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Hodgson E. Modern toxicology [2004].pdf
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MECHANISMS AND TARGETS OF FEMALE REPRODUCTIVE TOXICANTS

347

FSH LH

PITUITARY

FOLLICLES OVULATION CORPUS LUTEUM

OVARY

ESTROGEN

PROGESTERONE

UTERUS

2

4

6

8

10

12

16

18

20

22

24

26

28 days

PHASE

Menstruation

Follicular/Proliferative Lufeel/Secretory

The Hormonal Cycle

Figure 20.4 Women’s menstrual cycle. (Courtesy of Women’s Health Interactive, http://www.womens-health.com/healthcenter/gynecology/gyn repro menstrual.html.)

20.5 MECHANISMS AND TARGETS OF FEMALE REPRODUCTIVE TOXICANTS

Xenobiotics can adversely affect the normal functions of the cells/organs of the reproductive system. These agents may induce a variety of outcomes, including prevention of ovulation and impairment of ovum transport, fertilization, or implantation. Endocrine disruptors may mimic endogenous hormones as well as directly destroy cellular components, leading to cell death. More indirect effects may include inhibition of key enzymes involved in steroid synthesis.

20.5.1Tranquilizers, Narcotics, and Social Drugs

Compounds within this class of substances can inhibit hypothalamic–pituitary–ovarianaxis function by inhibiting gonadotropin secretion. Subsequently ovulation and estrus is suppress leading to infertility or reduced fertility.

348 REPRODUCTIVE SYSTEM

20.5.2Endocrine Disruptors (EDs)

Endocrine disruptors are compounds (synthetic and naturally occurring) that can alter the normal hormonal balance and function in animals. The historical ED diethylstilbestrol (DES) is a classic example of an endocrine disrupter affecting female reproductive health. In utero exposure of females to DES is associated with the induction of vaginal carcinomas apparent after puberty. In experimental mice, estrogenic substances cause accelerated sexual maturation and irregular estrous cycles and prolonged estrous. In rats, xenoestrogens such as kepone and methoxychlor cause masculinization of the exposed female rats. These rats do not ovulate, lack stimulation of the LH surge, and exhibit male sexual behavior. In humans, estrogen mimicking compounds can alter natural hormonal cycles and have been associated with breast cancer induction. Certain environmental EDs may function as promoters or inducers of carcinogenesis. Polychlorinated biphenyls (PCBs) and a trichloroethane compound (DDT) are persistent in the environment. Serum DDE (a DDT metabolite) levels have been found to correlate with breast cancer incidence.

20.5.3Effects on Germ Cells

As previously described for the male reproductive toxicity, the class of toxicants affecting germ cells can alter the structure of genetic material (chromosomal aberrations, alterations in meiosis, DNA synthesis, and replication). Mature oocytes have a DNA repair capacity different from that of mature sperm, but this capacity decreases at the period of meiotic maturation.

20.5.4Effects on the Ovaries and Uterus

Cyclophosphamide and vincristine are examples of alkylating agents capable of inducing gonadal dysfunction. Premature menopause is a primary outcome of exposure to these agents. Amenorrhea and abnormal hormonal levels are characteristics of the ovarian dysfunction induced by cyclophosphamide.

Premature ovarian failure can be induced in offspring exposed in utero by active metabolites such as 6-mercaptopurine.Tamoxifen (treatments for breast cancer) and clomiphene (to induce ovulation) are antiestrogens that can inhibit uterine decidual induction in pseudopregnant rats.

20.5.5Effects on Sexual Behavior

Normal sexual activity is associated with ovulation in most female mammals. Compounds affecting this process can adversely affect female libido. Ovarian failure induced by xenobiotic compounds has been associated with a decrease in libido in women. Certain types of oral contraceptives as well as drugs of abuse (methadone, cannabis, alcohol) cause decreases in female libido. The treatment for hirsutism, excessive growth of hair in both normal and abnormal locations, is the compound cyproterone acetate. It is an antiandrogen that has the side effect of severely decreasing libido in women.