att en grupp av proteiner som binder zink, så kallade metallothioneiner, skyddar njurarna från kadmiums giftighet.



Syftet med den första studien var att leta efter samband mellan variationer i järnrelaterade gener och kadmiumkoncentrationer i blod och urin hos två grupper av kvinnor. Den ena var från Bangladesh och den andra från argentinska Anderna. Syftet med den andra studien var att leta efter samband mellan gener som tillhör zinkmetabolismen och kadmiumkoncentrationer i samma två grupper. Syftet med den tredje studien var att hitta samband mellan variationer i metallothionein-gener och kadmiumkoncentrationer i blod och urin samt njurskada i en grupp män och kvinnor från södra Kina.



En variation i transferrinreceptor-genen visade sig vara förknippad med högre kadmiumkoncentrationer i urin hos båda kvinnogrupperna, särskilt bärare av den mer ovanliga varianten (ca 26% av kvinnorna i Anderna och 14% i Bangladesh). Dessutom fanns det samband mellan variationer i zinkrelaterade gener och kadmiumkoncentrationer i blod hos kvinnorna från Anderna. Kinastudien visade att bärare av en polymorfi i metallothionein 1A-genen hade högre risk för njurskada vid stigande exponering för kadmium.



Mycket lite har hittills varit känt om vilka gener som styr omsättningen och toxicitet av kadmium i människokroppen. Detta arbete har bidragit till kunskap om vilka gener, och mer specifikt vilka genvarianter, som har betydelse för kadmiums anrikning i människan och om dessa påverkar kadmiums skadlighet. (Less)
Abstract
Abstract: Cadmium (Cd) is ubiquitous in the environment. Human exposure in non-smokers occurs mainly via intake of healthy food like vegetables, cereals, and shellfish. Adverse health effects on kidney and bone at low-level environmental Cd exposure are well-documented in adults. There is considerable inter-individual variation in both metabolism (toxicokinetics) and toxicity (toxicodynamics) of Cd. This may be due to genetic factors.



The aim of this thesis was to identify genetic factors that are associated with Cd metabolism and toxicity.



As Cd is a foreign element, there is no endogenous metabolism of uptake. However, there is evidence that the transporters of other elements such as iron and zinc... (More)
Abstract: Cadmium (Cd) is ubiquitous in the environment. Human exposure in non-smokers occurs mainly via intake of healthy food like vegetables, cereals, and shellfish. Adverse health effects on kidney and bone at low-level environmental Cd exposure are well-documented in adults. There is considerable inter-individual variation in both metabolism (toxicokinetics) and toxicity (toxicodynamics) of Cd. This may be due to genetic factors.



The aim of this thesis was to identify genetic factors that are associated with Cd metabolism and toxicity.



As Cd is a foreign element, there is no endogenous metabolism of uptake. However, there is evidence that the transporters of other elements such as iron and zinc are not sufficiently specific to prevent uptake of Cd. Further, the zinc-binding protein metallothionein (MT) protects against toxicity of Cd in the kidney. Thus, the first study examined the association of single nucleotide polymorphisms (SNPs) in iron homeostasis genes with Cd concentrations in two groups of women, one from the Argentinean Andes and the other from rural Bangladesh. The second study examined the association of SNPs in two zinc homeostasis genes, SLC39A8 and SLC39A14 with Cd concentrations in the same groups of women as in the first study. The third study analysed whether polymorphisms in the metallothionein genes MT1A and MT2A influence Cd-related kidney damage in volunteers from three areas in southern China with various degrees of Cd pollution. All study designs were cross-sectional.



We found (1) that one SNP in the iron-related transferrin receptor gene TFRC (rs3804141) was associated with Cd concentrations in urine in both women from Argentina and Bangladesh: carriers of AA had 56-58% and carriers of GA had 22% higher urinary Cd concentrations than GG. The consistency of the results in two different populations hints at a causal relation. Further, we found (2) that SNPs in the zinc-related genes SLC39A14 and SLC39A8 were associated with blood Cd concentrations, for SLC39A14 this may occur via differential gene expression. Finally, we found (3) that AA carriers of rs11076161 MT1A had higher Cd concentrations in blood among individuals in the highest Cd exposure group. Also, with increasing Cd exposure, carriers of this genotype experienced more Cd-related kidney toxicity.



The present data are of significance for the theoretic understanding of the metabolism and toxicology of Cd, and, at the same time they are valuable in risk assessment, an issue of great importance, in light of the non-existing range between present exposure to Cd and toxicity in many parts of the world, including Sweden. (Less)
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author
supervisor
opponent
  • Prof Alexander, Jan, Deputy Director-General, Norwegian Institute of Public Health, Oslo, Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Cadmium, polymorphism, TFRC, SLC39A8, SLC39A14, MT1A
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:29
pages
95 pages
publisher
Division of Occupational and Environmental Medicine
defense location
Lecture Hall F3, Skåne University Hospital, Lund
defense date
2014-03-14 09:00
ISSN
1652-8220
ISBN
978-91-87651-53-3
language
English
LU publication?
yes
id
2853574d-8c61-4812-8474-df5676796260 (old id 4317735)
date added to LUP
2014-02-25 14:20:39
date last changed
2016-09-19 08:44:50
@phdthesis{2853574d-8c61-4812-8474-df5676796260,
  abstract     = {Abstract: Cadmium (Cd) is ubiquitous in the environment. Human exposure in non-smokers occurs mainly via intake of healthy food like vegetables, cereals, and shellfish. Adverse health effects on kidney and bone at low-level environmental Cd exposure are well-documented in adults. There is considerable inter-individual variation in both metabolism (toxicokinetics) and toxicity (toxicodynamics) of Cd. This may be due to genetic factors.<br/><br>
<br/><br>
The aim of this thesis was to identify genetic factors that are associated with Cd metabolism and toxicity.<br/><br>
 <br/><br>
As Cd is a foreign element, there is no endogenous metabolism of uptake. However, there is evidence that the transporters of other elements such as iron and zinc are not sufficiently specific to prevent uptake of Cd. Further, the zinc-binding protein metallothionein (MT) protects against toxicity of Cd in the kidney. Thus, the first study examined the association of single nucleotide polymorphisms (SNPs) in iron homeostasis genes with Cd concentrations in two groups of women, one from the Argentinean Andes and the other from rural Bangladesh. The second study examined the association of SNPs in two zinc homeostasis genes, SLC39A8 and SLC39A14 with Cd concentrations in the same groups of women as in the first study. The third study analysed whether polymorphisms in the metallothionein genes MT1A and MT2A influence Cd-related kidney damage in volunteers from three areas in southern China with various degrees of Cd pollution. All study designs were cross-sectional.<br/><br>
 <br/><br>
We found (1) that one SNP in the iron-related transferrin receptor gene TFRC (rs3804141) was associated with Cd concentrations in urine in both women from Argentina and Bangladesh: carriers of AA had 56-58% and carriers of GA had 22% higher urinary Cd concentrations than GG. The consistency of the results in two different populations hints at a causal relation. Further, we found (2) that SNPs in the zinc-related genes SLC39A14 and SLC39A8 were associated with blood Cd concentrations, for SLC39A14 this may occur via differential gene expression. Finally, we found (3) that AA carriers of rs11076161 MT1A had higher Cd concentrations in blood among individuals in the highest Cd exposure group. Also, with increasing Cd exposure, carriers of this genotype experienced more Cd-related kidney toxicity. <br/><br>
<br/><br>
The present data are of significance for the theoretic understanding of the metabolism and toxicology of Cd, and, at the same time they are valuable in risk assessment, an issue of great importance, in light of the non-existing range between present exposure to Cd and toxicity in many parts of the world, including Sweden.},
  author       = {Rentschler, Gerda},
  isbn         = {978-91-87651-53-3},
  issn         = {1652-8220},
  keyword      = {Cadmium,polymorphism,TFRC,SLC39A8,SLC39A14,MT1A},
  language     = {eng},
  pages        = {95},
  publisher    = {Division of Occupational and Environmental Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetic variability and cadmium metabolism and toxicity},
  volume       = {2014:29},
  year         = {2014},
}