Download Mechanisms of female reproductive toxicity

Mechanisms of female
reproductive toxicity
Helena Taskinen
Finnish Institute of
Occupational Health
Critical points of female fertility
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libido, sexual behaviour
oogenesis
hormonal function
fertilization
transportation
implantation
Developmental toxicity
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gameto-, embryo- and fetotoxicity
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abortion, stillbirth
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teratogenic effetcs
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intrauterine growth retardation
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functional defects
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impaired mental and physical postnatal development
up to puberty
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childhood cancer
Hypothalamo-pituitary-ovarian axis
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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
Mechanisms of toxins 1
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Direct acting toxins: structurally similar or
chemically reactive
Direct damage to cells, organelles, DNA/RNA,
enzymatic and biochemical pathways
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alkylating compunds, metals (boron, cadmium, lead,
mercury) and ionizing radiation
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Indirect toxins: metabolic activation
produces reactive intermediates:
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cyclophosphamide, DDT, PAH,
dibromochloropropane
Mechanisms of toxins 2
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Hormone agonists or antagonists
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oral contraceptives, DDT, methoxychlor,
polychlorinated biphenyls, polybrominated
biphenyls, organochlorine pesticides
Cellular (oocyte) death: necrosis
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pesticides, PAH in cigarette smoke,
chemotherapeutic agents, ionizing radiation,
nitrosamines, lead, mercury, cadmium,
4-vinylcyclohexene
Mechanisms of toxins 4
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Apoptosis, programmed cellular death
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is preceded by activation of calcium/ magnesiumdependent 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
Oocyte toxicants
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Polycyclic aromatic hydrocarbons can
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destroy primordial follicles
cause ovarian tumors
induce chromosomal aberrations in oocyte
meiosis
Busulfan and antineoplastic agents can
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destroy primordial germ cells or developing
follicles, and mutate preovulatory follicles
Toxicants 2
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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
Toxicants 3
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The hypothalamo-pituitary unit is
disturbed by
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anesthetics, stimulants, analgetics,
hallucinogens, marihuana, morphine,
cocaine
estrogenic chemicals, e.g. diethylstilbestrol
(DES)
Toxicity of diethylstilbestrol
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a synthetic estrogen, used to prevent
spontaneous abortions in 1938-1971
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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
Cadmium (Cd)
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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
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
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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)
Species differences
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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
Examples of agents causing toxic
effects early in the development
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Ionizing radiation
Methylnitrosourea
Medroxyprogesterone acetate
Nickel chloride
Ethylene oxide
Nitrous oxide
Isoflurane
Placenta
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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
Cadmium and placenta
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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
Other effects on placenta
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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
2-methoxyethanol (2-ME) & 2-ethoxyethanol
(2-EE) and their acetates
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alcohol and aldehyde dehydrogenase enzymes
active; if inhibited with 4-methylpyrazole, no
malformations
Teratogenic alcoxy acid metabolites:
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2-methoxyacetaldehyde and methoxy acetic acid
from 2-ME
ethoxyacetaldehyde and ethoxyacetic acid from 2EE
Heavy work
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Intraabdominal pressure rises, decreases
intrauterine blood flow
Growth retardation
In women 17 % fat needed for menstruation;
22 % for fertility
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hypoestrogenism
In men <5 % body fat decreases testosterone
and prolactin in the serum