Reproductive toxicology: the science today

Reproductive toxicology is concerned with chemical or physical agents interfering with fertility in both gender. Adverse effects may be induced directly, especially in adult males by damaging the semen producing epithelium (e.g., DBCP), or indirectly, predominantly by interfering with sex hormonal homeostasis. Many critical events must occur during well-defined periods of prenatal and early postnatal development of the reproductive system. Most of such differentiation processes, several of which in the male critically depend on inducing influences of androgens, cannot take place at later stages, and lack of "imprinting" will result in irreversible defects or dysfunctions. These processes might be disturbed by interfering agents (e.g., by anti-androgens: feminization), provided that the exposure is high enough. Several of the processes known to be essential for male development can also be altered in females by exposure to a large excess of androgens (masculinization). Essential processes required for normal male development include: 1) androgen-dependent differentiation of the male phenotype during late embryonic development, 2) differentiation of the male secondary sex organs during the fetal period, 3) formation of a fixed number of Sertoli cells during the perinatal period, 4) imprinting of male sexual behavior in defined brain areas during the perinatal period, 5) imprinting of the pulsatile GnRH regulation of hypophysial hormone formation in both gender via the hypothalamico-hypophysial axis, and 6) differentiation of the male organism during puberty. Many effects on fertility can be induced on the adult organism. Besides a direct action on the receptors, inhibition of the feed back mechanism that guarantees sex hormonal homeostasis is another mode of action. Many synthetic steroid compounds exhibit effects on more than one receptor, thus causing a complex situation. This must also be taken into account when analyzing possible effects of "ecohormones." Adverse hormonal actions are well established from experience in clinical and experimental medicine, using either natural or synthetic sex hormones, or enzyme inhibitors. Possible effects of "environmental" agents either mimicking or inhibiting sex hormonal actions are less well studied in clinical trials. Because of considerable species differences in hormonal effects, especially in pharmacokinetics, data of animal studies are of limited predictive value for extrapolations in preventive hazard minimization (but may be useful for revealing possible mechanisms of action). Data of in-vitro studies are even less suitable for extrapolations. It may be doubted that exposure of the general population to "ecohormones" or "xenohormones" is sufficient to induce clear-cut clinical effects. Adverse effects induced by, e.g., greatly unbalanced diets or after accidental overdoses cannot be excluded.