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Hodgson E. Modern toxicology [2004].pdf
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344 REPRODUCTIVE SYSTEM

Physiology of Reproductive System

Hypothalamic-pituitary-GonadalAxis

CNS

 

 

 

 

 

 

 

 

 

()

()

 

 

 

Hypothalamus

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Releasing Hormone(s)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(GnRH)

 

 

 

 

 

 

 

 

 

()

 

 

 

 

Anterior Pituitary

 

 

 

Tropic

 

 

 

 

 

 

 

 

Target Organ

Hormone

 

 

 

 

 

 

 

 

 

 

Hormone (Testosterone,

(FHS, LH)

 

 

 

 

 

 

 

 

 

 

Estrogens, Inhibin)

 

 

 

 

 

 

 

 

(+)

Target Organ(s)

Figure 20.1 Hypothalamic–pituitary–gonadalaxis. Negative feedback is designated by (), and positive feedback is designated by (+).

Sertoli’s Spermatogonium

Primary

Secondary

Spermatid Spermatids in process

spermatocyte

spermatocyte

of conversion to spermatozoa

cells

 

 

 

Figure 20.2 Spermatogenesis. (Adapted from J. A. Thomas, inCasarett and Doull’s Toxicology: The Basic Science of Poisons, 6th ed., C. D. Klassen, ed.,McGraw-Hill,2001.)

Two major components of the testis are the seminiferous tubules (site of spermatogenesis) and the interstitial compartment. The interstitial compartment contains Leydig cells, which produce testosterone under the influence of LH. Androgens control spermatogenesis (Figure 20.2), growth and activity of accessory sex glands, masculinization, male behavior, and various metabolic functions. Secretion of androgen by the developing fetal testis is essential for differentiation of the gonads, which includes regression of Mullerian¨ ducts and the development of Wolffian ducts.

20.3 MECHANISMS AND TARGETS OF MALE REPRODUCTIVE TOXICANTS

20.3.1General Mechanisms

Toxicants may mimic endogenous compounds (i.e., hormones), thus acting as agonists or antagonists. Toxicants may be directly cytotoxic or may be activated to toxic compounds. Some toxicants may have indirect effects by inhibiting key enzymes involved

MECHANISMS AND TARGETS OF MALE REPRODUCTIVE TOXICANTS

345

in steroid synthesis. Below are examples of how selected toxicants affect various susceptible targets of the male reproductive tract.

20.3.2Effects on Germ Cells

Epidemiological data have indicated that wives of men exposed to the compound vinyl chloride experience spontaneous abortion. Vinyl chloride is used to manufacture polyvinyl chloride (PVC). PVC is a component of various plastic products, including pipes, furniture, and automobile upholstery. Ethylnitrosourea (ENU) is a mutagenic agent that has been used extensively in mouse mutagenesis. ENU acts on male spermatogonial stem cells, introducing mutations. It is also capable of inducing reversible sterility in mice. Actinomycin D is an older chemotherapeutic drug that has been used in cancer therapy for many years. Actinomycin D is commonly used in the treatment of gestational trophoblastic cancers, testicular cancer, Wilm’s tumor, and rhabdomyosarcoma. Actinomycin D intercalates with DNA and disrupts the structure and function of the DNA of the spermatozoa.

20.3.3Effects on Spermatogenesis and Sperm Quality

The antibiotics and antimetabolites used in cancer treatment (i.e., vinblastine) are spermatotoxic and affect semen quality. Ionizing radiation is also spermatotoxic (with spermatogonial cells being the most sensitive). Prolonged scrotal heating is a factor that affects the earlier states of spermatogenesis.

20.3.4Effects on Sexual Behavior

Anabolic steroids, antidepressants and drugs of abuse affect libido, potency, and ejaculatory function. Anabolic steroids are derivatives of testosterone, and have strong genitotropic effects. There is published evidence indicating that anabolic steroids increases sexual desire; however, the frequency of erectile dysfunction is also increased. Treatment with the antidepressant fluoxetine has been associated with sexual side effects including delayed or nonexistent ejaculation and hyposexuality. Mice treated in utero with the anitleukemic agent 5-aza-2-deoxycytidineexhibit abnormal reproductive behavior and low reproductive capacity.

20.3.5Effects on Endocrine Function

Cimetidine (for treatment of peptic ulcers) competes with dihydrotestosterone for receptors in the testis and accessory sex glands. The more common sequelae are low sperm count and gynacomastia. Epidemiological evidence has shown that occupation exposure to oral contraceptives can induce gynacomastia in exposed males. Diethylstilbestrol (DES) antagonizes the activity of fetal testosterone. In the male offspring, testicular hypoplasia, abnormal semen parameters, and infertility result. Ketoconazole has be shown to be transported to the seminal fluid and to immobilize the sperm.