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310 ENDOCRINE SYSTEM

Accordingly the disrupting effect of the toxicant also is irreversible. These organizational effects may be evident only later in life during maturation or reproduction. Neonatal exposure to DES resulting in proliferation of epithelial cells of the reproductive tract at reproductive maturity is an example of an organizational effect of an endocrine toxicant. Organizational effects of endocrine toxicants have been of great concern to toxicologists and are the most difficult type of toxicity to diagnose owing to the temporal separation between exposure and effect.

An activational effect of an endocrine toxicant occurs in the same time frame as the exposure and is the consequence of the toxicant disrupting the immediate role of a hormone in some physiological process. Activational effects are reversible following cessation of exposure to the toxicant. For example, androgens contribute to maintenance of the prostate gland in the adult male. Exposure of adult males to an antiandrogen can result in a decrease in prostate size. Cessation of exposure to the antiandrogen then results in restoration of the prostate gland to its normal size.

17.3.4Inhibitors of Hormone Synthesis

Endocrine toxicants can elicit antihormone activity by lowering levels of endogenous hormone in the body. With steroid hormones, chemicals typically elicit this effect by inhibiting enzymes necessary for synthesis of the hormone. For example, the cytochrome P450 enzyme CYP19 is responsible for the aromatization of testosterone to form 17β-estradiol.CYP19 inhibitors such as fadrozol, anastrozole, and letrozole, can lower endogenous17β-estradiollevels resulting inde-feminization.Cytochrome P450s enzymes also are critical to various hydroxylation reactions that contribute to the synthesis of androgens and other steroid hormones and inhibition of these enzymes can result in a variety of antisteroid hormone effects. For example, the agricultural and medicinal fungicides propiconazole, ketoconazole, and fenarimol are capable of inhibiting P450 enzymes and reducing synthesis and circulating levels of testosterone and other steroid hormones. Toxicological consequences of the lowering of endogenous steroid hormone levels are typically comparable to those effects elicited by antagonists of the hormone’s receptor.

17.3.5Inducers of Hormone Clearance

In most species, steroid and thyroid hormones are inactivated and cleared from the body by the same biotransformation processes that are involved in chemical detoxification (see Chapter 7). Predominant among the hormone biotransformation processes in vertebrates are hydroxylation, glucuronic acid conjugation, and sulfate conjugation. The thyroid hormones T3 and T4 are inactivated and cleared following sulfate and glucuronic acid conjugation, respectively. The glucuronosyl transferase enzymes that are responsible for the elimination of T4 are induced following exposure to phenobarbitaltype inducers and Ah receptor ligands (see Chapter 9). Thus exposure to chemicals such as some dioxins and PCBs can result in enhanced clearance of thyroid hormone resulting in low circulating thyroid hormone levels. The resulting hypothyroid state can result in a variety of pathological conditions. In newborn infants, hypothyroidism is associated with cretinism. This organizational syndrome is characterized by mental retardation, short stature, and various neurological abnormalities. In children,