Mechanisms of female reproductive toxicity

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Mechanisms of female reproductive toxicity

• Helena Taskinen
• Finnish Institute of Occupational Health

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Critical points of female fertility

• libido, sexual behaviour
• oogenesis
• hormonal function
• fertilization
• transportation
• implantation

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Developmental toxicity

• gameto-, embryo- and fetotoxicity
• abortion, stillbirth
• teratogenic effetcs
• intrauterine growth retardation
• functional defects
• impaired mental and physical postnatal
  development up to puberty
• childhood cancer

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Hypothalamo-pituitary-ovarian axis

• Hypothalamus hypothalamic-releasing factor,
  gonadotropin-releasing hormone
• Pituitary Gonadotropin-releasing hormone,
  gonadotropins follicle stimulating hormone (FSH)
  and luteinizing hormone (LH)
• Ovary estrogen and progesterone
• Agents that disturb the axis can disrupt ovarian
  function

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Hypothalamo- Pituitary- Ovarian axis
Hypothalamus
Hypothalamic factors
Progesteron, estrogen
Pituitary gland
Gonadotropins, prolactin
Ovary
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Mechanisms of toxins 1

• Direct acting toxins structurally similar or
  chemically reactive
• Direct damage to cells, organelles, DNA/RNA,
  enzymatic and biochemical pathways
• alkylating compunds, metals (boron, cadmium,
  lead, mercury) and ionizing radiation

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• Indirect toxins metabolic activation produces
  reactive intermediates
• cyclophosphamide, DDT, PAH, dibromochloropropane

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Mechanisms of toxins 2

• Hormone agonists or antagonists
• oral contraceptives, DDT, methoxychlor,
  polychlorinated biphenyls, polybrominated
  biphenyls, organochlorine pesticides
• Cellular (oocyte) death necrosis
• pesticides, PAH in cigarette smoke,
  chemotherapeutic agents, ionizing radiation,
  nitrosamines, lead, mercury, cadmium,
  4-vinylcyclohexene

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Mechanisms of toxins 4

• Apoptosis, programmed cellular death
• is preceded by activation of calcium/
  magnesium-dependent endonuclease enzyme
• change in the cellular environment
• hyperthermia and radiation can trigger
• also a physiological form of cell death
• poorly understood, toxins possible, e.g.
  chemotherapeutics cisplatin and vinblastine

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Oogenesis

• A single follicle becomes graafian follicle,
  which releases the oocyte
• Toxicants interfering the oocyte maturation in
  the graafian follicle impair reproduction -
  recovery in next cycle possible
• Toxicants affecting primordial or primary
  follicle may lead to shortened reproductive life
  span and premature ovarian failure

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Oocyte toxicants

• Polycyclic aromatic hydrocarbons can
• destroy primordial follicles
• cause ovarian tumors
• induce chromosomal aberrations in oocyte meiosis
• Busulfan and antineoplastic agents can
• destroy primordial germ cells or developing
  follicles, and mutate preovulatory follicles

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Toxicants 2

• DDT and diethylstilbestrol (DES), estrogenic
  compounds, suppress ovarian progesterone
  production
• General anesthesia during periovulatory period
  lowers progesterone levels
• Benzo(a)pyrene in cigarette smoke inhibits
  corpora lutea formation and thus progesterone
  production

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Toxicants 3

• The hypothalamo-pituitary unit is disturbed by
• anesthetics, stimulants, analgetics,
  hallucinogens, marihuana, morphine, cocaine
• estrogenic chemicals, e.g. diethylstilbestrol
  (DES)

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Toxicity of diethylstilbestrol

• a synthetic estrogen, used to prevent spontaneous
  abortions in 1938-1971
• proven ineffective in later studies!
• mutagenic and carcinogenic effects mediated
  through production of reactive metabolites, DNA
  adducts
• clear cell vaginal carcinoma in daughters
• 18 of offspring (f) abnormal of the cervix

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Cadmium (Cd)

• Structural similarity with zinc - Cd can displace
  zinc in zinc-dependent enzymes
• in rats follicular atresia, changes in uterine
  microcirculation decreased uterine, ovarian and
  pituitary weights

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Developmental abnormalities

• Major malformation at birth among 3
• Problems of developmental origin among 6 -7 by
  1 year of age
• Among 12 - 14 by school age

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Causes of developmental abnormalities

• 20 - 28 familial genetic defect
• 10 - 3 external exposure (environmental, drugs,
  nutritional)
• 0 - 23 multifactorial cause
• 70 - 43 unknown cause (Wilson 1977 Nelson
  and Holmes 1989)

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Species differences

• Mammalian embryogenesis and fetal development
  relatively similar among all species
• Differences btw. species due to differences in
  xenobiotic absorption and metabolism
• e.g. thalidomide not soluble in rat blood - no
  teratogenecity in tests! When solubility was
  increased, teratogenic in low doses

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Examples of agents causing toxic effects early in
the development

• Ionizing radiation
• Methylnitrosourea
• Medroxyprogesterone acetate
• Nickel chloride
• Ethylene oxide
• Nitrous oxide
• Isoflurane

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• Methylnitrosoureas effect to blastocysts weak,
  nonlethal mutations may play a role in poor
  fetal outcome
• Ethylene oxide (and other chemicals) primary
  damage epigenetic, leads to disruption in the
  normal programming of gene expression during
  early embryogenesis
• Anesthetic gases direct effects, but mechanism
  unknown

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Placenta

• Provides nutrients, gas exchange and hormones for
  maintenance of pregnancy
• Placenta is a liver, kidney, lung, ovary,
  pituitary and hypothalamus in one organ!
• Acts as a barrier for toxicants, metabolizes them
  into less or more detrimental compounds

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Cadmium and placenta

• Cadmium induces placental necrosis at lower doses
  than renal toxicity
• deposited in placenta, little into fetus
• blocks nutrient and blood flow growth
  retardation, fetal death
• interferes with zinc
• responsible for the growth retardation caused by
  smoking

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Other effects on placenta

• Cholinergic system regulates amino acid transport
  in the placenta
• Nicotine, carbon monoxide, cyanide, nitrites (all
  present in cigarette smoke) inhibit amino acid
  uptake by placenta by blocking the cholinergic
  receptor
• Risks preeclampsia, growth retardation,
  premature delivery, and perinatal mortality

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2-methoxyethanol (2-ME) 2-ethoxyethanol (2-EE)
and their acetates

• alcohol and aldehyde dehydrogenase enzymes
  active if inhibited with 4-methylpyrazole, no
  malformations
• Teratogenic alcoxy acid metabolites
• 2-methoxyacetaldehyde and methoxy acetic acid
  from 2-ME
• ethoxyacetaldehyde and ethoxyacetic acid from 2-EE

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Heavy work

• Intraabdominal pressure rises, decreases
  intrauterine blood flow
• Growth retardation
• In women 17 fat needed for menstruation 22
  for fertility
• hypoestrogenism
• In men lt5 body fat decreases testosterone and
  prolactin in the serum