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Reproductive Toxicology Reproductive dysfunction is broadly defined in this chapter to include all effects resulting from paternal or maternal exposure that interfere with the conception, development, birth, and normal growth of offspring. Chap- ter 3 is a broad discussion of the end points included under the heading of reproductive toxicology with the exception of embryo (fetal) death, growth retardation, and malformations, which are covered in Chapter 2. The relationship between exposure and reproductive dysfunction is highly complex because exposure of the mother, the father, or both may influence reproductive outcome. In addition, these exposures may have occurred at some time in the past, immediately before conception, or during gestation. For some specific dysfunctions, the relevant period of exposure is limited; for others, it is not. For example, chromosome abnormalities detected in the embryo can arise from lesions in the germ cells of either parent before conception or at fertilization, or from direct exposure of embryonic tissues during gestation. Major malformations, however, usually occur when ex- posure occurs during a discrete period of pregnancy, extending from the third to the eighth week of human development. Many cases of infertility can probably be attributed to postfertilization reproductive failure, i.e., repeated early spontaneous abortion. Such peri- implantation embryonic mortality may not be clinically apparent, since abortion could occur before the expected time of menstruation. Approx- imately 15% of clinically recognized pregnancies terminate in spontaneous abortion. Embryonic death rates in humans may be substantially higher. In recent studies subclinical spontaneous abortion rates were found to be 21% (Chartier et al., 1979) and 34% (Overstreet, 19841. Nonetheless, 35

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36 DRINKING WATER AND HEALTH methods to assess early, subclinical spontaneous abortions are currently inadequate. Although there are extensive data on reproductive performance in human populations, most have been collected for routine surveillance not for environmental monitoring. Even though the effects of specific agents on reproductive function cannot be discerned from such data, useful infor- mation on trends and patterns in the frequency of various reproductive outcomes can be derived. For example, an estimated 11 million married couples in the United States are infertile (i.e., not capable of having children); 3 million of these couples have at least one partner who is noncontraceptively sterile (Mosher, 19851. Although early spontaneous abortions often go unreported, especially among pregnancies of less than 20 weeks duration, they are estimated to result in the termination of 15% of all pregnancies (Warburton and Fraser, 19641. This is generally regarded as an underestimate of the true rate insofar as most spontaneous abortions occur early in gestation, often before the mother is clinically recognized as pregnant. Approximately 7% of all babies are born prematurely (before the 37th week of gestation). Of those born at full term, an estimated 7% have low birth weights (2.5 kg or less) (Niswander and Gordon, 19721. Of the approximately 4 million infants born alive in the United States each year, 10.5 per 1,000 die within the first year (NCHS, 1985), and 2% to 3% of the 4 million infants have major congenital malformations that are recognized within that year (Edmonds et al., 19811. When defects that become apparent later in life are included, the frequency of major and minor malformations increases to about 16% (Chung and Myriantho- poulos, 19751. In very few cases has it been possible to separate a specific chemical exposure's impact on human reproduction from the background rate of spontaneous genetic defects or from other causes, such as radiation, in- fection, nutritional deficiencies, or maternal metabolic imbalance. There are also ethical limitations to conducting human studies, especially those concerning reproductive function. Consequently, the bulb of the infor- mation on specific exposures reported to affect reproductive function is derived from animal studies. The standard toxicological testing procedures for acute, subacute, and chronic exposures are not appropriate for detecting reproductive effects either in humans or in animals. Therefore, a separate series of tests has been developed to monitor reproductive function. These tests can provide both qualitative and quantitative analyses of reproductive toxicants in animals. This chapter contains brief descriptions of the biological development and function of the male and female reproductive systems. Stages partic- ularly susceptible to chemical insult are emphasized. This material is

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Reproductive Toxicology 37 presented to provide a context in which animal data can be applied to humans in estimating the risk of reproductive toxicity. Toxicity to the embryo, fetus, or placenta, resulting in spontaneous abortion, teratogenicity, or other reproductive anomalies, has long been of concern. Other areas not as extensively studied are toxicities affecting the male and female reproductive systems, resulting in sexual dysfunction and infertility. Direct damage to germ cells, neuroendocrine imbalances, and alterations in accessory reproductive organs, which can be involved in these toxicological processes, are described in the following sections as they have been elucidated in animal studies. Consideration is also given to the use of these data to predict reproductive risk to humans. SUSCEPTIBILITY OF THE NONPREGNANT FEMALE TO REPRODUCTIVE IMPAIRMENT Maturation of the Female Reproductive System The development of the female genital tract and subsequent attainment of fertility are processes susceptible to disruption by chemical agents. Reduced fertility in offspring is one of the most sensitive indicators of prenatal exposure to reproductive toxicants. The female fetus is particu- larly vulnerable to germ cell toxicity, since the development of the oocyte occurs prenatally and the maximum number of oocytes available for sub- sequent ovulation is present at the time of birth. Damage to oocytes during the perinatal period may result in decreased reproductive capacity that will not be evident until sexual maturity is reached. Early in embryonic development, the progenitors of the germ cells, called primordial germ cells, are segregated from somatic cells. At 3 weeks of human development, these germ cells are first detectable in the yoLk sac. Thereafter, they undergo mitotic divisions and migrate to the uro- genital ridge where they populate the so-called indifferent gonad. Pri- mordial germ cells then differentiate into oogonia. The oogonial stage is characterized by active mitotic divisions; the daughter cells do not separate, but remain attached to each other by interconnecting cytoplasmic bridges. In the human fetal ovary, approximately 1,700 germ cells migrate to the gonads. By 2 months of gestation, the number of germ cells increases to about 6 x 105. Mitotic activity peaks by the fifth month at approximately 7 x 106 cells. Oogonia first begin to enter meiosis at the third month, and by the end of the fifth month, all the oogonia have entered early prophase I of meiosis and are called primary oocytes (Gondos, 19781. The timing of gonadal sex differentiation and of ovarian germ cell development in various mammalian species is presented in Table 3-1.

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38 DRINKING WATER AND H"LTH TABLE 3-1 Ontogeny of Ovanan Germ Cell Development in Mammalsa Events in Germ Cell Development in Days of Gestation (or Postnatal Age) Length Completion Test of Gonadal Sex Initiation of Arrest of Animal Gestation Differentiation of Meiosis Oogenesisb Meiosis Mouse 19 12 13 16 (5) Rat 21 13-14 17 19 (5) Hamster 16 11-12 (1) (5) (9) Rabbit 31 15-16 (1) (10) (21) Rhesus monkey 165 38 56 165 Newborn Human 270 40-42 84 150 Newborn aAdapted from Gondos, 1978. bCompletion of oogenesis refers to the time when all oogonia have been transformed to primary oocytes. Replicative DNA synthesis occurs during the final interphase before the oogonia enter meiosis. The primary oocyte in prophase I of meiosis thus contains two sets of chromosomes; that is, it is diploid (2N) but contains four strands of DNA. The process of meiosis consists of two cell divisions. First, the number of chromosomes is halved, resulting in the formation of secondary oocytes, each containing one chromosome (IN), i.e., haploid, and two strands of DNA. In the second meiotic division, the chromosome number remains the same but the amount of DNA is halved. Thus, the ovum contains one chromosome and one strand of DNA. Figure 3-1 depicts the process of oocyte maturation in the fetus and adult. Each meiotic division has four stages: prophase, metaphase, anaphase, and telophase. The first meiotic division is initiated late in fetal life and progresses into early prophase during the fetal or neonatal period. By 8 weeks after birth, human oocytes have entered a resting phase of oocyte maturation, where meiosis remains blocked until the beginning of puberty (Biggers, 19801. Given the long duration of prophase I, this stage has been subdivided into five subphases: leptotene, zygotene, pachytene, dip- lotene, and dictyate (resting phase). Each substage is characterized by cytogenetic criteria of chromosome configuration. Extensive physiological degeneration of germ cells occurs during the oogonial and primary oocyte stages of development. In humans, an es- timated 70% of the germ cells present in a 5-month-old fetus are lost before birth (Biggers, 19801. Three distinct waves of degeneration occur in the human ovary, affecting oogonia in mitosis or in the. final interphase, oocytes in the pachytene stage, and oocytes in the diplotene stage of prophase. Oogonia connected by cytoplasmic bridges undergo atresia in

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FIRST MEIOTIC DIVISION PROPHASE RESUMPTION OF MEIOSIS 1 LE PTOTE N E 7 DIAKINESIS 2 ZYGOTENE I ~ ~ UJ 8 METAPHASE 3 PACHYTENE z 4 DIPLOTENE 5 D I CTYATE STAGE 6 9 ANAPHASE 1 0 TE LOPHASE Reproductive Toxicology 39 SECOND ME IOTIC D IV ISION 1 1 METAPHASE OVULATION 1 2 ANAPHASE < o C] 1 3 TELOPHASE 14 PRONUCLEAR EGG . , z o - ~r N J - LO IL FIGURE 3-1 Oocyte maturation. Prophase of the first meiotic division (1-4) occurs during fetal life. In the zygotene stage, homologous chromosomes pair; in the pachytene stage, they form bivalent chromosomes. Genetic material is interchanged by a crossover process. At the diplotene stage, the chromosomes remain united at the points of interchange, the chiasmata. The meiotic process is arrested at the dictyate stage. When meiosis is resumed, the first division is completed (7-11). Ovulation occurs at metaphase of the second division (11), and maturation of the oocyte occurs in the oviduct (12-14) following sperm penetration. Adapted from Tsafriri, 1978. synchrony, which accounts for the majority of germ cell loss. After com- pletion of the meiotic prophase, groups of oocytes no longer appear to undergo atresia simultaneously, but individual oocytes may degenerate at all stages of development. It is not understood why some oocytes degen- erate while others mature. At some point during oogonial proliferation, all the oocytes within a syncytial mass will recruit granulosa cells from the surrounding ovarian

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40 DRINKING WATER AND HEATH stroma and enter meiosis. The mechanism of this process, termed follic- ulogenesis or the formation of follicle complexes, is unknown. Once meiosis is initiated, germ cells lost to physiological atresia cannot be replaced. The maximum number of germ cells potentially available for ovulation in the offspring is fixed in the fetal period when oogonia mature into primary oocytes; the number continues to decrease due to physiolog- ical atresia and ovulation (Hertig and Barton, 1973~. During the prepubertal and reproductive periods, the majority of germ cells remain as primary oocytes enclosed within unilamellar follicles. These resting follicles comprise the pool from which a select number of oocytes are recruited for further maturation to preovulatory or graaf- ian follicles. In those follicles selected for maturation, a zone pellucida forms and separates the oocyte from the follicle cells. Thereafter, the follicular cell layer increases in size and the oocyte undergoes tremen- dous growth. Once a follicle embarks on this maturation process, it either reaches a preovulatory stage or it undergoes atresia (Tsafriri, 1978). At puberty, release of gonadotropins, particularly luteinizing hormone (LH) and to a lesser extent follicle-stimulating hormone (FSH), initiates the resumption of meiosis (see Figure 3-21. Following the rise in gonad- otropin levels, the primary oocytes in preovulatory follicles progress Trough the rest of the first meiotic division and form secondary oocytes that are blocked in metaphase of the second-division. The first polar body is extruded; this body contains half the chromosomes (IN) present in the primary oocytes (2N). As the time of ovulation nears, the follicle becomes more vascular and swells out from the ovarian surface. It is macroscop- ically visible as a blisterlike protuberance. The secondary oocyte is re- leased at metaphase of the second meiotic division, and it stays in this stage pending fertilization. At fertilization, the second meiotic division is completed, the second polar body is extruded, and the female pronucleus is formed. The male and female pronuclei combine to reestablish the diploid state (Espey, 19781. In the absence of fertilization, the secondary oocyte degenerates. When the menstrual cycle is established in humans, ovulation occurs on the average of every 28 days, during which time those follicles recruited from the resting follicle pool (graafian follicles) are stimulated to ovulate by elevation in gonadotropin levels. This process continues throughout the reproductive life until the population of primordial follicles is depleted or menopause occurs. Toxic effects on oocytes and effects on oogenesis are discussed in the following section. Germ cell mutagenesis is the subject of a separate section toward the end of this chapter.

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Reproductive Toxicology 41 Pituitary Gonadotropins, Mi U/ml 5 LU an: cn Gonadal ~ Steroid > Estrogen, pg/ml 200 c) 100 400 o 99 o Basa1 Body Temperature 98 97 60 _ j FSH 20 15 _ DEVELOPING - |~-- CORPORA- - | FOLLICLE is, LUTEA 10 Progesterone, ng/ml 5 O 1,, 1 1 1 1 1 1 1 1 1 1 ~ 1 1, 1 1 1 ~ 1 1 1 1 1 1 14 CYCLE DAYS ~FOLLICULAR |- LUTEAL PHASE PHASE OVU LATION FIGURE 3-2 Endocrinology of the menstrual cycle in humans. From Haney, 1985, with per- . . mlsslon. Oocyte Toxicity The ovary, as a repository of oocytes and as a source of steroid hormones that control the functional development of reproductive organs, plays a major role in fertility and initiation of pregnancy. As indicated in the preceding section, when folliculogenesis is complete in the female during the perinatal period, oogonial cells no longer persist. The ovary cannot replace oocytes destroyed by toxicants. Complete destruction of oocytes prepubertally will result in primary amenorrhea and failure of pubertal onset. Complete oocyte destruction after puberty will produce premature menopause (Mattison, 19831. Follicle growth can be separated into two phases: gonadotropin inde- pendent and gonadotropin dependent. Recruitment of follicles from the resting pool and the initial phase of follicle growth to the preantral stage is gonadotropin independent and may be controlled by an intraovarian

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42 DRINKING WATER AND HEALTH regulatory mechanism. Further growth and development to the preovu- latory stage requires the support of gonadotropins. Follicle growth is initiated at all ages, but in the absence of gonadotropins, growing follicles undergo atresia (Mattison, 1985~. If the dominant follicle is destroyed, fertility will be immediately in- terrupted. Follicles in the growing pool can repopulate the preovulatory pool, followed by a resumption in fertility. If a toxicant destroys growing, gonadotropin-independent follicles, but spares preovulatory follicles, the delay in the onset of infertility will be proportional to the time required for follicles to reach the preovulatory stage. Destruction of resting follicles has the greatest delayed effect on fertility, and the results will not be evident until the end of the reproductive life. Partial destruction of the resting follicle pool is manifested as premature onset of menopause. Men- opause generally occurs between 45 and 55 years of age; when it occurs before age 35, it is usually regarded as premature (Mattison, 19851. In a mathematical model of functional ovarian life span, Mattison ( 1985) has estimated that menopause occurs when there are fewer than 3,500 oocytes per ovary. Calculations based on this model indicate that the age of menopause is weakly dependent on the number of oocytes at birth. When 75%, 50%, or 25% of the normal complement of oocytes are present at birth, menopause is estimated to occur at 47, 44, or 37 years, respec- tively. Mattison reported, however, that varying the normal rate of atresia, or oocyte half-life (9.2 years), had a strong influence on age at menopause. When oocyte half-life was 75%, 50%, or 25% of the normal rate, the age at menopause was 38, 25, or 12 years, respectively. The results of this model are consistent with data on humans suggesting that most forms of premature ovarian failure, both genetically and xe- nobiotically determined, are due to an increased rate of atresia. Surgical procedures such as unilateral oophorectomy or bilateral wedge resection that decrease resting oocyte number without altering the rate of atresia do not appear to influence the age of menopause (Mattison, 19851. Effects of Radiation on Oogenesis In rodent species, female germ cells are extraordinarily sensitive to killing by exposure to ionizing radiation, especially during neonatal life. Primordial, or resting, follicles in juvenile mice have an LDso of only 6 reds (Dobson and Felton, 1983), whereas typical LDsoS for most other cell types range from 100 to 300 reds. The entire primordial follicle pool in female squirrel monkeys is destroyed by prenatal exposure to only 0.7 red/day throughout pregnancy. Histopathological examination of other tissues failed to yield evidence of cytotoxic effects at any other site (Dob- son and Felton, 19831. High oocyte radiosensitivity has been demonstrated

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Reproductive Toxicology 43 in relatively few species, most notably in the neonatal mouse (Dobson and Cooper, 1974), the prenatal pig (Erickson, 1978), and the prenatal squirrel monkey (Dobson et al., 1978~. In Swiss-Webster mice, oocyte radiosensitivity appears shortly after birth, increases rapidly to peak sen- sitivity from days 5 to 17 of life, and decreases moderately to adult levels (Dobson and Felton, 19831. The rat displays a similar pattern but is considerably less radiosensitive (Mandl and Beaumont, 19641. In contrast, maturing oocytes in the guinea pig are more radiosensitive than primordial oocytes (Oakberg and Clark, 19641. The magnitude of prenatal germ cell loss in squirrel monkeys has led to examinations of loss in other nonhuman primates. In one such study, exposure of rhesus and bonnet monkeys to radiation during pregnancy failed to yield evidence of oocyte radiosensitivity (Dobson and Felton, 19831. In another, Baker (1978) found that oocytes in humans are resistant to radioactivity, reporting that LDsoS from x-ray exposure have reached 400 reds. X-ray exposures of the human ovary have most often been examined at prepubertal and adult stages, however, and a critical period during late fetal to early neonatal life would most likely have been missed. In adult human females, the growing follicles appear to be most sensitive to ionizing radiation, partly because of the rapid rate of granu-losa cell proliferation. The effects of ionizing radiation on the ovaries of women of reproductive age have been tabulated by Ash (19801. Exposure to less than 60 reds had no deleterious effects at any age. At 150 reds, women over 40 were at risk of becoming sterile. From 250 to see reds, women under 40 had temporary amenorrhea and 60% of the women became permanently sterile. All women over 40 had become permanently sterile at this level of radiation. With the onset of preovulatory oocyte maturation and resumption of meiosis after the dictyate stage (see Figure 3-1), susceptibility to the lethal effects of radiation decreases but sensitivity to heritable genetic damage increases. Preovulatory oocytes in multilayered follicles are relatively resistant to radiation-induced death, but they are sensitive to induction of both recessive and dominant mutations. In irradiated preovulatory oocytes, the incidence of dominant lethal mutations is highest at the first metaphase, slightly less at the second, and low at other stages (Baker, 19781. Effects of Xenobiotic Compounds on Oogenesis POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) These compounds have been demonstrated to cause ovarian tumors, chromosome aberrations during oocyte meiosis, and decreased fertility in laboratory animals (see Mattison et al., 1983, for a review). Several

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44 DRINKING WATER AND H"LTH investigators have also demonstrated that PAHs destroy oocytes in resting follicles in mice and rats at a rate depending on strain, species, age, dose, and metabolism (Feiton et al., 1978; Mattison and Thorgeirsson, 1978, 1979; Mattison et al., 19831. The following PAHs are known to have this effect: benzofa~pyrene, 3-hydroxybenzoLa~pyrene, 4,5-dihydroepoxy- benzoLa~pyrene, cis-4,5-dihydrodiolbenzofa~pyrene, trans-4,5-dihydro- diolbenzoka~pyrene, 7,8-dihydrodiolbenzofa~pyrene, 7,12-dime- thylbenzota~pyrene, 7,12-dimethylbenzanthracene, and 3-methylcholan- threne (Chapman, 1983; Dobson and Felton, 1983; EPA-ORNL, 1982; Haney, 1985~. The oocytes are actually destroyed by reactive intermediates formed from the parent compound in the ovary by enzyme action. Although this metabolic process is necessary for oocyte destruction, inducibility at the Ah locus is not as highly correlated with this effect as is the rate of metabolism along the pathway leading to formation of the dihydrodiol epoxide (Felton et al., 1978; Mattison and Thorgeirsson, 1978, 1979; Mattison et al., 19831. There are indications that cigarette smoking causes a toxic ovarian response in humans, resulting in premature onset of menopause. The incidence of infertility, defined as a woman never being pregnant through- out her reproductive life, was approximately 12% among white non- smokers compared with 18% among white smokers from a total of 1,728 women in the study (Tokuhata, 19684. There are more than 3,000 iden- tifiable compounds in cigarette smoke, and the specific agents responsible for this effect are not known, although PAHs and nicotine have been implicated (Surgeon General, 1981~. ANTINEOPLASTIC AGENTS A variety of antineoplastic agents have also been associated with ovu- latory dysfunction and destruction of oocytes (Haney, 19851. Included among these are adriamycin, 5-fluorouracil, ~-asparaginase, 6-mercap- topurine, bleomycin, methotrexate, busulfan, nitrogen mustard (mechlor- ethamine), chlorambucil, prednisone, corticosteroids, procarbazine, cyclophosphamide, vinblastine, p-cytosine arabinoside, and vincristine (Chapman, 1983; Dobson and Felton, 1983; EPA-ORNL, 1982; Haney, 19851. These agents destroy rapidly dividing granulosa cells in growing fol- licles as well as in the resting primordial follicle. When prepubertal girls are treated with antineoplastic drugs, complete loss of germ cells is un- likely. In young, postpubertal women, however, fertility may be impaired despite the onset of normal menstrual cycles. As a general rule, the greater the number of chemotherapeutic agents used, and the older the woman,

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Reproductive Toxicology 45 the higher the likelihood of gonadal 1985). Dobson and Felton (1983) reviewed data on the oocyte toxicity of 77 chemicals in 11 chemical classes. Of the 77 chemicals tested, 21 caused destruction in resting primordial follicles in mice. Positive compounds were found in 7 of the 11 classes, notably among the PAHs, alkylating agents, esters, epoxides and carbamates, fungal toxins and antibiotics, and nitrosamines. The four negative classes were the aromatic amines, aryl halides, metals, and steroids. injury and permanent sterility (Haney, Alterations in Reproductive Endocrinology In addition to direct effects on the survival of oocytes, exposure to xenobiotic substances can impair female fertility through alterations in the function of the hypothalamic-pituitary-uterine-ovarian axis. The central nervous system (CNS) component of the female reproductive system func- tions in a permissive, integrating role. Hypothalamic neurons synthesize and secrete gonadotropin-releasing hormone (GnRH). These hypothalamic neurons adjoin a portal vascular system that transports GnRH, which is secreted in a pulsatile pattern to the anterior pituitary gland. GnRH func- tions at this site in a permissive capacity, allowing the release of FSH and LH. The pattern with which these gonadotropins are released is con- trolled by the circulating levels of sex hormones (Knobil, 19801. FSH and LH stimulate follicular maturation from the preantral to the preovulatory stage. In addition, they influence the synthesis and secretion of estrogen by thecal and granulosa cells in the follicle. Estrogen is critical to the viability of follicles because it is mitogenic to granulosa cells. During the surge in gonadotropins at midcycle, a series of events is set into motion that culminates in ovulation. These events include intrafollicular prosta- glandin synthesis, terminal oocyte maturation, a shift in steroidogenesis from estrogen to progesterone production by granulosa cells, morphologic luteinization, and, f~nally, rupture of the follicle and release of the oocyte (Takizawa and Mattison, 1983~. Without sustaining factors secreted by a conceptus, the corpus luteum undergoes regression. Peripheral progester- one levels begin to rise with the initiation of the LH surge and continue to increase until the midpoint of the luteal phase, when they begin a gradual decline that results in menses. In humans, human chorionic go- nadotropin appears responsible for maintenance of the corpus luteum dur- ing early pregnancy. There are a number of endocrine processes in which xenobiotic com- pounds can interfere with ovarian function aside from any direct injury of the oocyte. It is difficult, however, to separate direct injury to the follicle from alterations in hypothalamic-pituitary-gonadal function. In-

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