1
Q
What are two ways that gene mutations can be classified?
A
- Hereditary (aka germline)
- Acquired (or somatic)
2
Q
What is a hereditary mutation?
A
- inherited from parent
- occurring in germ cells (egg and sperm)
- present throughout a person’s life
- in EVERY cell in the body
3
Q
What is an acquired (or somatic) mutation?
A
- occur at some time during a person’s life
- occurs in somatic cells
- NOT in every cell in the body, only effect certain areas
- NOT passed on to offspring
4
Q
What are 3 endogenous sources to causing gene mutations?
A
- replication stress
- inflammation
- metabolism
5
Q
What are 3 exogenous sources to causing gene mutations?
A
- UV/ionizing radiation
- chemicals
- pathogens (infectious agents)
6
Q
What is a chromosomal genetic damage?
A
- arise during cell division
- can involve:
1. number of chromos
2. structure –> atypical configuration
7
Q
What is aneuploidy?
A
- abnormal number of chromosomes
- arise from errors in meiosis –> maternal meiosis 1
- most lethal (deadly)
- monosomy = missing one chromo
- cells very sensitive to loss of chromos!
8
Q
What is a frameshift mutation?
A
caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read
9
Q
What are 3 point mutations in DNA?
A
- silent
- nonsense
- missense
10
Q
What are the 7 types of genetic alternations in genes?
A
- insertion
- deletion
- duplication
- inversion
- transpositions (moved around)
- intron/exon inclusions and exclusions
- mutations in regulatory regions (affects how much protein is made, not the DNA itself)
11
Q
Most rare diseases are not genetic in origin. true or false
A
false –> they are
12
Q
Is autism highly heritable? How do we know?
A
YES
- from twin studies
13
Q
What factors contribute to autism?
A
environmental factors –> in utero exposure to a maternal immune response
14
Q
What condition is associated with autism that stems from a mutation in a single gene?
A
Fragile X syndrome
15
Q
How many genes are linked strongly to autism?
A
100
16
Q
What do the mutations look like in the brains of autism?
A
- combo of germline and somatic mutations
- specifically, deleterious somatic mutations (causing damage)
- strong association of de novo (not inherited) copy number mutations
- a lot of mutations were deletions
17
Q
What are 3 things that can have an affect on fetal outcomes (germline mutations)?
A
- age
- diet
- endocrine disrupting chemicals (EDCs)
18
Q
What is number one risk factor for germline mutations?
A
age!
19
Q
What is a selfish mutation in sperm?
A
- cancer-like process in the testicles
- certain mutations make stem cells divide abnormally
- overtime can increase
- explains why we have brain disorders –> autism and schizophrenia
20
Q
What are polyaromatic hydrocarbons (PAH)?
A
-come from natural or anthropogenic (human-made) sources
- carcinogenic
- teratogenic
- genotoxic
21
Q
What are minisatellites?
A
highly unstable, largely non coding genetic elements that are used to demonstrate that environmental factors can affect the germline mutation
22
Q
What was 3 PAHs that showed increased mutations in germline?
A
- paternal smoking before the partner became pregnant
- BaP
- ENU
23
Q
WHat is BaP? How is sperm affected by BaP?
A
- male germ cell mutagen
- dividing sperm are more sensitive to its effects
- impacts tandem repeat DNA
- affects testes weight, concentration, motility , and liver weight in utero exposure for male offspring repoductive parameters
24
Q
chemical exposures induce microsatellite mutations/ true or false
A
true
25
How was ovaries affected by BaP?
the more BaP, the less healthy ovarian follicles
26
What are the BaP effect in reproductive tissues?
- highly susceptible
- affects sperm development and function
- affects amount of healthy ovarian follicles
- have a significant impact on health and disease across generations
27
What is genomic imprinting?
inheritance process
- epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence
- one gene is silenced from one parent while the gene from another parent is expressed
28
What is the epigenetic mark that homolgous chromosomes in order to achieve parental specific expression?
Differently Methylated Region (DMR)
29
What are the two types of DMR?
1. germline --> methylation during gametogeneis
2. somatic --> other one becomes methylated after fertilization
30
What are the 2 major clusters of imprinted genes that are in humans?
1. short arm of chromosome 11
2. long arm of chromosome 15
31
What are the 2 major genome wide epigenetic reprogramming events that take place during germ cell development?
1. parental specific imprints are "erased"
2. new imprints reflecting the sex of embryo are established
32
children conceived with ART are more likely to have imprinting disorders. true or false
true
33
parental allele-specific epigenetic marks are heritable to daughter cells, but must be reset in each generation to establish specific imprints. true or false
true
34
What are 2 human diseases that are prevalent because of genomic imprinting?
1. angleman syndrome
2. prader-willi syndrome (PWS)
35
What chromosome is affected in angelman syndrome and PWS?
deletion on chromosome 15 paternal --> PWS
deletion on chromosome 15 maternal --> angelman
36
What is X-chromosome inactivation?
occurs randomly for one of the two X chromosomes in female cells
37
What are the steps in X-chromosome inactivation (x4)?
1. RNA transcribed from the Xist gene on the X chromosome from which it is expressed spread to coat the whole X chromosome (Xist RNA coating)
2. once inactivated, Xist and Tsix are differently regulated on the X that will become the active X chromosome (XA) and one that will become the inactive X chromosome (XI)
3. X chromos that become XI --> Xist transcripts spread and coat entire X chromo to establish "transcriptional silencing"
4. Tsix is silenced on the XI
38
What are characteristics in genes that escape the x-chromosome inactivation(x2)? what can it cause (x1)?
- lack repressive histone marks
- hypomethylated CpG regions
- can cause sex differences in gene expression
39
What is the SRY gene?
provides instructions for making a protein called "sex-determining region Y protein"
protein is involved in male-typical sex development
40
What are 2 ways that we can relieve the imbalance in the amount of genes between the Y chromosome and the X chromosome?
1. X upregulation of expressed genes in males and females
2. X inactivation or silencing of one X chromosome in females
41
What chromo contains more genes Y or X?
X
42
What are the pros and cons of having two X chromosomes?
pros
- improved blood pressure regulation
- increased capacity to blunt the effects of brain injuries
cons
- increased risk of developing an autoimmunity
43
What is the CRISPR-Cas9 editing?
- technology that allows us to edit parts of the genome by removing, adding, or altering sections of the DNA sequence
- based on the simplified version of the bacterial CRISPR-Cas9 antiviral defense system
- could treat inherited genetic diseases or somatic like cancer
- highly controversial
44
What are the limitations to the CRISPR-Cas9?
- hard to deliver CRISPR material to mature cells in large numbers
- not 100% efficient
- Not 100% accurate
- maltreatment of tech --> people could theoretically use it to enhance desirable traits instead of curing disease (by editing in gametes and early embryos)
45
What happened when CRISPR was used to deactivate the CCR5 gene in embryos made through IVF?
reduced infection as CCR 5 gene allows the HIV virus to enter into cells
46
Was their issues with CRISPR used in embryo IVF babies for the CCR5 gene?
YES see slide 54
- generated different mutations
- did not test any of this and went ahead implanting the embryos
- editing was not efficient
- mix of edited and unedited cells creating a mosaic
- technical issues
47
What is an endocrine disruptor?
- many chemicals both natural and man-made that may mimic or interfere with the body's hormones
- found in many everyday products
- some can be slow to breakdown in environment
- can be linked to developmental, reproductive, brain, and immune and other problems
48
What is BPA?
- makes polycarbonate plastics and epoxy resins
- in many plastic food storage containers
49
What is dioxins?
- byproduct in herbicide production and paper bleaching
- released into the environment during waste burning and fires
50
See slide 5 on endocrine disruptors for examples
51
What 3 things does the endocrine organs do for the body?
- regulate body's growth and development
- control function of various tissues that support pregnancy and reproductive stuff
- regulate metabolism
52
If there is too little or too much hormone, what can happen?
DISEASE or DYSFUNCTION
53
What are the 4 categories of human health impact from endocrine disruptors? (slide 10)
1. development
2. fertility
3. reproductive cancers
4. other endocrine disorders
54
What are 3 policy implications for exposure pathways?
1. environmental safety --> emission standards
2. food safety --> labelling, pesticides
3. occupational health and safety --> PPE, family safety
55
What are 4 main sources for endocrine disruptors?
1. food production
2. industrial activity
3. personal and home care
4. medical care
56
What are the 4 classic routes of exposure and what are 2 other routes of exposure in relation to DoHAD?
1. inhalation
2. ingestion
3. injection
4. absorption (dermal)
additional:
5. trans-placental (mom to bay through placenta)
6. lactation (through breast milk)
57
What does the Human Dose Assessment consist of for Endocrine disruptors?
- biomonitoring --> assessing and measuring chemicals and metabolites in human tissues
- tissues looked at:
a. blood
b. urine
c. hair
d. saliva
58
What are the 10 mechanisms of action for endocrine disrupting chemicals?
1. receptor antagonist
2. receptor expression
3. signal transduction
4. epigenetic alterations
5. hormone synthesis
6. hormone transport
7. hormone distribution or circulating hormone levels
8. hormone breakdown or clearance
9. fate
10. receptor ligand or agonist
59
What was endocrine disruptors been known to disturb in the reproductive system?
1. decrease sperm quality
2. decrease fertility
3. decrease implantation
60
What is a phthalate?
- group of chemicals used in a ton of products and personal care products
- make plastics more flexible and harder to break --> called "plasticizers"
- repoductive toxicants
61
What are the adverse effects of phthalates on reproductive stuff?
- infertility
- poor semen quality
- male subfertility
- influences neurodevelopment
- intrauterine death
- testicular atrophy
62
What are the 2 possible causes for a decrease in global semen quality in the last 50 years?
1. obesity
2. environmental factors --> EDCs
63
What is Cryptorchidism in males?
- One/both testicles fail to move into the
scrotum prior to birth
* Undescended testicles have an increased
likelihood of developing cancer
64
What is hypospadias in males?
- Opening of the urethra is on the
underside, rather than at the end, of the
penis
65
How does phthalates affect males prenatally exposed?
- reduced anogenital distance
- shorter penile length
- undescended testes
- shorter gestational age at birth
66
What is DES and what does it cause?
- most potent xenoestrogen
- was given to manage morning sickness
- appears to cause premature labor
67
Are their more abnormalities of DES seen in females or males when mom was exposed during first trimester? If so, what did it cause?
Females 14+
- causes abnormalities or cancer of....
a. uterus
b. vagina
c. cervix
68
What is the mechanism of action for DES?
inhibits Hoxa10 expression
69
What is Hoxa10?
participates in developmental patterning of the male and female reproductive systems under the regulation of estrogens
70
For women who were prescribed DES during pregnancy, what did put them at a higher risk for?
breast cancer
71
What type of cancer was daughters of mothers who took DES more likely to get?
clear-cell adenocarcinoma of the vagina and cervix
72
How were DES sons effected?
evidence is unclear
- increased risk for non-cancerous epididymal cysts (growths of testicles)
- genital development may be effected
73
What was DDT used for orignally?
- in WWII for malaria and typhus
- used as an agricultural pesticide
74
What is a problem with DDT?
- bioaccumulates in fatty tissues
- probably carcinogenic and a neurotoxin
- toxic effects on birds --> causing egg shell thinning
75
What is the mechanism of action for DDT and egg shell thinning in birds?
DDT metabolites p,p’- DDE --> inhibits Ca2+-ATPase --> reduced calcium transport --> reduced Ca2+
content in egg shell
76
What is atrazine?
- inexpensive and cost effective
- herbicide and pesticide
- found in ground water of states
77
What did atrazine cause to male frogs?
became hermaphrodites --> had multiple sets of both male and female sexual organs
78
What is the mechanism of action for atrazine?
- an enzyme called "aromatase" which increases estrogen and decreases androgen
- turns testosterone into estradiol
79
What is BPA?
- xenoestrogen
- weak estrogens
- binds both ER alpha and ER beta
- highest volume chemical worldwide --> seen in plastic bottles
- BPA binds ERs --> alters tissues, cells, and gene expression in estrogen target organs (brain, mammary gland, ovary, uterus, etc.)
80
What is the mechanism of action for BPA?
- inhibits the transcription of DNA methyltransferases genes (DNMTs)
81
How did we know what BPA did from looking at a mice study?
- fed pregnant yellow mice a methyl rich diet and her pups stayed brown and healthy for life
- BPA was introduced = reduced methylation of agouti gene (yellow offspring)
- BPA + methyl rich foods = normal methylation of agouti gene (brown offspring)
therefore, BPA inhibits transcription of DNMTS
82
In 2008, Canada became the first nation in
the world to ban BPA in both the
manufacture and importation
of baby bottles. true or false
true
83
In 2010, Canada was the first jurisdiction in the
world to declare the everyday plastic-
making compound bisphenol A to be
toxic. true or false
true
84
BPA-free does mean estrogen-free . true or false
false --> NO! most products labeled BPA-free still have estrogenic activity
85
What are the 4 central components to the precautionary principle?
1. taking preventive action in the face of uncertainty
2. shifting the burden of proof to the proponents of an activity
3. exploring a wide range of alternatives to possibly harmful actions
4. increasing public participation in decision making
86
What is an obesogen?
chemicals may affect human hormones and change the way our bodies make, store, and use fat
87
What are 3 categories of childhood-adult onset endpoints in relation to EDCs? (slide 61)
1. neurodevelopmental disorders
2. puberty
3. obesity
88
What are 7 sources for obesogens?
1. bisphenols
2. phthalates
3. parabens
4. non-steroid estrogens
5. brominated flame retardants
6. PCBs
7. oragnotins
89
What are 3 mechanisms of action of obesogens?
1. increasing adipocytes number
2. increasing adipocytes size
3. altering endocrine regulation of adipose tissue development
4. changing hypothalamic regulation of appetite and safety
5. altering basal metabolic rate and energy homeostasis
6. altering insulin sensitivity at organ level
90
different EDC concentrations could be associated with fetal growth restriction, thyroid dysfunction, and neurological disorders. True or false
true
91
Exposure during the prenatal period may result in epigenetic alterations modifying fetal programming and increasing, during postnatal life, the risk of
some non-communicable diseases. true or false
true
92
there cannot be transgenerational inheritance when exposed to EDCs during development. true or false
false they can
93
What are the 3 main targets of EDCs?
1. hypothalamus-pituitary gland-thyroid (HPT)
2. hypothalamus-pituitary gland-gonads (HPG)
3. hypothalamus-pituitary gland-adrenal (HPA)
94
HSS4102
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