lecture 3: persistent chemicals in the environment (dioxin and benzo[a]pyrene)

dioxin and benzo[a]pyrene can be produced by __________ (forest fire, volcanic activity), motor vehicles, and in cigartte smoke. these chemicals are considered _________ (IARC group 1), teratogens, and ________ disruptors

combustion, carcinogens, endocrine

describe the history of dioxin (TCDD). in 1965, the US military as a part of Operation Ranch Hand, used “Agent ________” to defoliate dense ground vegetation in Vietnam. reports suggested that it was responsible for miscarriage and congenital _______ defects. animal studies show that herbicides were not teratogenic at concentrations used _________-, but the contaminant was ___________

Orange, birth, environmentally, teratogenic

dioxin is produced as a ___-product during 2, 4, 5-T synthesis, and average concentration of TCDD in Agent Orange is ____ mg/kg, sprayed about ______ kg in Vietnam. dioxin _______ is not a herbicide, it is one of the strongest _______ that ________ can make. dioxin can be produced (naturally as well) by incomplete combustion

by, 13, 170, itself, toxicants, humans

describe TCDD remains in the environment in Vietnam. the concentrations of TCDD as high as ______ mg/kg were found in soil and sediment samples more than 30 years after Agent Orange sprays in most affected areas of Vietnam. the half life of TCDD is estimated as up to ______ years in the environment. this is because in the environment, it is generally very difficult to degrade __________ (CI, F, Br) compounds

1000, 100, halogenated

more of dioxin: source is _______ combustion, incineration, and _______. generation of dioxins could be ________ but found everywhere due to its __________ in the environment. bioaccumulation and ___________ occur. it is ________ and has a very ________ toxicity (LD50: ~0.02 mg/kg). the acute toxicity is skin ______, chloracne, and ________ damage. its chronic toxicity is suppression of the _______ system, nervous sytem, teratogenic (________ defects), carcinogenic, and endocrine disruption

incomplete, cigarette, local, stability, biomagnification, lipophilic, potent, lesions, liver, immune, birth

describe the human exposure to dioxin. >90% of human exposure comes from ________. the average daily intake is 1-____ pg/kg (60-200 pg/adult). bioaccumulation (fat tissues, milk) and biomagnification (through the food _______) occur. dioxin could pass placenta (affecting __________)

food, 3, chain, fetus

the dioxin metabolism in the body (cytochrom P-450) is very _______

slow

what happens during high dose exposure of dioxin aka acute dioxin toxicity? rapid _______ of body weight (1/3-1/2 body weight prior to death), _________ in lymphoid tissues (thymus and spleen), enlargement of ________ (but not observed in humans), and chloracne (hallmark of dioxin toxicity, hyperplastic and hyperkeratotic changes in________, very persistent >30 years in humans)

loss, atrophy, liver, skin

in the seveso disaster in 1976 in Italy, _____ immediate human death was reported therefore more resistant than other mammals

no

the health effects of dioxin may be explained by dioxin’s carcinogenicity, teratogenicity, and _________ disruptor

endocrine

what is the chronic health effect of dioxin exposure? endocrine disruptor, ___________ (IARC group 1 - carcinogenic to human), teratogenic (spina bifida, incomplete closure of spinal cord), shrinkage of thymus (impact on ___________ system), half-life in the body (human) is estimated 5-____ years. but dioxins are NOT _________ (any agent that permanently alters an organism’s genetic material)

carcinogenic, immune, 11, mutagenic

describe endocrine disruptors in human health. they disturb endogenous _________ signaling pathways. there are increased incidents in ___________ abnormalities, early puberty, growth abnormality and development of _________, and _________ disorders such as diabetes. _________ receptor (ER) and androgen receptor (AR) are common targets

hormone, reproductive, cancers, metabolic, estrogen

the shrinkage of thymus compromises ___ cell maturation (T cells cannot learn “self” and “non-self” issue with bone marrow lymphopoiesis

T

brief summary of dioxin’s carcinogenicity:

1. dioxin is _______ mutagenic (does not cause DNA mutation or damage)

2. dioxin is an _______ disruptor (hormonal imbalance leads to increasing risk of _________ and other health problems)

3. dioxin compromises the host _________ system (shrinkage of thymus = impaired T-cell maturation, reduced immune surveillance, detection and elimination of ________ cells)

not, endocrine, cancer, immune, tumor

overall, dioxins make cellular _______environment more “mitogenic” (promoting cell ________, growth and proliferation). SO therefore _________ or mutated cells could also survive and grow (it is called tumor _______) → this is “________” (means it fades)

micro, survival, damaged, promotor, reversible

what is Benzo[a]pyrene? it is produced during incomplete ________ of ______ fuel, ________, and coal, and in cigarette smoke, could distribute in _______ range (air, water, soil), and has an estimated half life of ________ in water, 290 in soil, and ____ days in body. bioaccumulation and biomagnification is ______. the carcinogenic is same as dioxin but it is also _________. teratogenic and endocrine disruptor

combustion, fossil, wood, wide, 875, 12, low, mutagenic

there is DNA base mutation by benzo[a]pyrene. the groove in the DNA base pair is the primary target for B[a]P, causing DNA adduct and mutation. only O and NH sites are available for hydrogen bonding _______ cannot be paired anymore. instead, _______ or adenine can form a pair with this

cytosine, thymine

Benzo[a]pyrene (BaP) can form DNA ______ that disrupt DNA. during _________, this damage can become a DNA mutation, causing irreversible tumor __________

adducts, replication, initiation

if mutations from BaP affect critical genes such as tumor _________ genes or oncogenes, cells may divide __________

suppressor, uncontrollably

what are the similarities btw Benzo[a]pyrene vs. dioxin in toxic mechanisms of action? they are both classified as _________, endocrine disruptors leading to abnormal ________ and cell _________, and they both damage the ___________ = impaired _______ system and surveillance (damaged or mutated cells could ____________)

carcinogens, growth, proliferation, thymus, immune, survive

what are the differences btw Benzo[a]pyrene vs. dioxin in toxic mechanisms of action? dioxin is _____ mutagenic, but B[a]P (its metabolite) is ________

not, mutagenic

tumor initiation is an ________ DNA mutation that __________ a damaged cell, while tumor __________ is a reversible signal that encourages that cell to survive and multiple

irreversible, creates, promotion