Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

S D Holladay; R J Smialowicz

doi:10.1289/ehp.00108s3463

Holladay, S D;Smialowicz, R J;

2000-06-01 00:00:00

Development of the Murine and Human Immune System: Differential Effects of Immunotoxicants Depend on Time of Exposure Steven D. Holladay1 and Ralph J. Smialowicz2 1Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA; 2Environmental Research Center, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA Fetal and early postnatal life represent critical periods in vertebrate immune system development. system (1). The postnatal immune system Disruption of such development by perinatal immunotoxic chemical exposure has been widely is, in turn, the product of a series of highly in described experimental animal models. The resultant inhibited postnatal immune responses in regulated developmental events that include such animals are often more dramatic and persistent than those after exposure during adult life. sequential waves of hematopoietic cell Further, recent reports suggest that prenatal exposure to immunotoxicants may exacerbate production, cellular migrations through aberrant immune postnatal responses (e.g., hypersensitivity disorders and autoimmune in disease) hematopoietic organs, cell-cell interactions rodents. Limited information is genetically predisposed available regarding the possibility of inhibited within these organs under microenvironmen- postnatal immune capacity in humans as a result of developmental immunotoxicant exposure. The tal influences, highly specific cytodifferentia- multifactorial nature of and autoimmune will hypersensitivity responses further complicate the tional steps, and final maturation, including elucidation of possible relationships between chemical exposure during ontogeny of the human the acquisition of definitive functional prop- immune and in system immune-mediated disease later life. Taken together, however, the available erties (2,3). Most available data regarding animal data suggest the potential for altered postnatal immune function in humans to exposed ontogenesis of the vertebrate immune system immunotoxicants (e.g., environmental chemicals and therapeutic during fetal agents) and/or early are derived from human and rodent studies, life. words: autoimmune postnatal Key disease, developmental immunotoxicity, diethylstilbestrol, and demonstrate multiple switching of immune development, TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, prenatal, therapeutic hematopoietic compartments during devel- - 1 immunosuppressant. Environ Health Perspect 08(suppl 3):463-473 (2000). opment (4-8). Relatively limited data are http.//ehpnetl.niehs. nih.gov/docs/2000/suppl-3/463-473holladay/abstract.html available in species other than humans and rodents, but those that exist suggest similar patterns of immune development. However, Establishment of the vertebrate immune responses in genetically predisposed individuals. the of stage development achieved at the system requires a sequential series of carefully The full extent of the immunological effects time of birth, and, thus, the degree of timed and coordinated developmental events resulting from exposure to environmental immunocompetence in early postnatal life, is that in life begin early embryonic/fetal and agents during immune system development is variable from species to species (9). continue the not yet the in through early postnatal period. known; however, potential for Early vertebrate development (e.g., at Perturbation or abrogation of this develop- serious consequences is obvious. 24 hr in the approximately chicken), meso- mental sequence of events can lead to Developmental immunotoxicology as a dermal-derived hemangioblasts give rise to immune dysfunctions that may be life threat- discipline is in its the earliest infancy, with much remain- progenitors of all blood cells. ening. Defects in the development of the ing to be learned. Indeed, limited human These pluripotent stem cells are first detected immune in data are system due to heritable changes available regarding the spectrum of in the area vasculosa, a plexus of vessels the elements clinical and immune formed on the lymphoid provide potential postnatal consequences surface of the yolk sac before experimental examples of the con- that may result from gestational and/or early the establishment of closed circulation (10). devastating of immune sequences impaired development. postnatal exposure to individual or mixtures Shortly thereafter, pluripotent stem cells Potential functional defects caused of immunotoxic in by compounds. We describe the appear blood islets within the yolk sac (5), exposure to toxic agents during development of the immune and at in development system and, approximately day 9 of gestation may range from life-threatening suppression compare the similarities and differences of the via the bloodstream to the mouse, migrate of vital the this in components of immune system to development humans and laboratory fetal liver and spleen. The liver and, to a lesser altered or that can review the that the then poorly regulated responses animals; evidence the develop- degree, spleen carry the burden of be debilitating. For example, studies in labo- ing immune system is sensitive to perturba- until after birth hematopoiesis shortly (8). rodents indicate that to tion ratory exposure by chemical and physical agents and that immunotoxicants environmental chemi- immune (e.g., consequent agent-induced dysfunc- cals, drugs, and ionizing radiation) during tion may continue through life; and identify This article is based on a at the presentation Workshop to Critical Windows of for Identify Exposure Children's this critical time of immune the in the system develop- gaps developmental immunotoxi- Health held 14-16 1999 in September Richmond, Virginia. ment may produce and in some cology knowledge base. persistent, Address S.D. correspondence to Holladay, cases dramatic, effects on postnatal immune Department of Biomedical Sciences and Pathobiology, of the Development Virginia-Maryland Regional College of Veterinary function. For certain chemical agents {e.g., Medicine, Virginia Polytechnic Institute and State Immune System and chlordane; benzo[a]pyrene (B[a]P); Phase VA University, II, Southgate Dr., Blacksburg, 2,3,7, 8-tetrachlorodibenzo-p-dioxin Cellular and humoral immune in responses 24061-0442 USA. 231-3372. Fax: Telephone: (540) 231-7367. E-mail: has been associ- the neonate differ both and (540) [email protected] (TCDD)}, perinatal exposure qualitatively This has been reviewed the report by be ated with what appears to from those of the adult. These lifelong quantitatively Environmental Protection Office of Research Agency's For some of the same differences are an result of lower immunosuppression. anticipated and and for Development approved publication. functional Approval does not signify that the contents and other chemical numbers and/or decreased capac- necessarily agents (e.g., therapeutic reflect the views and policies of the nor does agency or environmental and ity of T and B estrogens TCDD), leukocytes [e.g., lymphocytes, or commercial con- mention of trade names products there is evidence that in life natural killer and exposure early (NK) cells, myeloid-lineage stitute endorsement or recommendation for use. 7 March 2000. may exacerbate or induce autoimmune in the immune Received 10 January 2000; accepted cells] present early postnatal Environmental Health * Vol 3 2000 Perspectives 108, Supplement * June AND SMIALOWICZ HOLLADAY Fetal liver hematopoiesis is first detectable at day-16 fetal thymocytes, however (20), serum do not reach adult levels for 4-6 years of in mice indicating that CD3-bearing day-16 fetal after birth. Further, human neonates younger approximately day 10 gestation and at about the sixth week of gestation in thymocytes express a functional TCR before than 2 years age are not able to mount humans The mouse spleen actively TCR-ac4 structures are expressed (19). humoral responses to some antigens (e.g., car- (4,8). may contributes to hematopoiesis from approxi- In contrast to the mouse, where thymic bohydrate antigens), an observation that of gesta- in part explain the increased susceptibility of mately day 15 of gestation until several weeks colonization occurs in the latter half which time ele- tion, thymic colonization and early T-cell infants to certain bacterial infections (e.g., after birth, at erythropoietic ments predominate (6,8). Although the development occur in the first trimester of Streptococcuspnenumoniae) (1). in humans. Bloodborne spleen never completely loses hematopoietic fetal development in has stem cells enter the developing thymus at function the mouse, this organ largely Consequences of in humans by the time approximately 7 weeks of gestation, with sub- ceased hematopoiesis Immunotoxicant Exposure and of birth (but may regain hematopoietic func- sequent differentiation occurring rapidly Prenaal Exposure similar to that seen in the tion in abnormal situations) (11). following a pattern and mouse. The majority of these thymocytes Organogenesis of the immune system occurs Perinatally in both mice humans, cells in the liver to express TCR of the type at approximately during the prenatal and, to a lesser extent, pluripotent stem migrate y8 the liver becomes increas- 9.5 weeks of gestation and of the ax3 type by early postnatal periods of mammalian devel- bone marrow as As be predicted from this, the ingly devoted to metabolic function. The vas- about 10 weeks of gestation (1,21). Presently, opment. might the diversity of the T cell is a time of high sensitivity to cular mesenchyme within the bone marrow it is unclear whether perinatal period network repertoire in rodents and humans is lower at immunotoxicants that cross the placenta or forms a supporting reticular by ges- in mice and week 20 birth than in adulthood. Further, the capacity enter the neonate via lactation. Postnatal tational days 17-18 by T in humans at immunotoxic consequences from such chemi- in humans upon which the migrating of such cells rodents and can seed and proliferate birth to help for immunoglobulin cal exposure during the initial establishment pluripotent stem cells provide of granulopoietic activity domi- secretion is limited mainly to IgM produc- of the immune organs may be both more (12). Waves abil- severe and more than those that nate murine marrow hematopoietic function tion. This may in part be due to reduced persistent of T cells from neonates to produce occur in adult animals exposed at similar lev- from about day 19 of gestation until approxi- ity Limited interleukin (IL)-2, IL-4, and els [reviewed by Holladay and Luster (26)]. mately 3 months after birth. erythro- cytokines [e.g., in mouse bone marrow interferon-y] required for activation of Indeed, for a growing list of chemical agents, poietic activity begins the of animals to immuno- in humans well before birth T-helper (Th) cells, as well as macrophages, exposure pregnant after birth and NK and T toxicants at levels that produce limited tran- (8). A limited number of B cell progenitors cells, cytotoxic lymphocytes (1). in bone marrow on B can be identified in sient effects in adults produces long-lasting can be detected mouse lymphopoiesis in increase in number mouse fetal liver by days 12-13 of gestation or even permanent immune deficits day 19 of gestation; they in liver until about 2-4 months of at which time (22). Pre-B cells can be found the fetal the offspring. age, of the mice and B which Chemical agents that cause developmental they constitute approximately 20% of by day 14, lymphocytes, cell A limited number are for the most part restricted to IgM expres- immunotoxicity in rodents are diverse and nucleated population. aromatic hydrocarbons of T can be detected in murine sion, can be found by days 16-17. The gen- include halogenated lymphocytes at and eral scheme of B-cell in (HAHs), polycyclic aromatic hydrocarbons bone marrow birth, they slowly early development at about 2-4 months of mice includes a) a series of well characterized (PAHs), hormonal substances, therapeutic increase to plateau of metals and mycotoxins are sum- In both mice and humans, the bone molecular steps involving the assembly gene agents, heavy age (6). mol- marized as follows [modified from Holladay marrow then serves as the primary site of segments encoding the immunoglobulin life. to and Luster (26)]: hematopoiesis throughout postnatal ecule, b) heavy chain D-J rearrangements The rudiment forms at yield progenitor B cells, and c) light chain V-J * polycyclic halogenated hydrocarbons: epithelial thymic B and PBBs in the mouse (6,13), rearrangements to generate cells expressing TCDD, PCBs, gestational days 9-10 These mole- * aromatic after which colonization of the thymus by complete cell-surface Ig (23-25). polycyclic hydrocarbons: B[a]p; T cells from the fetal liver begins cular which have been demonstrated methylcholanthrene; and 7,12-dimethyl- precursor events, in the on 10-11 These thymocytes in both fetal liver and neonatal spleen benz[a]anthracene days (13,14). are double with to mouse, appear identical to those occurring * pesticides: chlor- initially negative respect hexachlorocyclohexane, in marrow. CD4 and CD8 cell-surface antigens, then throughout life adult bone dane, diazinon, DDT, and carbofuran CD8+ sin- neonatal mouse B * develop sequentially to immature However, lymphopoiesis fungicides: hexachlorobenzene and CD4+CD8+ (double posi- differs from the adult mouse in the level of heavy metals: methyl mercury, lead, and gle positive CD4+ or terminal cadmium tive) stages, and finally mature into expression of certain enzymes [e.g., CD8+ that to the periph- precursor hormonal substances: estrogens/ thymocytes migrate deoxynucleotidyl transferase, and ery as functional T-helper and cytotoxic lymphocyte-regulated myosin-like light chain, diethylstilbestrol (DES), testosterone, T lymphocytes, respectively. Rearrangement and in major histocompatibility complex cortisone class II surface expression]. * of T-cell receptor (TCR) gene segments (MHC) antigen therapeutic agents: acyclovir, busulfan, in A occurs during this maturation, resulting Hayakawa et al. (22) suggested that such fetal cyclophosphamide, and cyclosporin of double-positive thymocytes differences from adult B * T-2 appearance lymphopoiesis during mycotoxins: toxin TCR The TCR be in * expressing surface (15,16). development may related to differences irradiation: X rays. complex that includes a product of the TCR susceptibility to tolerance. With the exception of a limited database is on fetal thymocytes by days can be detected by approxi- in humans who were exposed to therapeutic y-gene present IgM synthesis of 14-15 gestation (17,18). At approxi- mately weeks 10-12 of gestation in human immunosuppressive drugs or to the nons- mately day 17 of fetal mouse development, fetal liver. Serum IgM concentrations are only teroidal estrogen DES during gestation, the TCR ac-heterodimer is expressed on the of adult levels at details approximately 10% birth, regarding postnatal consequences from majority of thymocytes (19). Anti-CD3 and do not reach adult levels until 1-2 years early human exposure to known adult monoclonal antibody is able to activate of age. Similarly, concentrations of IgG in immunotoxicants remain largely unavailable. 464 Environmental Health Perspectives * Vol 108, Supplement 3 * 2000 June DEVELOPMENTAL AND ADULT IMMUNOTOXICITY A concern is that Fabricius in chick were 4 relatively new and growing immune parameters including hematology, embryos PeCB, pg serum and 50 TCB, and such early human exposure to immunotoxic immunoglobulin antibody titer, 300 egg HCB, pg pg/kg compounds may not only cause postnatal delayed hypersensitivity whereas the mono-ortho-chlorinated analogs response, lympho- immunosuppression, but may also result in proliferative responses, and several macro- of TCB and PeCB were 1,000 times less increased expression of aberrant immune phage functions were not affected in the potent inhibitors of bursal development than responses (e.g., and auto- These PeCB. When mouse thymi hypersensitivity offspring (42). authors also found that were taken from immune disease). calves inadvertently exposed to PBB in utero gestational day 15 mouse fetuses and treated HAHs. Considerable effort has been displayed no significant alterations in ex vivo with TCDD or PCB in organ culture, devoted to the effects of PAHs immune responses. When pregnant mice inhibited thymocyte development again cor- understanding on the developing immune system. The most were dosed with 0.5 mg/kg/day of the PCB related with Ah receptor binding affinity. For studied compound in this group of chemicals 3,4,5,3 ',4',5'-hexachlorobiphenyl (HCB) example, PeCB was only one-tenth as potent for TCDD. Much of the immunotoxicity is beginning at the day of implantation, very = 2 x 10-9 M) as TCDD (EC50 = 2 x (EC50 immunotoxicity of TCDD and of marginal effects on the in congeners developing immune 10-10 M) inhibiting thymocyte develop- TCDD (halogenated biphenyls, chlorinated system were again observed (43). Similarly, ment, whereas the potencies of HCB and dibenzofurans, and other chlorinated diben- feeding pregnant mice throughout gestation TCB were approximately one-hundredth that is to the zodioxins) directly proportional and lactation with various combinations of of PeCB. No inhibition of thymocyte devel- of the individual lead and/or PCB resulted in negligible effects was in binding affinity congeners opment produced this system by con- to the aryl hydrocarbon (Ah) receptor (27). on the ability of the to mount an centrations of offspring mono-ortho-chlorinated PCB For this reason, many these immune of agents produce response (44). However, when lead as high as 106 M (50). a similar pattern of immunotoxic in alone was administered There are reports that responses throughout gestation document develop- animals (28). TCDD in particular produces and lactation, 35- to 45-day-old rats dis- mental immunotoxicity of certain mono- profound thymic atrophy in all species exam- played reduced thymic weights and delayed cyclic and polycyclic halogenated pesticides ined [reviewed by Vos and Luster (29)]. hypersensitivity responses and inhibited lym- and pesticide contaminants, including the when administered the phocyte proliferation (45). These reports Further, during matu- fungicide hexachlorobenzene (51); the herbi- rational development of the immune indicate that certain PBBs and PCBs are not system, cide contaminant 3,3',4,4'-tetrachloro- TCDD causes more persistent immunosup- potent developmental immunotoxicants. and the azoxybenzene (52); insecticides pression than if given in adult life (30). In contrast to the above results, significant hexachlorocyclohexane (53), diazinon, and in neonates and Thymic atrophy adults alterations were reported in peripheral lym- carbofuran and chlordane (55). (54) occurs after low-level to phocytes of 4-week-old piglets after perinatal Hexachlorobenzene remarkably exposure exposure at 0.5 TCDD and has been well characterized. exposure to a commercial mixture of PBB mglkg/day throughout gestation resulted in TCDD crosses the mouse placenta relatively (Firemaster BP-6) (46). Four-week-old mice long-lasting (into adulthood) depressed poorly [i.e., < 0.5% of an oral dose to a commercial mix- (31)]; exposed prenatally PCB delayed-type hypersensitivity (DTH) however, single-dose or subacute exposure of ture (Kanechlor 500) displayed T-helper responses and decreased numbers of splenic in pregnant mice to TCDD the low mil- activity reduced to 20% of control levels B cells in exposed mice in utero (51). When (47). causes a In another in utero of ligram-per-kilogram range highly sig- report, exposure mice pregnant mice were exposed to higher levels nificant involution of the fetal as well to PCB resulted in fetal thymic hypoplasia of thymus hexachlorobenzene, Barnett et al. (51) as inhibition of differentiation and inhibited cell in noted a significantly thymocyte lymphoid development impaired mixed lym- (32). Such exposure to TCDD results in thymic organ culture (thymi taken from phocyte response. In rats contrast, exposed inhibited T-cell responses lasting 8-10 weeks 14-day embryos) (48). Thus, published pre- and postnatally via their diet to approxi- after birth in mice Other effects exposed (33). reports have varied considerably regarding the mately 4, 20, or 100 mg/kg hexachloroben- on cell-mediated immune function after pre- toxicity of halogenated biphenyls to the zene had significantly enhanced humoral or perinatal TCDD exposure include sup- developing immune system. These different immune function and DTH responses (56). of T-cell in pression mitogen responses (34), immunotoxicity outcomes may part be the The reasons for this different observation in skin result of differences in structure of the con- rodents to graft rejection times, graft-versus-host exposed hexachlorobenzene is reactivity (35), and delayed hypersensitivity geners evaluated. In particular, for some toxic unknown but may be due to dose level. In In TCDD end this (30,36-39). addition, perinatal points, PCBs with chlorines in the para regard, when pregnant mice were increases to positions and in at least one of the meta to 10 or 100 exposure susceptibility challenge posi- exposed mg/kg body weight with infectious agents or syngeneic tumor tions of each ring, but not in any ortho posi- hexachlorocyclohexane (HCH), the DTH cells the collective available data are the most (30). Thus, tion, toxic members of this response at postnatal day 10 was significantly indicate that TCDD devel- chemical class These increased in mice exposure during (49). PCBs, including exposed to 10 mg/kg of the immune results in a rel- HCH and in mice opment system 3,3',4,4'-tetrachlorobiphenyl (TCB), significantly impaired of and exposed to 100 mg/kg HCH atively long-lasting postnatal impairment 3,3',4,4',5-pentachlorobiphenyl (PeCB), (53). Spleen cell-mediated immune function. bind the Ah cell to A 3,4,5,3',4',5'-HCB, receptor responses concanavalin (Con A) and Polyhalogenated with with less lipopolysaccharide (LPS) were 2- and 8-fold biphenyls [polychlori- relatively high affinity (though nated and than biphenyls (PCBs) polybrominated avidity TCDD) (50). Mono- and ortho- higher, respectively, and the number of anti- a chlorinated biphenyls, in contrast, are weak cells was 2-fold biphenyls (PBBs)] represent heterogeneous body plaque-forming (PFC) class of HAHs that have been associated with Ah and thus do not relative to control in from receptor ligands produce higher values pups in immunological effects humans and animals Ah-receptor mediated immunotoxicity at lev- the 10 mg/kg group, whereas neither mito- of immuno- els to with nor the PFC were altered (40-42). Reports developmental comparable congeners higher gen responses by caused PCB or PBB In of Ah 100 HCH. Immunostimulation has toxicity by exposure vary receptor affinity. support receptor mg/kg from little or no observed toxicity to highly as a mechanism been described at certain dose binding affinity explaining (usually low) immune alterations. For of PCB levels of chemicals that are otherwise significant system divergent reports immunotoxicity, instance, when PBBs were administered median effective dose values for the (ED50) immunosuppressive, although biological in mice and a of inhibition of the developing bursa of significance is unknown during gestation rats, variety (57-59P). Environmental Health * Vol 3 * 2000 465 Perspectives 108, Supplement June HOLLADAY AND SMIALOWICZ Selective and highly persistent immune with DNA, PAHs also bind the innate NK Ah receptor (i.e., cell activity), and cell- alterations have also been observed in mice and thus may cause TCDD-like immune mediated (T lymphocyte mitogen respon- after to the effects through gestational exposure organochlo- noncovalent interactions of siveness, graft-versus-host reaction, and rine insecticide chlordane. Mice exposed to the receptor-ligand complex with DNA. The immune function delayed hypersensitivity) chlordane during fetal life display significant observation of a TCDD-like inhibition of has been associated with perinatal DES expo- of that is thymocyte in depression cell-mediated immunity differentiation day-18 fetal sure in mice (75-78). Depression of these still present 101 days after birth, reduced mice exposed to TCDD from days 13-17 of functional has assays further been associated numbers of granulocyte-macrophage colony- gestation may suggest Ah-mediated immuno- with increased postnatal susceptibility to forming units and colony-forming units in toxicity from PAHs (70). In addition to viral-induced mammary tumors and to trans- the at 200 of inhibited spleen days age, and long-term thymocyte maturation, these planted primary and carcinogen-induced of both DTH and mixed authors severe fetal tumors It has depression lympho- reported thymic atrophy been suggested that a (79,80). cyte reactivity It is that and thymocyte depletion and decreased fetal possible relationship exist (55,60). noteworthy may between pre- these immune effects are either reduced or liver hematopoietic cell counts. Prolymphoid natal DES exposure and neoplastic growth in not observed in to chlor- T adult mice exposed cells (both and B precursors), identified by humans, including clear-cell adenocarcinoma dane at dose levels to those to the cell surface antigen expression and of the vagina equal given by the (92,93). pregnant mice. presence of terminal deoxynucleotidyl trans- Lead Administration of lead throughout PAHs. PAHs were also Immunosuppressive [e.g., ferase, significantly decreased. These gestation and lactation in rats resulted in authors that decreased numbers reduced thymic B[a] P, methylcholanthrene, and dimethyl- hypothesized weights and inhibited DTH have become of fetal liver contribute and lymphoproliferative at benz[a]anthracene] ubiquitous prothymocytes may to responses 35-45 environmental contaminants as a result of fetal thymic atrophy via reduced colonization days of age (45). Lead in both exposure rats their occurrence in petroleum, coal and coal of the thymus, and that reduced pre-B cells and chickens during also early development tars, soot, air pollutants, tobacco smoke, and may relate to the depressed humoral immu- caused persistent shifts in humoral immune certain nity caused by prenatal to cutting oils (61-63). The ability of exposure B[a]P. function, apparently as a result of effects on PAHs to cross the placenta as well as to Similar effects on the of immu- T-helper cells (94). It is important to note (64) development in produce immunosuppression in adult animals nity mice exposed to 7,12-dimethylben- that the dose levels of lead used in these studies raised questions about the intensity and per- zanthracene have been reported (71). did not cause immunologic effects in sistence of effects of these on the devel- Steroid hormones An altered adult rats. Bunn et al. (95) reported altered agents (estrogen). oping immune system. Urso and Gengozian prenatal hormonal environment has been Thl-/Th2-associated functions in female but associated with in not male (65,66) and Urso and Johnson (67) reported changes postnatal immune rats after exposure to lead during humoral immune function function in mice the role of the severely depressed (72). However, development. Further, lack of maternal in mice exposed to B[a]P from of sex steroids in the development of the influence in the developing chicken model days 13-17 In gestation. the latter of these immune system remains poorly understood used by these authors suggests a direct reports (67), these authors also observed highly persistent at best. Reports in the literature indicate that immunomodulatory effect of lead on the at 18 months of (still present age) impair- exogenous androgenic (73) or estrogenic developing immune system, at least in this ment of cell-mediated in can alter normal devel- species. Chen et al. immunity offspring compounds (74-81) (96) also suggested that in the form of suppressed of the immune The available there are periods of greater to mixed-lymphocyte opment system. sensitivity data and graft-versus-host responses. Increased largely report effects of estrogen and impairment by lead exposure during rodent tumor was further observed in the frequency estrogenic compounds (e.g., zearalenone and development. mice exposed to B[a]P before birth, suggest- the nonsteroidal to Therapeutic agents. estrogen DES). Exposure Many chemothera- ing the lesion to the developing immune sys- pharmacologic or suprapharmacologic levels peutic agents (e.g., alkylating antineoplastic tem a favorable environment for of either steroidal or nonsteroidal such as may provide estrogens drugs cyclophosphamide or chloram- the growth of neoplasms. results in numerous alterations of immune bucil) are potent immunosuppressants simply in The toxicity of B[a]P is part due to function, particularly when administered because they are powerful antiproliferative production of a reactive The effects of such administra- and highly epoxide perinatally. agents, many aspects of a functioning metabolite by microsomal mixed-function tion in rodents include immune system require active myelotoxicity proliferation. oxidase enzymes that covalently bind DNA (82,83), suppression of cell-mediated immu- Other such as drugs therapeutic immunosup- and other nucleophilic intracellular macro- nity (84), pronounced thymic atrophy pressants are specifically administered for molecules. NK their Thus, rapidly proliferating cells, (85,86), depression of cell activity immunotoxicity, to control autoim- such as those composing the immune (87,88), and stimulation of the reticuloen- mune and hypersensitivity diseases, to system, control are a evalu- dothelial targeted (68). Interestingly, study system (81,89). Studies examining certain inflammatory conditions, or to pre- ating the covalent binding of B[a]P in fetal postnatal immune function in humans vent organ transplant Human rejection. preg- mouse tissues found that liver in utero to can hematopoietic exposed exogenous estrogen are nancy exacerbate autoimmune disease, cells were the most active (69). Further, the limited to a few retrospective evaluations of requiring therapeutic intervention this during extent of transplacental induction adults to DES. critical enzyme exposed during pregnancy time. Further, recent advances in to control was in These compared greatest hemato- currently unconfirmed reports suggest organ success have resulted in transplant poietic cells (18-fold), followed closely by possible adverse immune effects in increasing numbers of humans, women becoming whole fetal liver Such including altered NK (16-fold) (67,69). T-lymphocyte and cell pregnant after an organ or tissue (allograft) results indicate that fetal the in liver, primary function adulthood and increased transplant These procedure. women require (76,90) hematopoietic organ in the fetus (4,6-8), and incidence of autoimmune diseases (74,91). therapeutic immunosuppressants throughout its hematopoietic cells are of The available rodent specific targets data support the pregnancy to prevent allograft rejection. Thus and B[a]P, may explain, at least in part, the indication in humans that developmental the probability of immunotoxic drug expo- significant to the immune to DES alter sure toxicity developing exposure may postnatal during pregnancy may in some cases be system resulting from exposure to this com- immunocompetence. Long-term impairment increasing. In other instances, women who In addition pound. to covalent interaction of both humoral are unaware are (antibody production), they pregnant may be 466 Environmental Health * Vol * Perspectives 108, Supplement 3 June 2000 DEVELOPMENTAL AND ADULT IMMUNOTOXICITY to a wide exposed variety of potentially powerful and less toxic antirejection within the drugs thymocytes fetal thymus, immunotoxic therapeutic regimens. are still highly desired and are currently the of completely blocking generation The antileukemic alkylating agent busulfan being developed and tested. mature T cells that the fetal (112), indicating caused severe in Numerous thymic hypoplasia mice successful births have been immune be maternal system may targeted by treated with a single dose during reported in women receiving midgesta- potent with CsA. Because low levels of CsA dosing tion (97), about the raising questions similar immunosuppressants throughout pregnancy, cross both the rat and human (138) effects of other including CsA therapeutic alkylating agents. AZA it is reasonable to (117,118,124-126), (133,139,140) placenta, Cyclophosphamide has been used as (117,118,127,128), and widely prednisolone anticipate that CsA affect the same tar- may an antineoplastic agent and, as an (118,129,130). Limited amounts previously, of CsA or in the as in the adult. get organs embryo immunosuppressant both after organ trans- AZA cross the placenta; however, observa- Further, laboratory mice exposed perinatally plant and for autoimmune disease control tions of transient neonatal thrombocytopenia, to CsA displayed hypoplastic peripheral lym- (98,99). Further, cyclophosphamide treat- leukopenia, and hypoplasia of the lymphatic phatic organs, impaired intrathymic thymo- ment in adults is particularly toxic to B lym- system in children exposed to CsA or cyte differentiation, absence of mature T cells (124) phocytes and results in to AZA (100,101) impaired and prednisolone (131,132) during in nodes and lymph spleens, and lack of func- antibody production to pregnancy T-dependent and suggest that some developmental tional T-cell in reactivity (141). However, T-independent antigens (102,103), decreased immunotoxicity results from maternal expo- these studies mice were to CsA exposed only lymphoproliferative responses (103), impaired sure to these agents. The long-term immune the during third trimester of pregnancy, with NK cell activity and (104), impaired host consequences (e.g., postpuberty) from such continued for exposure as long as 28 days resistance to infectious and in these agents syngeneic exposure children remains unknown. the postnatally. Thus, consequences of earlier tumor cells Chickens to Compared to (105). exposed AZA, CsA treatment during prenatal exposure, as well as the contribution cyclophosphamide human pregnancy carries during embryonic/neona- a higher risk of pre- of to prenatal exposure alone, immune alter- tal development displayed near-total eradica- mature delivery as well as for the delivery of ations were not determined. tion of the lymphocyte population within small-for-gestational-age (SGA) In CsA babies. a also interferes with tolerization of the bursa of and Fabricius, complete suppres- recent study of 238 women receiving a variety T developing lymphocytes after syngeneic sion of humoral of immunity (106,107). immunosuppressive drug regimens during bone-marrow reconstitution, resulting in in However, studies pregnant mice found no pregnancy, the rates for both prematurity and autoimmunity (i.e., syngeneic graft-vs.-host differences in or spleen thymus weight or SGA infants were high (49 and 29%, respec- in the disease) host animals (142,143). Such histology, hematological profiles, antibody tively) (133). Regimens that included CsA results raise questions about the ability of or DTH even at doses resulted in 66% prematurity responses, responses, (43% with CsA to induce or exacerbate autoimmune dis- of cyclophosphamide that significantly AZA) and 56% SGA babies (19% with ease in gestationally exposed individuals. decreased fetal body weight (108). Cyclo- AZA). However, data from this study indi- Zacharchuk et al. (144) recently found that phosphamide is metabolized to an cated, in contrast active to previous reports, that the susceptibility of thymocytes to clonal alkylating agent, and both the parent com- AZA may carry a higher risk of congenital deletion changes during ontogeny. Studies by pound and the active metabolite cross the malformation than CsA. Birth defects these authors indicate that there is a relatively Fetal placenta (109). metabolism of cyclo- presently associated with CsA administration synchronous wave of maturing thymocytes does not phosphamide appear to occur, how- during pregnancy include cataracts that are (116,134), susceptible to deletion signals during ever; or fetotoxic doses of facial thus, teratogenic dysmorphic appearance cleft fetal life and shortly after (135), birth, but not 7 this drug may be required before immuno- palate (136), aseptical necrosis of the femoral days after birth. Such an observation is in toxic levels of metabolite are formed in the head, and additional fetal malformations agreement with the current understanding of fetus induced (108). by recurrent viral infection neonatal tolerance and (137). further suggests that In the past, glucocorticoid hormones and The resultant uncertainty surrounding the failure to induce tolerization in glucocorti- cytotoxic were potential of these to induce (chemotherapeutic) drugs agents develop- coid-exposed 1-week-old mice reflects an widely used to inhibit tissue mental allograft rejec- malformations in humans, as well as alteration in to susceptibility normal clonal use and/or use of regarding tion; however, prolonged "safe" levels of these agents to be deletion during that time (144). Indeed, a larger doses of these was lim- administered drugs severely during pregnancy, was under- recent study of newborn mice dosed daily ited by numerous, and in cases scored by the results of a recent with many serious, survey of CsA during the first week of postnatal side effects (110). considerable pediatric in which the life Thus, gastroenterologists demonstrated the subsequent develop- research effort has been directed toward the "vast majority of responders were not certain ment of organ-specific autoimmune disease of new and more effective what to recommend with development respect to the use of (145). For such reasons, ablactation has been immunosuppressive drugs. The immunosuppressive agents prior to and dur- recommended in women potent treated with CsA A ing immunosuppressant, cyclosporin (CsA), pregnancy" (117). This remains true during pregnancy because of the transfer of was introduced into clinical trials in largely because the primary clinical 1978 objective CsA equivalent to 5% of an immunosuppres- as a result of such of (111) efforts, and since has such immunosuppressive until sive dose into the breast and because therapy, milk, of become the most used for the has been widely agent quite recently, maintaining the life the potential toxicity and unknown side of human of the prevention organ transplant rejec- recipient rather than allowing effects of CsA on the child's recipient immunologic tion CsA is now considered the individuals to conceive and bear (112-114). children. It system (146). Of perhaps greater importance, reason for the success of be major present organ may important that these studies did not it has now been determined that the blood of transplant Effective include neonatal immune end as a such newborns contains surgery (115). therapeu- points CsA concentrations tic with with the immunosuppression CsA, focus, especially consideration that as high as 65-85% of maternal levels however, (147). often requires simultaneous administration the immune is the of the Taken these studies raise system target organ together, questions of additional administered. the immunosuppressive drugs [e.g., drugs being regarding ability of transplacental CsA Rodent azathioprine (AZA), studies that use fetal exposure to contribute to the of 15-deoxyspergualin, thymic expression mizoribine, didemnin B, and corticosteroids, organ culture demonstrated that autoimmune disease later techniques in the life of More CsA alters of including prednisolone (116-123)]. exposure early gestationally exposed individuals. development Environmental Health * Vol 3 2000 467 Perspectives 108, Supplement June HOLLADAY AND SMIALOWICZ The use of therapeutic immunosuppres- to DES the of having estrogenic activity, resulted in a birth suggest possibility post- sants during pregnancy thus represents a rela- natal immune alterations, including increased number of immune abnormalities. These autoimmune disease. abnormalities T- tively new area of human developmental included reduced and B-cell In some Rodent studies that evaluated increased mitogen responses to PHA and LPS, respec- exposure to immunotoxic agents. regards, the effect of these drugs on the devel- expression of autoimmune disease after devel- tively; reduced antibody responses to SRBC oping immune system have largely been dis- opmental immunotoxicant exposure have and LPS; reduced T-helper cells; and reduced regarded in the assessment of risk to the been limited. However, a recent report indi- NK cell activity (88,158,159). known sensi- cates that mice predisposed to the develop- Toxic chemicals administered to young unborn despite the heightened immune to chemical ment of autoimmune disease display animals may also alter immune function, tivity of the system which than in insult during development. exacerbated disease if exposed to DES or may be more severe that adults et al. or which for a Prenatal chemical exposure and post- TCDD during gestation. Silverstone may persist longer period of The observation (150) found that a single fetal exposure to time. For example, the exposure of rat pups natal autoimmune disease. that CsA treatment in irradiated rodents leads TCDD in NZB x SWR (SNF1) mice signifi- to di-n-octyltin dichloride during the first 3 onset of in to expression of autoimmune disease after cantly reduced the time to postnatal weeks of life resulted suppression of the in the male PHA bone marrow transplantation raises questions autoimmune lupuslike nephritis response, which persisted up to 10 a similar weeks to about other chemical agents that might have offspring. These authors reported of age (160). Rat pups exposed a fetal 1-21 this effect. TCDD produces fetal thymic observation for DES, i.e., single expo- cocaine from postnatal day had in the effects of CsA in sure of SNF1 mice to DES induced auto- decreased peripheral blood lymphocytes on effects vivo similar to inhib- immune nephritis in male offspring between day 22, whereas pups exposed to both fetal thymic organ culture, including ited thymocyte maturation and reduced 5 and 10 months of age. Female SNF1 mice cocaine and ethanol had decreased total IgM rats expression of thymic MHC class II mole- develop this autoimmune syndrome sponta- levels (161). Weanling (i.e., 25-day-old) led to the neously during the first year of however, dosed 4 times over 17 days with 3,3',4,4'- cules. These observations sugges- life; tion that to TCDD male mice do not display significant autoim- tetrachloroazoxybenzene had reduced thy- gestational exposure may mus weights, antibody responses to SRBC, interfere with normal development of self tol- munity before 1 year of age. This report sug- It has that exposure to certain peritoneal macrophage chemiluminescence, erance [reviewed by Holladay (148)]. gests prenatal also been that humans to immunotoxicants may play a role in postnatal and bone marrow cellularity. These effects suggested exposed were in as immune dis- expression of autoimmunity. greater rats exposed weanlings DES during development may at the play increased incidence of autoimmune dis- compared to adults (i.e., 56 days old Postatal Immunotoxicant Exposure start of ease. A retrospective study of women (1,711 dosing) (52). There are few studies in which individuals) exposed to DES during preg- developmental that the overall of animals have been exposed to nancy found frequency any experimental and Comparison of Similarities autoimmune disease was com- immunotoxicants only during the postnatal 28.6/1,000 Differences Between Humans pared to 16.3/1,000 among unexposed con- period. and Laboratory Animals = it is not an immunotoxic trols (significantly different at p 0.02) (74). Although agent, The autoimmune diseases evaluated included malnutrition during early childhood adversely Direct comparison of immune development affects the immune system. Dietary protein between human and animals is complicated systemic lupus erythematosus, scleroderma, in malnourished children several factors. the most Grave disease, Hashimoto thyroiditis, perni- deprivation young by However, signifi- between 1 and of resulted in a cant difference lies in the developmental cious anemia, myasthenia gravis, thrombocy- 3 years age rheumatoid number of immune deficiencies. These maturity of the immune system before and topenic purpura, arthritis, toward regional enteritis, chronic ulcerative colitis, included decreased IgG and trends after parturition. This difference has been lower and decreased cuta- linked to the of For exam- multiple sclerosis, chronic lymphocytic IgA IgM levels, length gestation. and neuri- neous decreased ple, animals with short gestation periods (e.g., thyroiditis, Reiter syndrome, optic hypersensitivity responses, tis. When these autoimmune diseases were T lymphocyte responses to phytohemag- mice, rats, rabbits, and hamsters) have rela- to considered individually, however, only glutinin (PHA), and reduced responses tively immature immune systems at birth Salmonella vaccine Four- to six- to with Hashimoto thyroiditis occurred significantly (151). compared humans, significant typhi more often in the women = week-old mice fed a low protein diet displayed immune development occurring postpartum. exposed (p 0.04). humans T cells to A similar evaluation of 1,173 decreased and decreased responses Nevertheless, there are more similarities than to DES PHA and cells in the mixed- differences in the of the human exposed during development (1,079 allogeneic ontogeny females and found increased lymphocyte response (MLR), as well as retar- compared to laboratory animal immune sys- 94 males) and diabetes mellitus dation of immune maturation Zinc tems. In a asthma, arthritis, (152). fact, significant amount of our compared to prevalence rates for these dis- deficiency in the diet of lactating mouse dams knowledge about human immune system eases in the resulted in that displayed retardation of has been achieved because of general population (91). pups development However, in a more recent study evaluating thymus and spleen development, depressed animal research. rates of allergy, infection, and autoimmune T-cell and the absence of To present the similarities and differences mitogen responses, in in the disease DES-exposed individuals (253 men detectable IgM and IgG (153-155). ontogeny of immune system cells for and matched with similar unex- The administration of certain drugs which there are data in both humans and 296 women) individuals men and 246 in posed (241 during early postnatal life can also result mice, we used a convention to compare pre- in women), no differences disease occurrence altered immune function later in life. For natal immune system maturational landmarks were detected (149). Baird et al. (149) con- mice and rats to between the The example, 1-day-old exposed species. period of gestation cluded that a was needed to larger sample cortisol acetate or hydrocortisone, respec- for the mouse is approximately 20 days; that evaluate DES-associated risk of autoimmu- atrophy and reduced for the human is 40 weeks. tively, displayed thymic Therefore, each nity because autoimmune diseases are rela- to antibody responses sheep red blood cells day of gestation for a mouse is approximately rare tively in the human population. Thus, (SRBC) (156,157). When given to 1- to 5- equivalent to 2 weeks of gestation for the preliminary studies of humans exposed before day-old mice, DES, a nonsteroidal drug human. We the expressed time of gestational 468 Environmental Health Perspectives * Vol 108, Supplement 3 * June 2000 DEVELOPMENTAL AND ADULT IMMUNOTOXICITY maturational landmark The development of functional NK cells as the polysaccharide antigens found on the development for each are data for the in the human fetus occurs at 28 weeks of ges- cell walls of several infectious bacteria, for which there comparable mouse, as a decimal portion tation (dp = 0.35), with full-term newborns which also contributes to increased suscepti- human and the It is to of the periods displaying peripheral blood NK activity at bility to infections (175). interesting (dp) respective gestational levels the dichotomy between humans and (Table 1). For example, if a specific matura- approximately 60% that of adult (170). note landmark occurs on week 10 for the In contrast, NK cell activity in mice is absent mice in the maturation of antibody responses tional and -independent human and on day 12 for the mouse, the dp at birth and does not begin to appear until to T-cell-dependent = for the human and about 3 weeks of age (171). antigens. would be 10/40 0.25 = 0.60 for the mouse. The development of B lymphocytes in The immune responsiveness of human 12/20 influenced by their Embryonic hematopoietic stem cells in humans begins at approximately the same neonates appears to be T B (i.e., to antigens in utero and during the fetal yolk sac begin to migrate in the time as lymphocytes. lymphocytes sensitization 5 weeks (dp = lymphocytes bearing sIgM and sIgG) are first early postnatal life. There is ample evidence human fetus at approximately which results in the presence of lym- found in the liver at about 8 weeks of gesta- from laboratory studies to demonstrate that 0.125), raised from birth in a germ- phocyte precursors in the liver by 7 weeks tion (dp = 0.10) and in the spleen at about 12 when animals are = IgA-bearing cells free environment there is a delay in lymphoid (dp = 0.175) and in the thymus after 9 weeks weeks (dp 0. 15). IgD- and = At 10 weeks = at 12 weeks of (dp = Germ-free animals have (dp 0.225) (162). (dp 0.25) are found gestation development (176). fetal express the T-cell Adult levels of B lymphocytes bearing significantly reduced levels of Ig, which is due the thymocytes 0.15). markers CD3, CD4, CD5, and CD8 (163). slg of all classes are reached by 14-15 weeks to a 2-5 times lower rate of Ig synthesis. in = (172). However, of and IgM is more affected Lymphocytes begin to appear peripheral of gestation (dp 0.35) Synthesis IgA after their in the human neonatal B lymphocytes are function- than IgG synthesis in a germ-free environ- blood shortly appearance and then in the spleen In the ally defective in their capacity to generate ment. The number of plasma cells in these thymus (164). mouse, the thymic epithelial anlage is colo- antibody-producing cells in vitro compared to animals is approximately 10 times lower than on B cells from adults. In B lymphocytes in normal animals (172). Further, germ-free nized by bone marrow-derived stem cells general, 11 = of humans are inherently immature at birth. animals have a difficult time replacing mater- approximately gestation day (dp 0.55). 14 (dp = 0.70), murine thymocytes Although a small number of IgM-producing nal IgG, which is transported during gesta- By day CD4 and CD8 For these mat- cells are detected, no IgG- or IgA-producing tion across the placenta, with a sufficient express (165). B to urational landmarks the mouse is chronologi- cells can be identified. The ability of cells production of IgG of their own. immature than antibodies of the IgG and IgA dasses At birth nearly all of the IgG in the new- cally 2- to almost 3-fold more produce the human, respectively. increases with age, with adult levels reached by born human is of maternal origin. During the PHA-responsive lymphocytes in the 5 and 12 years of age, respectively (173). In first 3-6 weeks of life, there is an exponential 12 fetal B cells in the decrease in that reaches its lowest level human fetal thymus are detectable by mice, expressing sIg appear IgG weeks = 0.3), with splenic and peripheral liver, spleen, and bone marrow on day 17 (dp between 1.5 and 3 months of age, when IgG (dp blood responsiveness to PHA = 0.85) (6), which represents an approximate synthesis by the newborn begins; however, lymphocyte 4 later = In not detectable approximately weeks (dp 3-fold delay compared to the human. mice, adult IgG levels are reached until 5-6 to Con A have been responses to T-cell-independent of On the other hand, IgM levels 0.4) (166). Responses antibody years age. observed with cells at 13-14 weeks of antigens occur soon after birth and reach rise rapidly during the early months of life, thymus within 12 = and with cells at near-adult levels by 2 or 3 weeks. In contrast, with IgM at 75% of adult levels gestation (dp 0.35) spleen in life. adult levels 18 weeks of gestation (dp = T-cell-dependent antibody responses mice months of Only 20% of IgA approximately 2 at 1 adult levels are reached At 11-15 weeks of gestation (dp begin after weeks and do not reach adult are present year; 0.45) (167). = from human until 6-8 weeks of after 10 of age The early 0.275-0.375), lymphocytes levels age (174). only years (177). are of stimulating and It is not clear why there are such delays increase in IgM levels in newborns parallels fetuses capable in to lymphocytes in an in B lymphocyte function. Deficiencies IgG the development of natural antibodies to responding allogeneic mouse and the of enterobacteria. Studies with humans indicate MLR (168). On the other hand, thy- IgA responses during early period to to PHA, Con life have been described as reflecting regula- that exposure to various nonpathogenic mocytes only begin respond or vaccines in life A, and in an MLR by gestation day 17 (dp = tion by T cells (suppressor cells) as opposed to microorganisms early gives a 2-fold in B cells. This rise to higher serum Ig titers than seen in which is greater than delay a deficiency high-suppressor 0.85), to the human. the levels T-cell activity has been reported to exist noninfected/nonimmunized infants (177). compared Although Human fetal of responsiveness to PHA and in throughout infancy with decreasing intensity macrophages originate thymocyte in similar to adult and 2 of from hemopoietic stem cells and appear in the MLR mice are levels, disappears by approximately years A does not reach adult or later (173). On the other hand, a case tissues through the circulation after vascular- Con responsiveness age In immature can weeks after birth has been made that deficient B-cell function ization. mice, macrophages levels until 2-3 (169). first several of life is due to a be found in the sac at during the years yolk approximately defect or rather than to a day 10-11 and then in other tis- B-cell immaturity gestation 1. Time of Table gestational development (dp). 12 or later negative influence by T-suppressor cells or sues and in circulation at day landmarks Human Mouse Maturational In it has fetal macrophages generally monocytes (172,175). any event, (178). Although the to kill certain bacteria after on B cells 0.10-0.15 0.85 been that the greater susceptibil- lack ability sig expression postulated Fetal liver 0.15 0.50 hematopoiesis of human newborns to certain bacterial neonatal rodents possess bacte- ity phagocytosis, first detected due to deficient B-cell ricidal albeit less than that of adults infections is function, activity, 0.23 0.55 Lymphocyte precursors the because of the in (179). On the other hand, phagocytic particularly delay produc- in thymus of and antibodies and antitumor activities of newborn mouse tion IgG IgA (172). 0.35 0.85 responsive Mitogen well to T-cell- are than those of adult Infants to macrophages higher appear respond hymocytes mice 0.35 > 1.0 ade- (178). Functional NK cells dependent antigens primarily through 0.85 Pluripotent stem cells seed 0.50 of The functional immaturity of leukocytes quate production IgM. However, they bone marrow all such factor in the human neonate's respond poorly or not at to antigens is a significant Health Vol 3 2000 Environmental Perspectives * 108, Supplement June HOLLADAY AND SMIALOWICZ regarding possible conse- impaired host defenses (180). The neonate's in general the lowest among the fetal tissue Information newborns and chil- of exposure to immunotoxicants very inflammatory response is insignificant com- and the highest among quences of the adult. This decrease in dren. However, the data suggested that the early in gestation (e.g., postconception/pre- pared to that of human lym- implantation) is also essentially unavailable. inflammatory responsiveness in the neonate is interferon-producing capacity phocytes remains relatively constant through- For instance, it is presently not known if cer- characterized by a higher proportion of func- neu- out intrauterine and postnatal life (186). tain chemical agents may affect hematopoi- tionally immature polymorphonuclear etic progenitor cells in the yolk sac before and fewer monocytes during trophils (PMNs) in Knowledge Gaps migration to fetal liver, affecting immune the early hours of inflammation compared to several gaps in the present knowledge development. Similarly, no information is infants 3-5 months of age. During the early There are number of base of drug- and chemical-induced develop- available regarding possible adult exposures period of inflammation, a large that may have the poten- are which is unique to mental immunotoxicity in humans and (i.e., preconception) eosinophils observed, it is known tial to alter the development of the fetal this of life (181). PMNs and animals. For example, although early period components of the immune system. The National Toxicology monocytes from neonates (i.e., cord blood) when certain structural of immune system first appear and become Program (NTP) of the National Institute are deficient in their chemotactic responses Environmental Health Sciences has, over the cells from adults functional during development, comparative compared to (180,182). the outcome of past 15 years, developed a two-generation Variable results have been obtained in studies information regarding expo- chemical or mixtures of chemi- study design (i.e., reproductive assessment by on the bactericidal activity of PMNs from sure to agents aimed at but in the absence of cals before, during, or shortly after any given continuous breeding) specifically newborn humans, is hazards to male and/or this to aspect of immune development largely identifying potential unusual circumstances activity appears a case in it is not female reproductive performance resulting normal After infection, the unavailable. As point, be (180,182). known if exposure to TCDD before, during, from exposure to toxic chemicals (190). This of PMN and PMN precursors in the pool or after the establishment of the thymic rudi- NTP paradigm for detecting reproductive newborn animal is rapidly depleted compared in the offspring of rodents in Furthermore, the number ment contributes most to the postnatal impairment to adults (183). this chemical. which the male and/or the female parent was rate at which PMNs reach the site of immunosuppression caused by and is true for any immunotoxi- exposed to chemical agents before and/or infection in newborn rats are decreased Such essentially cant one may wish to consider. throughout the breeding and lactating period compared to adults (184). remain the could be directly applied to studying effects and Continued animal studies Complement components activity to define the most sensi- of chemical exposure on immune been studied during fetal and neonatal most obvious way parental have tive of immune system development development of the offspring. life in humans. The complement component periods In An recent area of concern in in fetal tissues as as 6 weeks to immunotoxicant exposure. this regard, additional C3 appears early are numerous studies in lab- immunotoxicity is that early- with C2 and C4 detected at 8 although there developmental of gestation, The of rodents that have demonstrated the life exposure to certain chemical agents may weeks of gestation appearance oratory (185). is due to immune development not only produce postnatal immunosuppres- complement in fetal tissue synthesis sensitivity of system or no transfer of to or chemical sion but also contribute to increased expres- by the fetus because little perturbation by physical responses or occurs across the insults, many of these studies used both pre- sion of hypersensitivity complement placenta (186). it is autoimmune diseases later in life. A careful In it that many of the com- and postnatal exposure regimens. Thus, general, appears well as the often unclear which of such expo- evaluation of this possibility that gestational of as portion ponents complement, may are sure contributes most to subsequent exposure to certain immunotoxicants hemolytic activity of complement, signifi- A first in making relate to postnatal expression of aberrant lower in newborns to adult immune impairment. step cantly compared this would involve cross- immune function is needed and represents a levels. Maturation of components of the das- determination in our understanding of fostering studies with known developmental major gap present sical and alternative complement pathways and com- the consequences of immunotoxicant in an with C2, C4, immunotoxicants to determine possible occurs age-related fashion, B adult levels 6 the effects of in utero versus lactational exposure during development. Although C6, and reaching by pare C5, will be to providing these and/or early postnatal exposure. In addi- rodent studies critical months of age (187). Although quanti- and of data to fill this gap, recent success in organ deficiencies are not associ- tion, the development application tative necessarily the increase in more sensitive and end points of transplant procedures is resulting in a cohort ated with functional defects, predictive the first 6 immunotoxicity would facil- of humans who were exposed to therapeutic complement proteins during developmental of critical windows drugs from the precon- months of life may partially explain the age- itate the identification immunosuppressive infection of These restricted susceptibility to bacterial exposure. ception period throughout gestation. In evidence that deficien- Another in present knowledge is the individuals offer an unusual opportunity to (188). fact, suggests gap the human immuno- cies in the opsonizing capacity of comple- role that toxicokinetic and/or toxicodynamic expand developmental be carefully ment in neonatal serum may contribute to mechanisms play in age-dependent responses. toxicity database, and should Work in fetal it is uncertain if the inherent followed in clinical and epidemiologic studies. this susceptibility (180). sheep Specifically, and has demonstrated that whole com- increased susceptibility of the young pigs Summary in serum is not detectable animal/human to immunotoxicants is due to plement activity of in the to metabolize and/or excrete Experimental studies suggest that the until after day 123 gestation sheep reduced ability immuno- (normal gestation of 145 days) and that in the toxic moiety, or is more the result of the production of long-term secondary the levels of C8 and C9 are only 30% of occurring during critical develop- in adult animals requires either pigs exposure deficiency term mental that waves of rapid cel- continued to the or adult levels at (189). phases require exposure inducing agent In The in vitro induction of interferon lular proliferation and differentiation. Kinetic damage to primitive hematopoietic cells. in lymphocytes obtained from studies and studies evaluating immunotoxi- contrast, low-level single-dose exposure to production fetal of cant effects on the regulating cell cycle immunotoxicants immune (8-17 weeks gestation), newborn, genes certain during child (1 10 and tissue in immune tissues development may produce changes in the month to years), adult and apoptosis developing have been studied. The interferon titers were are needed to begin to answer these questions. immune system that are long-lasting or Environmental Health Perspectives * Vol 108, Supplement 3 * June 2000 470 DEVELOPMENTAL AND ADULT IMMUNOTOXICITY permanent, and that may be irreversible. 18. Pardoll DM, Fowikes BJ, Bluestone JA, Kruisbeek AM, Maloy 41. Bekesi JG, Holland JF, Anderson HA, Fischbein AS, Rom W, WL, Coligan JE, Schwartz RH. Differential expression of two Wolff MS, Selikoff IJ. 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Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

Holladay, S D; Smialowicz, R J

Environmental Health Perspectives – Jun 1, 2000

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DOI: 10.1289/ehp.00108s3463
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Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

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Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure.

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