Endocrine Toxicology Flashcards

final exam

1
Q

how are horrmes secreted usually? why?

A

pulsatile since there is a negative feedback mechanism

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2
Q

what is the steroid pyramid? explain it.

A
  • cholesterol at the bottom (highest concentration): precursor to all steroids
  • then metabolized into progestins (lower concentration)
  • then metabolized into androgens (lower concentration)
  • androgens are estrogen precursors (present in very low concentration): explains why estrogen receptors are very sensitive to anything that looks like an estrogen
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3
Q

WHO definition of an endocrine disruptor

A

an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations

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4
Q

effect of DDT on eggshells

A

thickness of shell directly related to DDT concentration (the higher the concentration, the thinner the eggshell)

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5
Q

examples of endocrine disruptors

A
  • PAHs
  • Bisphenol A
  • cleaning products
  • plasticizers
  • flame retardants
  • metals, plastics
  • drugs
  • herb-, pest-, fung-icides
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6
Q

Actions of Endocrine Disruptors

A
  • mimic natural hormones
  • block the effect of a hormone
  • stimulate or inhibit system
  • cause under- or over-production of hormones
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7
Q

Health effects reported for some EDCs

A
  • obesity
  • female fertility (oocyte)
  • embryo development – affecting the future life of the child
  • thyroid – affects many systems/functions
  • male fertility (sperm)
  • brain function (e.g. BPA in baby products such as bottle)
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8
Q

why do endocrine disruptors have the potential for long-lasting consequences?

A

affect gametes (sperm and oocytes) such that they are not functional or altered in a way (leading to transgenerational impact)

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9
Q

what is the The Developmental Origins of Health and Disease (DOHAD) based on?

A

on evidence that the roots of many diseases and dysfunctions occur very early in life, especially the embryo, fetus, infant, and child.

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10
Q

effect of under or over nutrition of pregnant women

A

influence on the fetus’s propensity to develop metabolic disorders including obesity, cancer and diabetes later in life

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11
Q

which systems and cells are more vulnerable to endocrine disruptors?

A
  • developing germ cells (even at low doses)
  • nervous system
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12
Q

which environmental influences in early life can affect the health and disease of the infant later in life?

A
  • cigarette smoke,
  • air pollution,
  • environmental chemicals
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13
Q

Epigenetic Mechanisms of Endocrine Disruptors

A

they will:
- cause primordial germ-cell re-methylation
- altered germline DNA methylation, which leads to:
1. altered testis transcriptome, leading to spermatogenic defects
2. alter non-coding RNAs, which may lead to other diseases

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14
Q

potential sites for endocrine disruption

A
  • brain: releasing factors
  • pituitary: LH, FSH, GH
  • liver: enzymes
  • gonads: Estrogen, androgens
  • blood: binding proteins
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15
Q

effect of POCBs on alligators, bald eagles, and cormorants

A
  • lower levels of DHT and testosterone (meaning that chemicals are release that later Leydig function)
  • leads to beak, skeletal, reproductive abnormalities
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16
Q

what happened to the minnows in the St. Lawrence River?

A
  • Increased Intersex in Fish
  • decreases numbers close to Iles de la Paix
17
Q

how does the bioactive concentration (aka the affinity) of BPA to GPFR, ERRy, ERa, and ERb compare)

A

GPER < ERRy = ERa < ERb

18
Q

effect of BPA

A

prevent translocation of ERa/B

19
Q

mechanism of BPA

A

is nonmonotonic dose-response relationship:
- low dose: binds ERb only, leading to decrease Ca2+ in the cell from decrease mRNA production of receptor
- high dose: binds both ERa and ERb, leading to both decreased receptor and increase activation via PI3K pathway (overall increase Ca2+ entry)

20
Q

health effects of OPEs

A
  • neurotoxicity
  • thyroid dysfunction
  • developmental issues
  • others: liver, adipose, pancreas, bone, reproductive
21
Q

which subgroup of OPEs is more lipophilic, why?

A

triaryl (vs nontriaryl) since have more rings

22
Q

what is IVIVE

A
  • in vitro in vivo extrapolation
  • make calculation to see what in vitro exposure would be in humans
23
Q

effects of TMPP on cell phenotypes

A
  • decreases cell count
  • decreases lysosomes
  • increases lipid droplets
  • increases ROS (oxidative stress)
24
Q

what are phthalates?

A

plasticizers

25
Q

most common plastisizer

A

DEHP

26
Q

property of phthalates

A

Non-covalently bound – leach from products (aka is volatile)

27
Q

endpoints affected by phthalate esters in the male reproductive system

A
  • altered sex hormones
  • reduced anogenital distance
  • hypospadias
  • cryptorchidism
  • reduced sperm production
28
Q

endpoints affected by phthalate esters

A
  • male reproduction: Leydig, Sertoli and germ cells
  • female reproduction: folliculogenesis, oocytes, early menopause
  • adrenal: steroid production
  • fat cells: metabolism
  • respiratory system: asthma
  • cancer: liver and maybe breast cancer
  • CNS: maybe Child neurobehavioral development
29
Q

Mechanism of Action of MEHP (phthalate ester)

A
  • decreases synthetic enzyme levels and gene expression in Leydig cells (lead to hypospadias, cryptorchidism)
  • decreases cyclin D in Sertoli cells (ability of Sertoli cells to form tight junctions) – leads to multinucleated gonocytes
30
Q

A proposed Adverse Outcome Pathway (AOP) for “Phthalate Syndrome”

A
  • exposure: absorption via ingestion, inhalation, dermal)
  • molecular interaction: using QSAR or NAMs find effect in Leydig cells and Seminiferous cord
  • cellular effects: decreased production/enzymes/markers in Leydig cells and decreased proliferation in Seminiferous cord
  • organ effects: using organ-on-a-chip or animal samples see effects on genitals, accessory reproductive organs, and testes
  • organism effects: in vivo look at spermatogenesis, sperm abnormalities and fertility
31
Q

toxicity of DINP, DEHA, and TXIB (phthalate plasticizer replacements)

A
  • DINP: very toxic (more than what was used before)
  • DEHA and TXIB: no toxicity
32
Q

which plasticizers affect the following cell lines more:
- MA-10 cells
- KGN cells
- TM4 cells
- C18 cells

A
  • MA-10: most by MEHP (oxidative stress, lipid droplets) and DINP (mitochondria, lysosomes)
  • KGN: most by DINP (oxidative stress, mitochondria, lysosomes) and by MEHP and DINCH and DIDA (lipid droplets)
  • TM4: MEHP and DINCH (lipid droplets, oxidative stress) and by DEHTP (oxidative stress)
  • C18: DINP (Calcein) and DIDA (oxidative stress)