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Study of senescence and possible mechanisms involved in arsenic-induced carcinogenesis in humans

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Title Study of senescence and possible mechanisms involved in
arsenic-induced carcinogenesis in humans
 
Creator Chatterjee, Debmita
 
Subject Cell Biology & Physiology
 
Description Arsenic (As) induces various patho-physiological outcomes in humans like cancers including skin cancers, peripheral neuropathy (PN) and respiratory diseases. Though reports
have shown that arsenic induced senescence (AIS) in vitro; population based studies on AIS and epigenetic regulation of AIS contributing to As-induced diseases remains unexplored. We investigated AIS, senescence-associated secretory phenotype (SASP) markers, telomere
length alteration, epigenetic regulation involving altered senescence associated miRNA (SAmiRs)
expression in arsenic exposed individuals with characteristic skin lesions and
peripheral neuropathy. We also made an attempt to check the genetic damage, overall health
status and telomere length in arsenic exposed children. Exposure assessment was done from
drinking water and urine collected from arsenic exposed (N=120) and unexposed (N=60)
individuals recruited from West Bengal, India. Senescence and telomere length alteration was
evaluated using SA β-gal activity, ELISA and quantification of senescence proteins,
alternative lengthening of telomere (ALT) associated proteins and telomerase activity.
Relative telomere length (RTL) and SA-miRs in AIS was determined by qPCR. The
downstream molecule of the miRNA associated with As-induced PN was quantified by
immuoblotting. In vitro studies were conducted with sodium arsenite exposed HEK 293 cells,
to revalidate the observations.
As-exposed individuals exhibited significantly increased senescent cells, upregulated
senescence inducers, p53/p21 and SASP markers when compared to unexposed controls. Asexposed
skin lesion group showed significantly increased RTL, which was telomeraseindependent
but exhibited an over-expression of ALT associated proteins. All the SA-miRs
assessed were upregulated in the As-exposed compared to controls, specifically miR-29a.
Further analysis found that highest expression of miR29a and peripheral myelin protein 22
(PMP22), a direct target of miR 29a, was among As-exposed individuals with PN. Analyzing
other intermediate players regulating PMP22 expression revealed up-regulation of β-catenin
and down-regulation of GSK-3β. Our findings suggest that up-regulation of β-catenin,
possibly by miR29a mediated negative regulation of β-catenin inhibitors, may play a
predominant role in expression of PMP22 which leads to formation of aggresomes. Further
work to validate this mechanism is in process in vitro. Arsenic exposed children showed
considerable genetic damage as measured by micronucleus assay in the three cell types and
also adverse health outcomes like decreased haemoglobin content and gastritis. Telomere
length of arsenic exposed children was slightly elevated though it did not reach the
significance level.
Our findings suggest that arsenic exposure induces senescence in vivo and telomeraseindependent
elongation of telomere length is strictly associated with As-induced skin lesions
in adults. Epigenetically, arsenic alters the expression of SA-miRs and the mir29a/beta
catenin/PMP22 axis might be responsible for arsenic induced PN. However, in children, the
telomere length increase and genetic damage in the three cell types and adverse health
outcomes suggested that children are equally at danger of arsenic poisoning.
 
Date 2017
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
application/pdf
 
Identifier http://www.eprints.iicb.res.in/2766/1/FULL_THESIS_DEBMITA_CHATTERJEE.pdf
http://www.eprints.iicb.res.in/2766/2/ABSTRACT_DEBMITA_CHATTERJEE.pdf
Chatterjee, Debmita (2017) Study of senescence and possible mechanisms involved in arsenic-induced carcinogenesis in humans. PhD thesis, Jadavpur University.
 
Relation http://www.eprints.iicb.res.in/2766/