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Gametes & Embryos > Environmental Toxins, Radiation, & Teratogenesis > Flashcards

Environmental Toxins, Radiation, & Teratogenesis Flashcards

1
Q

Explain why outcomes of mutations caused by the environment in female gametes is different than that in males.

A
  1. Chemicals and ionizing radiation affects arrested oocytes in minor ways but after this stage they are killed (accelerates menopause).
  2. Exposure of toxins to sensitive stages of meiosis I and II causes structural and numerical chromosome abnormality.
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2
Q

Explain why outcomes of mutations caused by the environment in male gametes is different than that in females.

A
  1. Clinical and environmental toxins cause more gene mutations and transmissible structure chromosome aberrations (reciprocal translocations) and numerous chromosome aberrations (aneuploidy) than in females.
  2. Perhaps because they have no cytoplasm, mature spermatozoa are highly vulnerable to mutagens and have no DNA-repair capacity (in contrast to BOTH oocytes and somatic cells).
  3. Cell killing by mutagens predominantly affects differentiating spermatogonia and primary spermatocytes.
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3
Q

What two animal studies developed to analyze toxic affects in human gonads?

A
  1. ICSI - spermatozoa from humans injected into mice oocytes (human chromosomes from sperm analyzed in 1-cell hybrid).
  2. IVF - spermatozoa from humans used with golden hamster oocytes and thus, studies of human cytogenetics carried out over last two decades.
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4
Q

What is C-band staining used for?

A

A method for studying gonadal toxins (C stands for centromere).

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5
Q

How is the micronucleus test used to study gonadal toxins?

A

As a substitute for sperm chromosome analysis; detects incidence of spermatozoa with chromosomal breaks or fragmentation after radiation (called “clastogen” effects)

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6
Q

What are four methods used today to study gonadal toxicity?

A
  1. C-band staining
  2. Micronucleus test (MN)
  3. TUNEL assay
  4. FISH & chromosome paint
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7
Q

What is a “clastogen” effect?

A

Structural changes to chromosomes that are usually detectable by a light microscope and caused by radiation damage.

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8
Q

How is metabolic activation of toxins in gonads addressed?

A
  1. S9, an extract from homogenized rat liver, is used.
  2. S9 has enhanced levels of metabolizing agents involved in activation and detox of drugs.
  3. Can convert non-genotoxic compounds into genotoxic metabolites.
  4. NOTE: This is required for genotoxicity assessments of compounds that only become toxic to genes AFTER being metabolized.
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9
Q

How is the TUNEL assay used to study DNA fragmentation in gonad toxicity studies?

A

TUNEL labels nick ends of DNA so that DNA fragmentation can be sen after using a special dye (usually fluorescent).

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10
Q

What are three examples of environmental toxins or other causes of DNA fragmentation in gametes?

A
  1. pesticides
  2. heavy metals
  3. oxidative stress
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11
Q

How is FISH used to study gonadal toxins?

A

FISH with chromosome-specific DNA probes assesses aneuploidy (usually disomy) and diploidy in sperm of any species; also useful for identifying chromosomal translocation in metaphase chromosomes and for karyotyping.

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12
Q

How is chromosomal paint used to study gonadal toxins?

A

Chromosomal paint and FISH probes help by staining ALL human chromosomes and then computer analysis analyzes karyotype and locates translocations/etc.

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13
Q

How are chemical mutagens of human sperm characterized?

A

By their differential spermatogenic responses (ex. different chemicals induce mutations in different germ cell stages).

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14
Q

Knowledge of what is essential for test agents that evaluate genetic hazard of sperm? Give an example.

A

Sensitive germ cell stages; example: stem cell effects present permanent genetic hazards and post-stem cell effects present transient hazards.

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15
Q

Increased structural chromosomal aberrations in human sperm were found in spermatozoa treated with what type of agent?

A

Antineoplastic agents like bleomycin, daunomycin, methyl methanesulfonate, triethylenemelanime, neocarzinostatin, and mitomycin C.
NOTE: Also seen with carcinogens like N-methyl-N-nitro-N-nitrosoguanidine.

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16
Q

How was the motility and fertilizing ability of sperm treated with antineoplastic and carcinogenic agents affected if at all, and what does this indicate?

A

Not effected; suggesting there is no selection of spermatozoa with chromosome aberrations at fertilization.

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17
Q

What are antineoplastic agents used for?

A

Inhibit or prevent the maturation and proliferation of neoplasms by targeting DNA (most chemotherapy drugs are antineoplastic).

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18
Q

What are five kinds of ionizing radiation of which their effect on human chromosomes has been well studied?

A
  1. 137Cs-gamma
  2. 60Co-gamma
  3. X-ray
  4. 3H-beta rays
  5. 252Cf fission neutrons
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19
Q

Ionizing radiation affects what male germ cell stages and in particular what type of sperm cell?

A
  1. ALL stages

2. Particularly spermatogonial stem cells

20
Q

How are sperm chromosomal aberrations affected by increasing doses of ionizing radiation?

A

Dose-dependent increases.

21
Q

What two things did in vivo study of male cancer patients demonstrate?

A
  1. High fertilizing ability retained which means that there isn’t a mechanism to prevent transmission of affected spermatozoa to next generation at fertilization.
  2. Majority of de novo structural chromosome aberrations in fetuses and newborns are of paternal origin.
22
Q

What is one common long-term consequence of chemotherapy and radiation in females?

A

Premature ovarian failure.

23
Q

Contrast between cytotoxic-induced damage in the somatic cells (like bone marrow) vs. gametes in a female after chemotherapy or radiation.

A

Damage is reversible in rapidly dividing cells like bone marrow but appears to be irreversible and progressive in ovary, where number of germ cells is fixed.

24
Q

Studies show that infertility is one of the main long-term consequences of combination chemotherapy given to young women with what two types of cancer?

A
  1. Hodgkin lymphoma
  2. Leukemia
  3. Among others
25
Q

What are four important things to know about arsenic?

A
  1. An environmental contaminant produces a variety of stress responses in mammalian cells, including metabolic abnormalities accompanied by growth inhibition and carcinogenesis.
  2. Much of the toxicity of arsenic is known to stem from its uncoupling effects on mitochondria.
  3. In vivo study using moue model showed abnormalities of spindle formation and chromosome alignment at metaphase II oocytes, suggesting that it causes meiotic aberrations.
  4. In mouse study, untreated fertilized eggs showed signs of apoptosis from arsenic poisoning (zygotes which were treated did develop).
26
Q

What are six important effects of cigarettes on fertility?

A
  1. Polycyclic aromatic hydrocarbons found in both cigarettes and air pollution interact with the aryl hydrocarbon receptor to cause reproductive defects.
  2. Smoking is associated with low sperm quality but clinical effects are not recognized. Cadmium (heavy metal), nicotine (toxic alkaloid), and its metabolite, cottoning, are detectable in gonadal tissues and fluids in association with smoking.
  3. Ovary and oocytes in particular are targets for toxic agents in tobacco smoke, which has been called the “greatest reproductive poison.”
  4. Smoking alters the meiotic spindle of oocytes and spermatozoa, which will lead to chromosome errors.
  5. Smoking is associated with reduced numbers of retrieved oocytes, leading to early age of menopause.
  6. Smoking may change reactive oxygen species and cause oxidative DNA damage (as well as nicotine-induced aneuploidy in mice studies).
27
Q

What are four important things to know about benzoapyrine?

A
  1. Carcinogenic polycyclic aromatic hydrocarbon from cigarette combustion.
  2. Its reactive metabolite binds covalently to DNA and creates adducts.
  3. These adducts were found in ovarian granulose-lutein cells, oocytes, spermatozoa and preimplantation embryos.
  4. Transmission of altered DNA from smoking by spermatozoa was demonstrated in preimplantation embryos in association with increased risk of childhood cancer.
28
Q

What three chemical occupational exposures were found to significantly affect male patients in fertility clinics?

A
  1. Metals (lead, mercury).
  2. Pesticides (dibromochlorophane, 2,4-dichlorophenoxyacetic acid).
  3. Ethylene glycol ethers and estrogens.
29
Q

What two physical exposures were found to deteriorate sperm parameters?

A
  1. Radiation (both ionized and microwaves)

2. Heat

30
Q

How does occupational exposure to organophosphate pesticides affect sperm aneuploidy based on what study?

A
  1. Moderately increases prevalence.

2. Five disomic and one diploid mouse sperm after FISH.

31
Q

What are two specific examples of harmful occupational exposure to toxins and radiation?

A
  1. Isoprene (colorless liquid with a faint odor used to manufacture synthetic natural rubber and elastomer plastics).
  2. Butadiene (mainly used in production of synthetic rubber but is also found in smaller amounts in plastics and fuel; exposure mainly occurs in workplace).
32
Q

What harm was isoprene shown to cause with respect to fertility in studies?

A
  1. Reduced fetal body weight and decreased maternal weight gain after exposure; also affected ovarian follicles (mice).
  2. Reduction in testicular function parameters, including weight and sperm motility.
33
Q

What harm was butadiene shown to cause with respect to fertility in studies?

A

Evidence of congenital malformations in mice after exposure as well as linear concentration-related induction of heritable translocations in mice, and the risk of producing a child with a balanced reciprocal translocation is twice as high as background risk.

34
Q

Accute exposure to polycyclic aromatic hydrocarbons cause what to happen to germ cells and follicles and what are the reasons for this?

A

Apoptosis; little is known about reasons but it occurs in all species studied.

35
Q

What are five strategies to preserve female fertility before chemotherapy?

A
  1. IVF and embryo cryopreservation
  2. Ovarian cryopreservation and autotransplantation
  3. Ovarian cryopreservation and xenotransplantation
  4. Ovarian cryopreservation and IVM
  5. GnRH analogs
36
Q

What are two advantages and disadvantages in using IVF and embryo cryopreservation to preserve fertility prior to chemotherapy?

A
  1. Advantages: very efficient & clinically available.

2. Disadvantages: Invaluable in very young, single patients & possibly dangerous in estrogen-dependent cancers.

37
Q

What are two advantages and disadvantages in using ovarian cryopreservation and autotransplantation to preserve fertility prior to chemotherapy?

A
  1. Advantages: High potential & effective in animals like sheep and mice.
  2. Disadvantages: Low efficacy in humans & investigational still.
38
Q

What are advantages and disadvantages in using ovarian cryopreservation and xenotransplantation to preserve fertility prior to chemotherapy?

A
  1. Advantage: High potential.

2. Disadvantages: Cancer cells may be reinstitute, and investigational.

39
Q

What are advantages and disadvantages in using ovarian cryopreservation and IVM to preserve fertility prior to chemotherapy?

A
  1. Advantage: High potential.

2. Disadvantages: Technology not yet developed, low efficacy in humans, and investigational.

40
Q

What are some advantages and disadvantages in using GnRH analogues to preserve fertility prior to chemotherapy?

A
  1. Advantages: Simple, inexpensive, minimal side effects, promising preliminary results (ideal when effective).
  2. Disadvantages: Non-applicable to radiotherapy, not effective in very aggressive chemotherapy like BMT, investigational.
41
Q

What strategies are used for sperm preservation prior to chemotherapy?

A

Cryopreservation of sperm and testicular tissue.

42
Q

Studies show that what percentage of adult females undergoing cancer therapy experienced one or more symptoms of ovarian failure?

A

64%

43
Q

Compare chances of maintaining gonadal function between girls and boys post-cancer treatment.

A

Significantly greater, respectively.

44
Q

What were the results of a long-term fertility follow-up of 240 s disease?

A
  1. Azoospermia in 83% of boys.
  2. Ovarian failure in 13% of girls
    NOTE: Treatment included Mechlorethamine, Vincristine, Procarbazine, Prednisolone.
45
Q

What is one suggestion to render germinal epithelium less susceptible to effects of chemotherapy in both genders?

A

Inhibition of pituitary-gonadal access to reduce the rate of spermatogenesis and oogenesis.

46
Q

What is one possible way that pituitary-gonadal axis can be inhibited to protect against sterilizing effects of chemotherapy? What studies lend support to this idea?

A
  1. By using GnRH-agonist to decrease secretion of pituitary gonadotropin, therefore decreasing gonadal function.
  2. It prevented chemotherapy-induced ovarian follicular depletion in rat; and it protects the ovary against cyclophosphamide-induced damage in Rhesus monkeys by decreasing amount of follicle loss during chemotherapeutic insult and decreasing daily rate of follicular decline.

Gametes & Embryos (15 decks)

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