REVIEW ARTICLE Mechanisms of teratogenesis* › content › develop › 36 › 1 › 1.full.pdf ·...

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/. Embryol. exp. Morph. Vol. 36, 1, pp. 1-12, 1976 Printed in Great Britain REVIEW ARTICLE Mechanisms of teratogenesis* ByLAURI SAXEN 1 From the III Department of Pathology, University of Helsinki Introduction Site of Action Introduction Intracellular compartment Cell surface Extracellular matrix Fetal environment Stage of Action Introduction Determination Proliferation Organization Migration Morphogenetic cell death Remarks References INTRODUCTION In view of the great number of teratogenic factors known and the vast array of congenital defects, disorders and syndromes, it would probably be a waste of time to search for unifying mechanisms and principles in abnormal develop- ment. Instead, therefore, I shall describe a selection of teratogens and their consequences, and try to arrange them in a certain hierarchy based on a simpli- fied model of how they act. The assumption underlying the model (Figs. 1 and 2) is that the result of a teratogenic insult is determined by its site of action and the stage of development of the target organ. This is supposed to hold for all congenital defects, whether due to genes or caused by exogenous agents. In genetic defects the scheme indicates the site and stage of development at which the mutant gene is expressed; in nongenetic defects the site and stage refer to exposure to an exogenous teratogen. * This article is based on a paper presented in Martinique at a meeting co-sponsored by the Institut de la Vie and the U.S. National Cancer Institute. 1 Author's address: III Department of Pathology, University of Helsinki, SF-00290, Helsinki 29, Finland. I EMB 36

Transcript of REVIEW ARTICLE Mechanisms of teratogenesis* › content › develop › 36 › 1 › 1.full.pdf ·...

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/ . Embryol. exp. Morph. Vol. 36, 1, pp. 1-12, 1976

Printed in Great Britain

REVIEW ARTICLE

Mechanisms of teratogenesis*

ByLAURI SAXEN1

From the III Department of Pathology, University of Helsinki

IntroductionSite of Action

IntroductionIntracellular compartmentCell surfaceExtracellular matrixFetal environment

Stage of ActionIntroductionDeterminationProliferationOrganizationMigrationMorphogenetic cell death

RemarksReferences

INTRODUCTION

In view of the great number of teratogenic factors known and the vast arrayof congenital defects, disorders and syndromes, it would probably be a waste oftime to search for unifying mechanisms and principles in abnormal develop-ment. Instead, therefore, I shall describe a selection of teratogens and theirconsequences, and try to arrange them in a certain hierarchy based on a simpli-fied model of how they act.

The assumption underlying the model (Figs. 1 and 2) is that the result of ateratogenic insult is determined by its site of action and the stage of developmentof the target organ. This is supposed to hold for all congenital defects, whetherdue to genes or caused by exogenous agents. In genetic defects the schemeindicates the site and stage of development at which the mutant gene is expressed;in nongenetic defects the site and stage refer to exposure to an exogenousteratogen.

* This article is based on a paper presented in Martinique at a meeting co-sponsored by theInstitut de la Vie and the U.S. National Cancer Institute.

1 Author's address: III Department of Pathology, University of Helsinki, SF-00290,Helsinki 29, Finland.

I EMB 36

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Epigenetic

Fig. 1

SITE OF ACTION

The four main levels of action of a defective gene or an exogenous teratogenare illustrated in Fig. 1. Action may primarily be exerted on (1) the intracellularcompartment, i.e. on the chain of interactions between the nucleus and thecytoplasm leading to the specific metabolic products of the cell. The primaryaction may also be expressed as (2) abnormalities in the structure and functionof the cell surface, or (3) of the extracellular matrix. Finally, detectable defectsmay result from primary effects on (4) the fetal environment, i.e. from abnor-malities at the organismal level or in the feto-maternal relation. Although sucha schematic classification into four main levels of teratogenic action is no doubtan oversimplification, it may be useful to consider the mechanisms involved inabnormal development in such a hierarchy. In what follows, examples of bothgenetic and nongenetic defects of these four categories of teratogenic insult willbe presented.

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Intracellular compartment

During the last two decades, the processes of nucleo-cytoplasmic interactionhave been mapped, and with this rapidly growing knowledge, information hasaccumulated on the modes of action of mutant genes and of various inhibitors.

Genetic. Perhaps the best analyzed hereditary defects in the intracellularcompartment are the 'inborn errors of metabolism', a category of diseases sonamed long ago by Sir Archibald Garrod. In these diseases a mutant gene leadsto deficiency of an enzyme activity, with the result that a metabolic pathway isblocked. There are three possible consequences, (1) the metabolite before theblock may accumulate, (2) the metabolite beyond the deficient enzyme may belacking, and (3) the metabolite before the block may take an alternative pathway.An example of the first type will illustrate how such an intracellular mishap mayprofoundly affect the whole organism.

In the mucopolysaccharidoses, enzyme defects result in blockage of thedegradation of mucopolysaccharides and accumulation (or secretion) of theirpolymers. For instance, Hurler's syndrome is due to deficiency of the lysosomalenzyme a-L-iduronidase, and subsequent accumulation of both heparin sulfateand dermatan sulfate in the cells. Excessive accumulation of these metabolitesin cells of various types gradually leads to the manifestation of a severe disorder,characterized by retardation of growth, mental regression, and various skeletaldefects, accompanied by cardiac failure with hepatosplenomegaly (Leroy &Crocker, 1966).

Nongenetic. The various steps of the nucleocytoplasmic interactions may beblocked more or less specifically by appropriate inhibitors. As, by definition,these inhibitors prevent the process of the reading of genetic information, theyshould all cause defects mimicking hereditary disorders (phenocopies). How-ever, this may be difficult to demonstrate for two reasons. If the function in-hibited is essential to life, the effect is usually lethal and so can never give rise toa detectable malformation (Wilson, 1973). Secondly, the effect may be reversible,and the result therefore transient. The first difficulty has been overcome bytreating isolated organs in vitro followed by retransplantation. By this method,actinomycin D has been shown to be teratogenic to early brain anlagen,where it produces severe eye defects (Diethelm & Schowing, 1974). Concerningreversible inhibition, tissue culture methods have proved useful, because normaland disturbed development can be followed constantly. Cycloheximidine, whenadded to cultures of kidney rudiments, stops both protein synthesis and morpho-genesis. But after the drug is withdrawn, both processes continue normally, andthe short lag period is masked by the subsequent normal development (Saxen,unpublished observations).

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Cell surface

Experiments of various types have repeatedly shown the importance of thecell surface in many developmental processes such as cell recognition andaggregation, morphogenetic cell interactions, and cell migrations (see Mos-cona, 1974a). Consequently, it may be expected that both genetic defects andexperimentally induced alterations of the cell surface will lead to impaireddevelopment.

Genetic. Extensive studies on mice with mutant genes at the T locus haveshown that the homozygotes have various defects and are usually inviable. Oneof these lethal alleles, t9, seems to exert its effect via a primary abnormality ofthe cell surface. Development seems to proceed normally until gastrulation.Then, migration of the mesodermal cells between the ecto- and entoderm isseverely impaired, and ectodermal-mesenchymal relations are disrupted.Electron microscopy shows that at the gastrula stage embryos homozygous forthe /9 gene have mesodermal cells of abnormal shape and with abnormal inter-cellular relations. Genes at the T locus also determine surface components onspermatozoa carrying the various mutants. The surface antigens of the four talleles so far tested are different, and no cross-reactions have been detected.Thus the t9 allele seems to act primarily upon the cell surface components,thereby leading to impaired cell-to-cell interactions and altered cell behaviorand ultimately to a total block of development (Bennett, 1975).

Nongenetic. The formation of the secondary palate terminates with a fusionof the palatal shelves, a process which can occur only after the epithelium liningthe mesenchymal shelves has disappeared. If this 'morphogenetic cell death'were prevented, fusion would be incomplete, and the result would probablybe a cleft palate. Death of the epithelial cells and fusion of the shelves werepreceded by rapid synthesis of mucopolysaccharides on the epithelial surface.This observation led Pratt and his collaborators (Pratt & Hassell, 1975;Greene & Pratt, 1975) to study the effect of inhibiting polysaccharide synthesis.The antagonist of glutamine, 6-diazo-5-oxo-norleucine (DON), was used toblock the synthesis of glycosaminoglycans, and the success of the treatment wasconfirmed by various techniques of light and electron microscopy. In the pre-sence of DON, epithelial necrosis was prevented, and subsequent fusion of theshelves was incomplete. Excess of glutamine restored the synthesis of the surface-associated glycosaminoglycans and allowed programmed death of the epithelialcells and complete fusion.

Extracellular matrix

In various tissues, structure and function are defined by an extracellularmatrix. Each matrix has a composition unique to its particular tissue. Hence ateratogen may be expected to affect the function of a tissue by interfering withthe production or maturation of this extracellular material.

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Mechanisms of teratogenesis 5Genetic. Dermatosparaxis is a hereditary disease recently detected in cattle,

and characterized by a fragile skin with an inelastic dermal tissue. The basicdefect seems to be abnormal or insufficient production of collagen in the dermalconnective tissue. The mutant cells are devoid of the enzyme procollagenpeptidase. Consequently, the procollagen accumulated is abnormal, containingN-terminal extensions of noncollagen protein and its capacity to form fibrils isdefective. This, in turn, leads to a severe disturbance in the architecture of thecollagen fibrils and in their cross-linkages (Lenaers, Ansay, Nusgens & Lapiere,1971; Hanset & Lapiere, 1974). The same enzyme defect was subsequentlyfound in patients suffering from one form of the hereditary Ehlers-Danlossyndrome (Lichtenstein et al. 1973).

Nongenetic. The antibiotics of the tetracycline group will serve to illustratehow teratogens may affect development by acting on extracellular compounds,and not directly on the cells producing these molecules. The tetracyclines areknown to be incorporated in the mineralizing tissues, where they may retardgrowth and cause hypoplasia. Their mode of action has been thoroughlyanalyzed in vitro, with fetal mouse bones as target tissue. At concentrations thatinhibited bone growth, tetracycline hydrochloride did not reduce the rate ofproliferation of chondroblasts. Nor did these concentrations affect the synthesisof collagen and mucopolysaccharides, which are the main components of thecartilaginous matrix. The primary action of the drug was finally shown to beexerted on the bone mineral crystals; in the presence of low concentrations oftetracycline their formation and growth were definitely retarded. The drugapparently acts by competing with the inorganic ions building the bone mineral(Kaitila, 1971; Saxen & Kaitila, 1972).

Fetal environment

The development of a mammalian embryo is controlled by a complex offactors, maternal, placental, and autogenous; these factors include hormones,protective mechanisms (immune system), and nutritional factors. Changes inthese might be expected to lead to developmental abnormalities.

Genetic. Numerous hereditary defects give rise to changes in the internalenvironment that secondarily affect various organs. Many endocrine disorderscan be placed in this category. For example, the hereditary Pendred's syndromeis characterized by congenital deafness and hypothyroidism. To study theassociation between these two defects, Deol (1973) mimicked the syndrome inmice by treating pregnant females with propylthiouracil. This treatment led tosevere lesions in the inner ear, especially in the tectorial membrane, whichcaused loss of hearing. Addition of thyroxine to the mother's drinking waterresulted in offspring with normal morphology of the inner ear and normalhearing. These experimental results suggest that in Pendred's syndrome, deaf-ness is a secondary consequence of the endocrine disorder.

A peculiar hereditary syndrome in mice is caused by the l tail-short' mutant

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gene. This mutant is characterized by a short, kinky tail associated with variousother skeletal defects and retarded growth. Deol (1961) showed that in theearly stages of development affected embryos suffer from transient anemia. Thiscan be traced back to the formation of blood in the yolk-sac; at this stage themutants have smaller blood islets than the wild-type embryos. This led Deol tosuggest that anemia, by leading to differential retardation of various organs,might be the primary cause of the syndrome.

Nongenetic. The embryonic 'macromilieu' is susceptible to many externalinfluences: nutritional deficiencies, placental insufficiency, altered maternalendocrine status and immunization following feto-maternal incompatibilitymay have deleterious effects on the developing organism. As an example, I shallcite the work of Brent (summarized in 1971). He showed that rabbit antiseraagainst certain rat tissues, when injected into pregnant rats, caused congenitaldefects in the offspring. Yet the antibodies never crossed the placenta. Theyaccumulated in the yolk-sac epithelium, a structure peculiar to the placenta inrodents and rabbits. There, apparently, the immunoglobulins impaired placentalfunction by impeding the transport of nutritional and other vital factors. Asimilar mode of action has been suggested for certain azo dyes that causespecific defects in embryos without actually entering the fetal organism (Beck,1967).

STAGE OF ACTION

IntroductionThe development of various organs during embryogenesis is best considered

not as a continuous process of 'maturation', but as a chain of distinguishablesteps strictly controlled in time and space. The fate of cells, which were originallyidentical with the same genome, diverges step by step, and this determinationis followed by various events that lead to an orderly arrangement of tissuecomponents of specific shape, size and function. There is good reason to believethat these basic steps of development are highly sensitive to both hereditary andexogenous factors, and that insults at such stages will have profound terato-logical consequences. Thus, development involves a series of tight corners atwhich normal embryogenesis is determined, but vulnerability is increased.

Fig. 2 illustrates the development of a hypothetical organ, in which thefollowing events can be distinguished: determination, proliferation, cellularorganization, migration, and morphogenetic cell death. Several congenital defectsand syndromes, both genetic and nongenetic, can be traced back to failures inthese events.

Determination

The determination of embryonic cells with the same genetic information andtheir subsequent morphogenesis are processes guided by the position of the celland its relation to other cells. Determination thus depends on interactionbetween cells. Numerous examples of such 'inductive cell interactions' have

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Mechanisms of teratogenesis

Morphogcncticcell death

Organization

Proliferation

Determination

Progressive development

Fig. 2

been described, but the underlying molecular mechanisms are virtually unknown(see Kratochwil, 1972; Saxen et al. 1976). These events are likewise sensitive toboth genetic and exogenous factors.

Genetic. A mutant strain of mice in which the homozygotes are born eyelessor with severe microphthalmia was analyzed by Chase & Chase (1941). Inhomozygous embryos the early development of the optic vesicle was completelynormal and progressed as in the wild type. Before the stage at which the opticcup makes contact with the overlying presumptive lens epidermis, growthseemed to slow down and the two tissue components either failed to meet orestablished contact over a restricted area only. Consequently, the 'inducingstimulus' which determines the lens and requires close apposition of the tissueswas not passed from the optic bud and no lens developed (or the lens formed wasvery small). Subsequent studies on this mutant strain have suggested that theprimary cause of incomplete interaction might be not the retarded growth of

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the optic bud, but failure of some intervening mesenchymal cells to undergonormal 'morphogenetic cell death' (see below) (Silver & Hughes, 1974).

Nongenetic. Inductive cell interactions can be blocked by various means, bothchemical and physical. The effects of various chemicals are difficult to interpret,because our knowledge of the molecular basis of these interactions is so frag-mentary. Like various mutant genes, an inhibitor may act on the inductortissues, on the transmission of inductive signals, or directly on the respondingtissue (see Saxen, 1973). Some direct physical effects are easier to explain. Theexample deals with one of the best studied interactive systems, that occurringbetween the amphibian gastrula ectoderm and the invaginating mesoderm ofthe archenteron roof. In his classic experiment, Mangold (1931) interfered withthis process by a microsurgical manipulation. He cut a flap in the respondingectoderm, the presumptive neural plate, lifted it, removed a piece from themidline of the underlying archenteron roof, and replaced the ectoderm in itsoriginal position. The wounds healed. The ectoderm was now exposed to anabnormally narrow inductive 'template' of mesoderm. As a result, the neuralplate was narrowed and the lateral edges approached each other, the outcomefrequently being fused optic cups (synophthalmia). The extreme form wascomplete fusion of the eyes (cyclopia).

Proliferation

As spatially and temporally controlled proliferation of cells is vital for normalembryogenesis, disturbances in proliferation rates should result in a variety ofdefects. General inhibition would result in abnormally small embryos and morelocalized effects in organ hypoplasia or - when differential proliferation ratesdetermine the shape of the organ - to misshapen or defective organs.

Genetic. The anomaly known as dextrocardia, which is frequently associatedwith situs inversus, appears to result from the action of an autosomal recessivegene. During early embryonic life, the primitive cardiac loop, instead of bulgingto the left, bulges to the right. Normal curvature of the cardiac loop and regionaldifferentiation and shaping of the heart have been shown to result from dif-ferential proliferation of the embryonic heart cells. The heart cells display thisintrinsic capacity in vitro in the absence of any other tissues, thus showing thatthey are somehow programmed for differential proliferation. Consequently,dextrocardia is the result of a failure or rather a reversal of the normal patternof proliferation in the embryonic heart (DeHaan, 1967).

Nongenetic. Irradiation and radiomimetic drugs acting primarily on dividingcells have a typical stage-dependent spectrum of consequences as the tissuesusually affected are those that proliferate most rapidly. This can be shown inthe developing eye. During early development, mitoses occur throughout theouter layer of the neural retina, but as cytodifferentiation of the central partadvances, proliferation is restricted to a narrow peripheral zone. Consequently,triethylene-melamine (TEM), a radiomimetic drug, has different effects at

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different stages. When applied in early development, it produces cell necrosisand blocks mitoses all over the retina, the result being anophthalmia. At a laterstage, treatment affects only the peripheral zone of proliferation and the end-result is less drastic, mainly microphthalmia (see Saxen & Rapola, 1969).

Organization

Determination and differentiation of cells lead to surface specialization, withthe result that like cells can recognize each other. They then tend to adhere toeach other and form aggregates. These are the anlagen for various organs andcomponents of organ.

Genetic. The recognition mechanism and adhesive properties of embryoniccells may be genetically defective. This was shown by Ede and his collaborators,who studied the talpid3 mutant chick characterized by a variety of skeletaldefects (Ede & Agerback, 1968; Ede, Bellairs & Bancroft, 1974). The authorsused the technique of enzymatic disaggregation and subsequent reaggregationto study the mesenchymal cells of these embryos. Comparison with a wild-typeembryo at the same stage showed that reaggregation of the mutant cells wasenhanced and the aggregates formed were larger. Ultrastructural studies showedchanges in the surface of these cells and their intercellular relations. In all proba-bility, the many defects in this mutant strain are due to altered surface propertiesof the mesenchymal cells resulting in increased adhesiveness and abnormalintercellular relations.

Nongenetic. The cells of the embryonic neural retina synthesize glutaminesynthetase (GS), an enzyme which can be induced with hydrocortisone (Moscona,1972). This induction depends on homotypic contacts between the retinal cellsand their retinotypic organization. In vitro, dispersed cells on monolayers donot respond to hydrocortisone, but when freshly dissociated cells are allowed toreassemble, the clusters can be induced to synthesize GS (Morris & Moscona,1971). In vivo, the dependence can be demonstrated by treating the embryoswith 5-bromodeoxyuridine (BrdU). This thymidine analog is incorporated intoDNA and interferes with cell proliferation. When applied to early embryos withmitoses still occurring throughout the neural retina, it disorganizes the tissueand the chaotic cell population that results does not respond to hydrocortisone.When given somewhat later, similar BrdU treatment does not markedly harmthe architecture of the neural retina, and, consequently synthesis of GS can beinduced with hydrocortisone (Moscona, 19746).

Migration

During morphogenesis, in addition to moving and aggregating at random,cells and cell clusters undergo oriented movements. Such migrating cells arerestricted to certain paths, apparently provided by neighboring cells or theirproducts. Interference with this guiding principle would stop migration or leadto formation of abnormal patterns.

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Genetic. The postnatal development of the weaver mutant mouse (wv) ischaracterized by gradual regression of the cerebellar cortex and consequentmotoric dysfunction. Here electron microscopy has revealed a primary failurein the migration pattern of the granular cells. Normally, these cells proliferatein the external granular layer and migrate from there to their adult position inthe granular layer. This migration, a prerequisite for the maturation of the cells,is guided by the fibers of the Bergman glial cells, which extend all the way fromthe external granular layer to the granular layer. In the mutant mice, Bergmancells are mostly lacking, and the granular cells, deprived of their guiding effect,never reach their final position and ultimately degenerate. Similar changes,though less marked, have been demonstrated in the +fwv heterozygote mice(Rakic & Sidman, 1973; Sidman, 1974).

Nongenetic. The vertebrate heart develops from two lateral populations ofprecardiac mesenchymal cells. These migrate towards their final anterior andventral position, and again, this migration of cells and cell clusters seems to beguided. The filamentous processes of the mesenchymal cells sense a path pro-vided by the underlying entoderm. If the binding Ca2+ ions are removed fromthe milieu experimentally, contact between the filaments and their substancesis broken, migration stops, and the cells form a paired heart anlage (cardiabifida). The key role of the Ca2+ ions was further demonstrated in experimentsin which the chelating agent added to the medium was accompanied by anequimolar amount of Ca2+. Then migration and heart formation proceedednormally (DeHaan, 1958).

Morphogenetic cell death

Various embryonic organs and tissue components are eliminated selectivelyduring embryogenesis, and this programmed 'morphogenetic cell death' can beregarded as one important event in morphogenesis, shaping and carving dif-ferent organs. Both excessive and inhibited cell death should therefore result inabnormal development and congenital anomalies.

Genetic. Various sites and stages of limb development are characterized bycell death. This is strictly timed and localized. At the borders of the limb-bud,necrotic zones determine the size and shape of the limb, and necrosis betweenthe anlagen separates the digits. In talpid3 mutant chick embryos, these necroticprocesses are impaired. Absence of necrotic zones at the limb-bud borders leadsto abnormally large limb-buds with supernumerary digits, and incompleteinterdigital necrosis results in partial soft-part syndactyly, in which the digits arewebbed (Hinchliffe & Ede, 1967; Hinchliffe & Thorogood, 1974).

Nongenetic. Exogenous factors will also prevent interdigital necrosis innormal, wild-type embryos. Chick embryos develop soft-part syndactyly whentreated with Janus green before interdigital necrosis is visible (Menkes &Delanu, 1964; Saunders & Fallon, 1966). The experiment has been repeated inrabbit embryos with the same result (Saxen, unpublished observations).

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Mechanisms of teratogenesis 11

REMARKS

The schemes of Figs. 1 and 2 postulate that the effect of a teratogen and thepathogenesis of the resulting maldevelopment are determined by the site ofaction of the teratogen and the stage of development of the target tissue.Various examples from genetics, human pathology and experimental teratologyseem to support this classification, but do not necessarily establish its validity.Like all classifications, the scheme should be regarded mainly as an attempt toproduce order out of chaos. It is intended as an operational guide until a deeperknowledge of teratogenesis yields a simpler, and, perhaps, more unifying theoryof abnormal development.

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{Received 17 February 1976)