Exam 3 Flashcards
what are the stages of carcinogenesis?
initiation, promotion, progression
describe intiation
initiating events include
i. mutagenesis
ii. epigenetic modifications
iii. DNA repair errors
iv. modified target genes (proto-oncogenes changed to oncogenes; tumor
suppressor genes inactivated; DNA repair enzymes altered).
examples: Toxins: heavy metals (cadmium), benzo[a]pyrene (grilling),
nitrosamines, Aflatoxin B1
describe promotion
altered gene expression, increased cell proliferation, inhibition of
apoptosis, no direct structural alteration in DNA by toxin or metabolites.
examples: Dioxins, PCBs, estrogen, endocrine disruptors
describe progression
neoplasm formation, complex genetic alterations, morphologically
discernible alterations in cellular genomic structure, extensive alteration of gene
expression
examples: arsenic, asbestos fibers
how might environmental toxins induce carcinogenesis?
toxins may cause:
a.) DNA adduct formation (chemicals covalently bound to DNA)
b.) epigenetic changes (enhanced methylation at tumor suppressor gene would
decrease expression)
c.) free radicals generated from cytochrome p450 action lead oxidative stress
d.) alteration of gene expression
e.) disruption of apoptosis
f.) chromosomal instability, genetic alterations, phenotypic disarray
g.) promotion
how might DNA mutagenesis be important in the development of
cancer?
it can result in:
a.) altered DNA repair
b.) initiation of oncogenic activity/inhibition of tumor suppressor genes
c.) disruption of cell cycle/apoptosis regulators
If replication occurs, the DNA mutation can be amplified leading to additional mutations
and chromosomal instability. The disruption of the nuclear microenvironment enhances
sensitivity to other factors including dietary impact and promoter and progressor agents
to advance neoplasm formation and tumorigenesis
endocrine disruptors… ?
include prenatal exposure that may alter gene expression programming the effects of which may
not be observed until adulthood
how may endocrine disruptors directly impact cellular processes?
BPA may alter gene expression by
i. directly binding to nuclear receptor such as estrogen or thyroid hormone to
mimic or antagonize hormone action
ii. interfere with transcription factor binding to a hormone receptor (disrupt
protein-protein interaction)
iii. altering cell signaling pathways (e.g. phosphorylation) to alter hormone
receptor interaction with DNA response element
iv. induce epigenetic changes through methyltransferase activation resulting in
changed DNA methylation which may decrease gene expression
(methylation=condensed chromatin) or increase gene expression
(unmethylated=relaxed or open chromatin)
identify a possible source for an environmental toxin and describe
how to establish effects as an endocrine disruptor
source for toxin: e.g. pesticides from soil or in the food system; phthlates from cosmetics etc.
bisphenol A from plastics etc..
determine endocrine disruption toxicity by:
a. epidemiological studies/environmental monitoring: what systems appear altered e.g.
altered reproductive organ development, fertility; disruption of endocrine hormone
homeostasis: altered hormone levels, altered hormone transport, altered hormone
metabolism.
b. in vivo and in vitro studies: (e.g. amphibian metamorphosis, exposure to mammals
(rats, mice) in utero)
i. exposure over broad dose range;
ii. exposure over different ages (prenatal to adult);
iii. determine different endpoints (phenotypic vs genotypic)- rapid vs. long-term
effects (latency);
iv. determine mechanism e.g : determine requirement for hormonal system:
receptor binding, binding to DNA hormone response element, nuclear protein
assembly, intracellular signaling changes-; determine genomic vs epigenetic
changes (transgenerational impact)
