Mechanisms of female reproductive toxicity

Helena Taskinen

Finnish Institute of Occupational Health

Critical points of female fertility

libido, sexual behaviour oogenesis hormonal function fertilization transportation implantation

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

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

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

Indirect toxins: metabolic activation produces reactive intermediates: – cyclophosphamide, DDT, PAH,

dibromochloropropane

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

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

Oocyte toxicants

Polycyclic aromatic hydrocarbons can – destroy primordial follicles– cause ovarian tumors– induce chromosomal aberrations in oocyte

meiosisBusulfan and antineoplastic agents can

– destroy primordial germ cells or developing follicles, and mutate preovulatory follicles

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

Toxicants 3

The hypothalamo-pituitary unit is disturbed by– anesthetics, stimulants, analgetics,

hallucinogens, marihuana, morphine, cocaine

– estrogenic chemicals, e.g. diethylstilbestrol (DES)

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

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

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

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)

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

Examples of agents causing toxic effects early in the development

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

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

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

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

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

Heavy work

Intraabdominal pressure rises, decreases intrauterine blood flow

Growth retardation In women 17 % fat needed for menstruation;

22 % for fertility– hypoestrogenism

In men <5 % body fat decreases testosterone and prolactin in the serum