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17 Introduction This section of the report assesses mark- ers of maternal, embryonic, fetal, and placental physiologic and biochemical processes and ways to develop biologic markers for clinical utility in humans. Validation of such markers in humans is a critical concern. A biologic marker is useful to confirm a potential risk, as well as to document that an adverse event has occurred. How- ever, the use of biologic markers for risk assessment during pregnancy is only beginning. The goal is to develop markers that can establish that a mother or concep- tus might be at risk for a toxic response before expression of that response, to permit intervention to prevent the toxic response. Successful pregnancy in mammals in- volves the progression through processes of fertilization, implantation, organo- genesis, fetal development, and parturi- tion. Three principal compartments must be coordinated during this progression; the maternal host, the placenta, and the embryo or fetus. Interactions that mark the progression of a concentus through gestation are attended by specific bio- chemical and physiologic responses. These interactions occur at various levels of biologic organization, and data on them are not uniform. The differences are most 205 obvious when data on events that take place before and around implantation are com- pared with those on events that take place during the fetal period. Few markers of cell-, tissue-, or stage-specific reac- tions, which make it possible to detect critical periods, are available in early development. Such markers are products of laboratory investigation; as pregnancy proceeds, different methods for analyses can be used, including clinical diagnostic procedures. Data on developmental events during the fetal period (i.e., after 8 weeks of gestation) are more numerous. Research into the early events of preg- nancy has identified many markers. But because the understanding of these early events is provisional and fragmentary, essentially no information regarding toxic exposure has been gathered. Inter- pretation of markers often is plagued by the absence of critical assays or by in- appropriate application of or failure to apply available diagnostic methods. For example, amniocentesis and chorionic villus biopsy have not been used to docu- ment potential adverse effects of xeno- biotic exposure. Nevertheless, these tests might yield valuable information regarding doses of toxicants in the tissues or genotoxic effects of exposure. A few assessment tools are peculiar

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206 to pregnancy, such as amniocentesis, chor- ionic villus biopsy, Doppler blood flow velocity measures, fetal blood sampling, fetoscopy, products of conception, real- time ultrasound, and incidence of pregnan- cy loss. However, many of the properties of the biologic markers derived with those tools are not well established, even for normal pregnancies. This part of the re- port discusses the possible use of those biologic markers to study exposures to therapeutic or environmental agents, but those markers have not been used to study whether exposures to specific xenobiotic agents are associated directly with phar- macodynamic events. This chapter is a brief review of the biologic processes and changes that occur to the mother, conceptus, and placen- ta during pregnancy. This is followed by chapters that focus on disciplines in biol- ogy that are developing markers of pregnan- cy. Advances in molecular biology, immu- nology, cell biology, physiology, and pharmacology are discussed. The subcom- mittee's conclusions- and recommendations regarding opportunities and directions for a program on biologic markers of preg- nancy are presented in Chapter 24. A sum- mary table lists and categorizes biologic markers according to whether each marker may be used in large-scale human studies or only in studies of special populations and whether it needs further development or needs to be applied in animal studies. THE EVENTS OF PREGNANCY Normal ovulation in the human occurs approximately 14 days before the onset of the next menses. The period during which the ovum then can be fertilized is esti- mated to be 18-24 hours. Fertilization of the ovum normally takes place in a fal- lopian tube. Entry of a spermatozoon into the ovum prevents the entry of addi- tional spermatozoa and is followed by fu- sion of the spermatozoa! nucleus with the nucleus of the fertilized ovum, which results in a zygote. The zygote continues its transport through the fallopian tube, undergoing a series of cell divisions. Approximately 6 or 7 days after ovulation, the embryo attaches to the apical surfaces of the endometrial epithelial cells. TOXIC17YDURING PREGNANCY By the time the developing embryo enters the uterus, a cavity is formed-the blas- tocoele. The outer cellular layer of the blastocyst surrounds the blastocoele and the embryo (also referred to as the inner cell mass). The placental contribution from the embryo-the trophoblastattaches to the uterine epithelium; that attachment initiates migration of the trophoblast through the epithelium and its basal lam- ina. Trophoblast cells in each mammalian species differentiate according to a spe- cies-specific series of morphologic and functional changes before interacting with the maternal vasculature and estab- lishing a definitive placenta. During the course of these changes, the embryo initiates rapid cell division, growth, and differentiation that culmi- nates in gastrulation. The gastrula in- cludes two primary germ cell layers-the ectoderm and endoderm. Further develop- ment yields the third primary germ layer- the mesoderm-and is followed by regional differentiation of the embryonic disk. Each step of placental and embryonic differentiation is a possible point of adverse action of a xenobiotic agent. The concept of critical windows of exposure must be considered for specific altera- tions for organ development in the embryo. MATERNAL PHYSIOLOGY The embryo-placental unit (and later the fetal-placental unit) must alter ma- ternal responses without jeopardizing the mother. The prodigious production of polypeptide and steroid hormones by the embryo-placental unit results in phys- iologic adaptations of virtually every maternal organ system. Maternal weight increases an average of 25 lb during pregnancy. The pulse rate increases by about 20%, and blood volume per heartbeat (stroke output) also in- creases. The net result is an increase in cardiac output of some 30% by the end of pregnancy. The respiration rate is unchanged, but the tidal volume increases by 30-40%. Those changes might mean that an internal dose of certain airborne toxi- cants would be greater in a pregnant woman than in a nonpregnant woman.

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INTRODUCTION Gastric emptying time increases by as much as 50%. Renal flow also increases by as much as 50% during the first trimes- ter. The glomerular filtration rate in- creases early and then levels off. Changes in filtration and elimination rates might mean that toxic materials remain in the circulation of a pregnant woman longer than in that of a nonpregnant woman. Hormonal concentrations are changed as a result of alterations in pituitary, adrenocortical, thyroid and parathyroid gland, and pancreatic function. Concen- trations are affected further by altered clearance rates that result from increased glomerular filtration and decreased anion excretion in the mother and modified clear- ance of steroids and protein hormones by the placenta. The many changes in the organ systems of the pregnant woman can influence the exposure concentration, metabolism, and elimination of a xenobiotic agent. These processes together affect the pharmaco- kinetic properties of a substance, so preg- nant women might have different responses or magnitudes of response to exposure from similarly exposed nonpregnant women. EMBRYONIC/FETAL CHANGES In utero development is a time-sensitive process during which all mechanisms of possible interactions between and among cells leading to cellular proliferation or degradation result in modified struc- tural and functional changes. Individual processes indicate not only cellular sen- sitivity but critical windows of develop- ment in which specific agents may induce damage, for example: Thalidomide appears to produce its major effects on development in humans- limb abnormalities-when exposure occurs between 25-40 days of development. Such exposure correlates with the develon- ment of the upper and lower limb buds in the human (Newman, 1985~. Diethylstilbesterol (DES) is a devel- opmental toxin that can alter reproductive tract development when administered be- tween 8-18 weeks of gestation in the human. This is the period for development of the 207 reproductive tract in the human. Not only are vaginal tumors noted from DES exposure, but also ovarian, uterine, and vaginal/ cervical malformations (Herbst and Bern, 1981~. Retinoids (isotretinoin) produce major alterations in cranio-facial, thy- mus, cardiac, and otic development, ap- parently due to early embryonic effects on neural crest cell migration and func- t~on (Lammer et al., 1985; Teratology Society, 1987~. Methylmercury also is noted to be a human teratogen, yet its principal effect is on the CNS, resulting in substantive alterations in function. Such effects of methylmercury are correlated with ex- posures during the fetal and neonatal per- iod, when rapid proliferation of neurons occur (Weiss and Doherty, 1975; Harada, 1978~. All of these human terata resulting from xenobiotic exposures also have been identified in animal models, and have been investigated for mechanisms of action. Thus, not only must important surveil- lience techniques be applied to human study models, but effects and timing of exposures must be based upon a fundamental under- standing of basic embryology in the human and animal systems investigated. For ex- ample, in the rodent, development of the vagina and cervix during the fetal/neona- tal period demonstrates structural mal- formations and tumorigenesis but is dif- ferent from exposures in humans. Several considerations of the differ- ences between fetal and adult physiology are relevant to a consideration of biologic markers, because the resulting internal dose or biologically effective doses might differ as a result of these properties. For instance, from a cardiopulmonary standpoint, the fetus maintains normal tissue oxygenation in the face of what in the adult would be considered patholog- ically low arterial O2 tension, by main- taining a per-kilogram cardiac output of more than twice that of an adult. There- fore, the dissemination of blood constitu- ents is much more rapid in the fetus than in the adult. Some specific differences are detailed in Table 17-1. Much of the morphologic information , -

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208 TOXICI7~YDURING PREGNANCY TABLE 17-1 Comparisons of Fetal and Adult Cardiovascular Functions paO ,torr 25 100 paCi:)2, torr 48 40 pH 735 7.40 V.O2,ml/min per kilogram 8 4 Hemoglobin concentration, g/dl 17.5 11.5 Hematocnt, % 55 35 O2 content, ~nl/dl 16 15.4 O2 content, mM 7 6.7 Blood volume, ml/kg 130 80 Descending aorta pressure, mm Hg 45 95 Pulmonary artery pressure, mm Hg 45 15 Cardiac output, ml/min per kilogram 200a 100 Systemic vascular resistance Low High Vascular compliance High Low aCalculated for right and left ventncles. about the human fetus is based on the study of abortuses or inferences from stud- ies of other organisms. Information about fetal organ function is even less direct, in that embryos aborted spontane- ously usually have abnormal functioning of some organs, and fully developed organs are not comparable with fetal organs. target receptors, modulators, and regu- lators of steroids and protein hormones develop at different times during gesta- tion. Furthermore, the developing fetus has a unique endocrine system, owing to the interdependence of the maternal-pla- cental-fetal complex. The extraembryonic membranes contain key enzymes to metabol- ize steroids and prostaglandins that are absent or present in very low concentra- tions in the fetus; the fetal adrenal glands and liver contain key enzymes absent from the placenta. Dehydroepiandroster- one sulfate (DHEA-S) serves as a substrate for biosynthesis of placental estrone and estradiolhormones that probably are important in mediating many maternal adap- tations to pregnancy (Longo, 1983~. Mater- nal urinary and serum estriol measurements have been important measures of fetal com- ~ promise; however, many xenoolotlcs, an- tibiotics, and glucocorticords are noted to alter estriol excretion. These interac- tions between normal physiology and drug therapy demonstrate how xenobiotics can alter fetal and maternal function without compromising fetal survival. The fetal adrenal gland also produces large amounts of cortisol, which is impor- tant in the maturation of the lung, pan- creas, and other organs and which initiates hormonal events in extraembryonic tissues (including a decrease in progesterone and increases in estrogen production and pros- taglandin synthesis). The stimuli for fetal adrenal hormone synthesis are un- clear; fetal adrenocorticotropin (ACTH) plays a role, as do peptides derived from pro-opiomelanocortin (POMC) and several other growth factors. Other endocrine systems peculiar to fetal life are the para-aortic chromaffin . . . system active In catecholamlne synthesis; the fetal intermediate pituitary, which secretes c'-melanocyte-stimulating hor- mone and p-endorphin; and the posterior pituitary, which secretes arginine vaso- tocin, vasopressin, and pregnancy-specif- ic proteins (Rosen, 1986), such as several pituitary-like hormones and neuropep- tides. The concentrations of many of these hor- mones and other polypeptides can serve as biologic markers. Various chemicals and toxicants can affect the fetal hypo- thalamus, and adrenals, the placenta, and other tissues, thereby inhibiting enzymes and metabolic pathways and altering the

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INTRODUCTION synthesis of and response to various hor- mones and growth factors. Because of the uniqueness of fetal hormones, the fetus may be susceptible to chemicals that the adult is not susceptible to. The extent to which this occurs remains to be demon- strated. PLACENTAL INVOLVEMENT The placenta provides biologic communi- cation between mother and fetus while main- taining immunologic and genetic integrity of the two organisms. Placental tissues are embryonic in origin; however, the pla- centa functions autonomously during the first trimester. By the end of the first trimester, the fetal endocrine system develops sufficiently to influence pla- cental function and provides hormone pre- cursors to the placenta. After implantation, the trophoblast invades the maternal endometrium. Two layers of the developing placenta are evi- dent: the syncytiotrophoblast (adjacent to the endometrium) and the cytotropho- blast. The syncytiotrophoblast is derived 209 from the precursor cytotrophoblast of the embryo, is the source of hormone produc- tion, and is in direct contact with the maternal blood supply. Hormonal products of the placenta include human chorionic gonadotropin (hCG); human chorionic so- matomammotropin (hCS), also called human placental lactogen (hPL); and several other peptides that are not as well de- fined. The concentration of maternal serum hCG doubles every 2 days during the early weeks of pregnancy and peaks at about the tenth week of gestation. hCG is known to have several activities, but their sig- nificance is not entirely understood. For instance, hCG is luteotropic; it stimu- lates increased progesterone production by the corpus luteum cells. hCG also in- creases placental conversion of precur- sors to pregnenolone and progesterone and demonstrates thyroid - s ti mutating - ho r- mone-like activities. The polypeptide hormone hPL, which contributes to in- creased glucose metabolism and mobiliza- tion of free fatty acids, is not detectable in the maternal blood until 4-5 weeks of gestation.

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