Developmental Anomalies in Farm Animals: I. Theoretical ...

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Developmental Anomalies in Farm Animals 1. Theoretical Considerations Colin G. Rousseaux Abstract The incidence of developmental abnormalities in domestic animals is low, however there is continuing pressure on the veterinarian to answer concerns of the producer as to why the abnormality occurred and what significance it has for the rest of the herd. Generally, both normal and abnormal development are products of both genetic and environmental factors. These genetic and environmental factors can be single or multiple in nature. Interactions between environment and genes may confuse matters further. In addition, a number of genetic or environmental factors may pro- duce the same abnormality. For these reasons, one must be aware of the complex principles of normal development and how they may be disturbed before attempting a methodological approach to solve etiology. Resum6 Anomalies de developpoment chez les animaux de la forme 1. Consid6ratlons th6oriques L'incidence des anomalies de developpement chez les animaux de la ferme est faible, mais les veterinaires subissent une pression constante de la part des eleveurs qui veulent savoir pourquoi une anomalie s'est pro- duite et en connaitre la portee sur le reste du troupeau. Que le developpement soit normal ou anormal, il resulte generalement de facteurs genetiques et environ- nementaux qui peuvent etre de nature simple ou mul- tiple. Des influences reciproques entre l'environnement et les genes peuvent ajouter A la confusion. De plus, un certain nombre de facteurs gen6tiques ou environ- nementaux peuvent produire la meme anomalie. Pour ces raisons, il faut connatitre les principes complexes du developpement et la faVon dont ils peuvent etre desorganis6s, avant de tenter une approche metho- dique visant a elucider l'etiologie des anomalies de developpement. Can Vet J 1988; 28: 23-29 Introduction The birth of a defective mammal, be it an arthro- grypotic calf or a phocomelic human being, can cause severe social problems. For many years, such abnormalities were thought to have a supernatural existence (1), and even now, with our increased knowledge of cause of birth defects, we continue to regard deformed offspring as something more than a congenital accident. The social implications of defor- mity are obvious in man, but when deformities occur in farm animals, producers often fear that their breed- ing stock is doomed because of one or two defective offspring. This is not necessarily the case, as the genetic constitution is not the only factor that determines the final form of the fetus (2). Defective offspring are not necessarily mutants of the normal population. More than a half century ago, an overall picture of defective genes, environment, and their interaction with the fetus was proposed (3). The teratogenic action of thalidomide (4) highlighted the fact that the environment can cause some birth defects. More recently, it has been realized that both genetic and environmental factors may be necessary for defec- tive development to occur (5). The aim of this review is to outline the theoretical genetic, environmental, and combined genetic/ environmental influences on fetal development, thereby introducing the practitioner to the complexity of normal and abnormal development. With this back- ground information, the approach to defining etiology can be better understood. Terminology Congenital is a descriptive term denoting a condition existing at birth; hence congenital malformations or congenital deformities are defined as abnormalities of structure present at birth. Developmental or congenital abnormalities, defects and anomalies, include func- tional as well as morphological imperfections. Monsters are greatly deformed fetuses. The term genetic implies a dependence upon the hereditary units, the genes, in contrast to environ- mental causation. Genetic defects are due to gene mutations or chromosomal variations. Congenital defects are not synonymous with genetic or hereditary defects as not all defects have a purely genetic basis. Hereditary defects are genetic defects that can be passed on from generation to generation. Teratology is- the division of embryology and prenatal pathology dealing with abnormal develop- ment and congenital defects. A teratogen is any chemical, physical, or biological agent that causes abnormal development. The genotype of the fetus or parent is the entire genetic constitution of the individual, whereas the pheno- type of the fetus or parent is the entire physical, bio- chemical and physiological makeup of the individual as determined both genetically and environmentally. Statement The phenotype of a fetus is determined by its genetic constitution and is modified by environmental forces at the molecular, cellular, and organ system levels of Can Vet J Volume 29, January 1988 Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N OWO 23

Transcript of Developmental Anomalies in Farm Animals: I. Theoretical ...

Page 1: Developmental Anomalies in Farm Animals: I. Theoretical ...

Developmental Anomalies in Farm Animals1. Theoretical Considerations

Colin G. Rousseaux

AbstractThe incidence of developmental abnormalities indomestic animals is low, however there is continuingpressure on the veterinarian to answer concerns of theproducer as to why the abnormality occurred and whatsignificance it has for the rest of the herd. Generally,both normal and abnormal development are productsof both genetic and environmental factors. Thesegenetic and environmental factors can be single ormultiple in nature. Interactions between environmentand genes may confuse matters further. In addition,a number of genetic or environmental factors may pro-duce the same abnormality. For these reasons, onemust be aware of the complex principles of normaldevelopment and how they may be disturbed beforeattempting a methodological approach to solveetiology.

Resum6Anomalies de developpoment chez lesanimaux de la forme1. Consid6ratlons th6oriquesL'incidence des anomalies de developpement chez lesanimaux de la ferme est faible, mais les veterinairessubissent une pression constante de la part des eleveursqui veulent savoir pourquoi une anomalie s'est pro-duite et en connaitre la portee sur le reste du troupeau.Que le developpement soit normal ou anormal, ilresulte generalement de facteurs genetiques et environ-nementaux qui peuvent etre de nature simple ou mul-tiple. Des influences reciproques entre l'environnementet les genes peuvent ajouter A la confusion. De plus,un certain nombre de facteurs gen6tiques ou environ-nementaux peuvent produire la meme anomalie. Pources raisons, il faut connatitre les principes complexesdu developpement et la faVon dont ils peuvent etredesorganis6s, avant de tenter une approche metho-dique visant a elucider l'etiologie des anomalies dedeveloppement.

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IntroductionThe birth of a defective mammal, be it an arthro-

grypotic calf or a phocomelic human being, cancause severe social problems. For many years, suchabnormalities were thought to have a supernaturalexistence (1), and even now, with our increasedknowledge of cause of birth defects, we continue toregard deformed offspring as something more than acongenital accident. The social implications of defor-

mity are obvious in man, but when deformities occurin farm animals, producers often fear that their breed-ing stock is doomed because of one or two defectiveoffspring. This is not necessarily the case, as the geneticconstitution is not the only factor that determines thefinal form of the fetus (2).

Defective offspring are not necessarily mutants ofthe normal population. More than a half century ago,an overall picture of defective genes, environment, andtheir interaction with the fetus was proposed (3). Theteratogenic action of thalidomide (4) highlighted thefact that the environment can cause some birth defects.More recently, it has been realized that both geneticand environmental factors may be necessary for defec-tive development to occur (5).The aim of this review is to outline the theoretical

genetic, environmental, and combined genetic/environmental influences on fetal development,thereby introducing the practitioner to the complexityof normal and abnormal development. With this back-ground information, the approach to defining etiologycan be better understood.

TerminologyCongenital is a descriptive term denoting a conditionexisting at birth; hence congenital malformations orcongenital deformities are defined as abnormalities ofstructure present at birth. Developmental or congenitalabnormalities, defects and anomalies, include func-tional as well as morphological imperfections.Monsters are greatly deformed fetuses.The term genetic implies a dependence upon the

hereditary units, the genes, in contrast to environ-mental causation. Genetic defects are due to genemutations or chromosomal variations. Congenitaldefects are not synonymous with genetic or hereditarydefects as not all defects have a purely genetic basis.Hereditary defects are genetic defects that can bepassed on from generation to generation.

Teratology is- the division of embryology andprenatal pathology dealing with abnormal develop-ment and congenital defects. A teratogen is anychemical, physical, or biological agent that causesabnormal development.The genotype of the fetus or parent is the entire

genetic constitution of the individual, whereas the pheno-type of the fetus or parent is the entire physical, bio-chemical and physiological makeup of the individualas determined both genetically and environmentally.

StatementThe phenotype of a fetus is determined by its geneticconstitution and is modified by environmental forcesat the molecular, cellular, and organ system levels of

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development. The production of an abnormal pheno-type may be a result of a defect in the genotype,environmental insult, or genotype-environmental inter-action. Some defective development occurs because ofmultiple genetic and/or environmental factors. Failureof tissues to interact with each other at the correct placeand time may also result in abnormalities even thoughthe genotype of the individual is normal and externalenvironmental insults absent.

Requirements for Normal andAbnormal DevelopmentThe requirements for normal fetal developmentinclude the correct amount of genetic information,intracellular, intercellular and tissue order of presen-tation of genetic information, developmental environ-ment, and tissue temporal-spatial orientation. Anydeviation from these requirements may result in abnor-mal development.

Amount of Genetic Information - Each cell carriesthe hereditary material, the genes, on chromosomes.Chromosomes, both sex chromosomes and autosomes,occur in pairs in all body cells (except gametes) thatpossess a nucleus. Cells containing pairs of chromo-somes are called diploid, whereas the gametic form istermed haploid. The chromosomal constitution orkaryotype is constant for each species. Eachchromosome contains many genes along its length,somewhat similar to a long string of beads, where eachbead is a gene. In addition, the whole complement ofchromosomes in each cell contains all the genetic infor-mation necessary for the production of any cell orcellular product. For a cell to function normally, thecorrect amount of genetic information, or gene dosagemust be present.To regulate and interpret this information in each

chromosome, there are two principal types of genes:the structural genes, which are responsible for synthesisof the various kinds of proteins in the cell; and theregulatory genes, which regulate the activity of struc-tural genes, and hence control protein synthesis indi-rectly (7).Abnormal karyotypes usually involve the loss or

addition of a chromosome or deletion of part of achromosome with resulting incorrect gene dosage. Thisexcess or loss of genetic information usually results inphenotypic abnormalities in several organ systems (8),because a single chromosome carries genetic informa-tion important to many metabolic and developmentalpathways (9).

Karyotypic abnormalities have been demonstratedin most farm animals (10,1 1,12,13,14,15) and consistof modifications of chromosomal number or chromo-somal structure (16).

(a) Modification of Chromosome Numbers - Whensomatic cells have chromosome numbers that are exactmultiples of the haploid number for the species, theindividual is termed euploid, e.g. a normal individual,or a triploid individual. Triploidy has been found inthe chicken (17) and in early embryos of cattle (16),but has not been reported in livestock at birth.

Aneuploidy refers to a situation where an individual'scells do not.contain an exact multiple of the haploidnumber for the species. Usually one wholechromosome is added or deleted during meiosis.Aneuploidy has been recognized as a cause ofdevelopmental anomalies in farm animals (15),the most common forms of which are trisomy andmonosomy. Trisomy is characterized by an extrachromosome and monosomy is characterized by a lossof one chromosome. The classical example for trisomyis Down's syndrome (trisomy 21) in man (16).

(b) Modification of Chromosome Structure - Dele-tion or deficiency of part of a chromosome happenswhen a break occurs and part of the chromosome islost. Deletion of longer segments of a chromosomemay remove genes essential for life and reproductionof the animal; deletion of short segments may gounnoticed.A duplication results when a small part of a chromo-

some is repeated. So far, deletions and duplicationshave not been reported in farm animals, probablybecause such a small part of the chromosome is usuallylost or gained. Identification of the defective chromo-somes of farm animals is difficult, so it is likely thatthese aberrations do occur but have been overlooked.Deletions and duplications have been identified in manusing banding techniques. Each chromosome has acharacteristic banded pattern when partially digestedwith trypsin and subsequently stained. Modern band-ing techniques such as G, Q, C, and R banding (18,19)that are now available may help further define modi-fication of chromosome structure in farm animals.

All of the preceding chromosomal aberrations resultin incorrect gene dosages and are referred to asunbalanced karyotypic anomalies. Balanced chromo-somal aberrations can also occur when breaks, andsubsequent fusion, occur in two different chromo-somes of the same nucleus. This break and fusion mayresult in translocation or the attachment of a fragmentof one chromosome to a nonhomologous chromo-some. Hence the number of chromosomes may be lessthan diploid even though the gene dosage is correct.For this reason, developmental defects are not assevere with such anomalies (7). Animals with suchchromosomal abnormalities may be phenotypicallynormal, but usually have poor reproductive success.

(c) Mosaicism, Chimerism, and Intersexes - Amongthe known chromosomal aberrations in farm animals,mosaicism and chimerism are particularly important.Mosaicism means that a proportion of the cells in

the tissues of the offspring contain a chromosomalcomplement that is different from other cells in theanimal, although they originate from the same zygote.Mosaicism originates from a postzygotic accident,where usually one chromosome is lost during mitosis.Some of the cells in an animal with chromosomalmosaicism will be euploid and the remainder aneuploid.Chromosomal mosaicism has recently been found tobe a relatively common occurrence in farm animals,e.g. 6OXX/59X cows (20).

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Chimerism results when cells from one twin implantin the other and grow, e.g. freemartinism. Chimerismand mosaicism are characterized by differences in thechromosomal complement in different cells of thebody (Figure 1). As a result many subtle gene dif-

Mosaicism Chimerism

Figure 1. Diagrammatic representation of the differencesbetween mosaicism and chimerism.

ferences may or may not be expressed. Chromosomalmosaicism is often responsible for severe congenitaldefects, fetal death or abortion (20), because a large,usually unbalanced change in the genetic material hasoccurred through a chromosomal aberration. Chimerismmay or may not cause abnormalities of the reproduc-tive tract. In fact, it is possible that all bovine twinsare chimeras.

Sexual ambiguity, often referred to as intersex inlivestock, can have a number of causes as the sex ofan animal is determined by three main factors: thegenotype, gonadal development and development ofsecondary accessory genital organs. The sex of anembryo is determined by the genotype but the expres-sion of the sex greatly depends on the function of theembryonic gonads and adrenal cortex (20). Hence,numerical and structural aberrations of the sexchromosomes may produce, but are not the only causeof, intersexuality in farm animals. These chromosomalintersexes occur in livestock at a low frequency in mostspecies (16).

Order of Genetic Information - Genes exert theireffect on development by producing specific enzymesand proteins. As previously mentioned, structuralgenes are controlled by regulator genes. Each of thesubstances produced by the structural and regulatorgenes requires a specific sequence of DNA bases.Without the exact sequence of DNA bases, nonfunc-tional structural and regulator gene products are likelyto be produced. Damaged regulator genes may havejust as severe an effect on cell structure and function

as mutation in structural genes.Mutations or changes in DNA cause defects, some

of which are inherited in a Mendelian pattern. Thesedefects may be expressed as anatomical defects second-ary to a biochemical disorder, e.g. hypotrichosis (22),alpha-mannosidosis (23), bovine congenital porphyria(24), and dwarfism (25).

Modes of InheritanceMany inherited abnormalities, which result from achange in the DNA base sequence, follow Mendel'sprinciples of independent assortment through chromo-somal segregation. Structural genes can be on auto-somes or sex chromosomes (27). Genes located on theX or Y chromosome are said to be sex-linked, as thegenes in question are associated with the sex of theanimal. An example of sex linkage is hemophilia A,which is associated with the X chromosome in dogs(19). Sex-linked characteristics are expressed morecommonly in males, because females require the defec-tive gene on both X chromosomes for expression ofthe defect.Not all inherited abnormalities follow Mendel's

principles of dominant and recessive inheritance.Polygenic inheritance helps explain qualitativehereditary characteristics such as thin egg shells inpoultry (27). Sometimes no simple mode of inheritancecan be established and no teratogenic agent is obvious.In such cases, abnormal development may be a resultof failure of gene control, failure of cellular and tissueinteractions or local environmental effects on geneexpression (28).

Gene Expression - Control of gene expression byother than regulator genes is complicated and not com-pletely understood, but may be important in the pro-duction of a morphologically abnormal cell. Geneexpression can be controlled at the level of transcrip-tion, translation, and processing (29,30,31,32).Theoretically, environmental modifications at thecellular level can, through various mechanisms, alterDNA unravelling (33), transcription (34), translation,and processing (Figure 2) thereby producing morpho-logically abnormal cells, tissues, and possibly aphenotypically abnormal animal.

Phenotype and PhenocopyPhenotype can be defined as "the entire physical,biochemical and physiological make-up of an indivi-dual as determined both genetically and environmen-tally" (35), whereas phenocopy is "an environmentalphenotype mimicking one usually produced by a spe-cific genotype" (35). The principle of phenocopydemonstrates that a certain developmental anomalymay have a common pathogenesis, regardless ofwhether the etiology is purely genetic or environ-mental. This phenomenon in cattle is seen in calveswith arthrogryposis produced by feeding either lupins(Lupinus sericeus and L. caudatus) to pregnant cowsbetween days 40 and 70 of gestation (36), or by thegenetically determined syndrome of arthrogryposis,kyphosis, torticollis, scoliosis, and cleft palate (37).

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Figure 2. A diagrammatic representation of protein syn-thesis illustrating points (control) where environmental forcesmay alter gene expression.

Lupine-derived arthrogryposis can be considered aphenocopy of the genetic abnormality. Although theexact pathogenesis of arthrogryposis is still underreview, the defect probably has a common patho-genesis, e.g. paralysis in utero.

Environmentally-DeterminedAbnormal DevelopmentNormal development is influenced both directly by theamniotic environment, and indirectly by the maternalenvironment. Maternal health, correct fetal placenta-tion, maternal nutrition, drugs and chemicals must bewithin the limits of fetal tolerance. Xenobiotics andphysical agents have been associated with abnormaldevelopment (39). These anomalies do not have afamilial pattern as seen in purely genetic conditions.

General Principles and PresentConcepts in TeratologyTeratology is the study of abnormal development andcongenital defects associated with teratogens. Thename arises from the Greek word for monster. Somesix general principles are presently recognized in thefield of teratology (40).1. Genetic susceptibility: the susceptibility of a fetus

to teratogens depends upon the genotype of theconceptus and the manner in which this interactswith teratogenic factors.

2. Time of exposure: susceptibility to teratogenicagents varies with the developmental stage at thetime of insult. The embryo is much more suscep-tible to teratogenic factors than the fetus, especiallyduring organogenesis.

3. Pathogenesis of defective development: teratogenicagents act on cells and tissues by specificmechanisms to initiate abnormal embryogenesis.

4. Definition of abnormal development: the finalmanifestations of abnormal development includedeath, followed by resorption or abortion, mor-

phological malformation, growth retardation, anddisordered function.

5. Chemical nature of the teratogen: the access ofadverse environmental influences to developingtissues and organs depends upon the biological,chemical, or physical nature of the teratogen.

6. Dosage: manifestations of deviant developmentincrease in degree, from no effect to lethality, asthe dosage increases.

Temporal-Spatial Effectsof DevelopmentThe formation of a normal fetus depends on complexintracellular, intercellular and tissue temporal-spatialinteractions. Time and space are very important atmolecular, cellular, and tissue levels during develop-ment. At a molecular level, the times at which certaingenes of individual cells are expressed are importantin the production of the correct cell mass and cell prod-ucts necessary for organ formation. Microscopically,a critical mass of cells must be reached for its manytissues to proceed with differentiation to organ for-mation, e.g. formation of teeth. Some tissues mayrequire inductive stimuli from other tissues at a specifictime before they will proceed further along the devel-opmental pathway, e.g. the eye. Other structures maybe formed by fusion of other tissues, e.g. palate for-mation (41). This fusion, critical mass formation, andinduction must occur in the correct time and occupythe correct space; otherwise, defective developmentwill occur even though the basic genotype and pheno-type of the individual cells may be normal. This isknown as the "critical period of development" of theorgan in question. Development of a cleft palaterepresents the failure to meet the temporal-spatialrequirements during the critical period of palatinefusion (42).

Multifactorial Threshold ConceptMany common congenital malformations havefamilial distributions that cannot be accounted for bysimple Mendelian models or exposure to a potentteratogen, but can be explained in terms of a con-tinuous variable "liability", with the threshold valuebeyond which individuals will be affected (Figure 3).Both genetic and environmental factors add to thisliability, making the system multifactorial in nature(5). At any given time, a number of individuals in thepopulation will have defects because their geneticliabilities place them beyond the threshold, whereasothers may have genetic liabilities that place them nearor on the threshold of abnormal development, so thatonly a little environmental "push" is required to resultin defective development and subsequent defectivephenotype. Other members of the population with aminimal genetic liability, will require a massiveenvironmental insult to produce an abnormalphenotype. For example, it has been postulated thatarthrogryposis may have both genetic and environ-mental liabilities which may be additive thereby push-ing the fetus over the threshold (43).

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Figure 3. The multifactorial threshold concept, in whichgenetic and environmental liabilities can result in abnormaldevelopment once a threshold has been reached.

Pathogenesis of AbnormalDevelopmentThe pathogenesis of abnormal development at acellular level involves disruption of the temporal-spatial aspects of development.

Cell Death - Cell death is a normal event in thedevelopment of some structures of the fetus, partic-ularly of the extremities. Should this process not occurfully, vestigial or extra pieces may remain as part ofthe organ, e.g. polydactyly, or failure of separationmay occur, e.g. syndactyly (44,45).Many teratogenic agents cause death of excessive

numbers of cells (2). Indiscriminate cell death reducesthe cell mass so that the critical mass is not reached;hence temporal-spatial requirements are not fulfilledand cell interaction and/or subsequent differentiationmay fail (46). An agent or chemical that is capable ofkilling individual cells through damaging chromo-somes, DNA, RNA, or cell membranes may operateas a teratogen in this manner, e.g. cyclophosphamide.

Altered Proliferative Rate of Cells - Reduced orincreased cellular proliferative rate may result in afailure to reach the temporal-spatial requirements ofthe critical period. Mutation (47), chromosomaldamage (48), interference with the mitotic apparatusand subsequent cellular division (49), and DNA andRNA damage (50), e.g. radiation injury; lack ofprecursors and substrates needed for cellular bio-synthesis (51), e.g. vitamin and mineral deficiencies;altered energy sources (52), e.g. starvation; and enzymeinhibitions (53), e.g. enzymopathies, may all changethe rate of cellular proliferation and hence alter themass of developing cells.

Cell Interaction - Abnormal cellular and tissue inter-action can occur as a result of abnormal cellular move-ment (54), or abnormal characteristics of cellularmembranes (55). Normal cellular movements dependon microfilaments; changes in the normal structureand function of these microfilaments may result inmorphologically normal cells that are functionallyabnormal. Similarly, cellular adhesion depends on

a number of cell adhesion molecules includingfibronectin and glycosaminoglycans (56,57). Disrup-tion of the adhesion molecules and failure of move-ment of cells during development can easily disruptthe temporal spatial requirements of normal develop-ment, e.g. vincristine and colchicine.

Mechanical Disruption - Mechanical disruptionresulting from cellular osmolar imbalance (58), crush-ing injuries through rectal palpation (59), or a pro-longed loss of amniotic fluid may directly affect thedeveloping embryo (60). Limb amputation may occurif the limb penetrates the fetal membranes, atresia anican follow rectal palpation, and prolonged absence ofamniotic fluid may result in contraction band defects.Acute short-term trauma to the fetus is unlikely toresult in developmental abnormalities (60).

Fetal, Maternal and ExternalEnvironmental ConsiderationsThe fetus lives in a uterine environment influenced byexternal environmental insults and modified by thedam, placenta, and its own limited detoxificationsystem.

Maternal Factors- The role of the dam is to supportthe growing embryo and fetus in a nutritionally, chem-ically and physically stable environment. Aberrationsin homeostatic mechanisms may produce disastrousresults on fetal development, e.g. hyperthermia hasbeen shown to cause microencephaly, brain cavitation,and dwarfism in lambs (61). Similarly, hypoxia (62)and mineral excesses and deficiencies (63) causedefects such as hydranencephaly in copper deficientlambs (64).The dam has the ability to biotransform xenobiotics.

Sometimes biotransformation of xenobiotics is inad-equate or produces toxic metabolites (65,66). Someteratogens require biotransformation to become theactive teratogen (65,66), e.g. cyclophosphamide.Abnormal levels of maternal hormone may result

in the production of a defective fetus. Although thefetus is able to produce sufficient quantities of its ownfunctional hormones, it cannot cope with certainexcesses such as androgens. Androgen producingtumors in the dam have been associated with mascu-linization of the external genitalia of the female fetus(67). The dam usually protects the fetus from physicalinjury, however, rectal palpation during organogenesismay produce atresia ani in calves (68), or earlyamniotic rupture may result in compression-relatedor amputation-like defects, such as digital or limbamputation (60).

Fetal Factors - The fetus has little control over itsenvironment, but can biotransform certain damagingxenobiotics or ameliorate insults to a limited degree,particularly in the latter third of pregnancy (69).

Placental Factors- The placenta plays a minimal rolein determination of abnormal development. It canbiotransform xenobiotics only to a limited extent (70).The main role of the placenta in aiding abnormal

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development is through either allowing prohibitedsubstances into the blood stream of the fetus or fail-ing to provide nutrition and oxygenation. Bovine free-martinizm occurs when joint placentation results inanomalies of the reproductive tract in the female twinby allowing the passage of cells and/or hormonesfrom the male to the female twin (71). Inadequateplacentation can cause decreased nutrient and gasexchange (72) in small premature fetuses, however,morphological anomalies are not usually associatedwith abnormal placentation.

Physiological Factors - The physiological factors thataffect absorption, distribution, and elimination of ateratogen are the same as those for any pharma-cological model (73). The pharmacokinetic model mostsuited to the mammalian fetus is the two compart-mental model, in which fluid diffuses between thematernal and fetal compartments. However, morecomplicated distribution patterns probably occurbecause of the chemical nature of some compounds(74). The fetus may preferentially accumulate someteratogenic compounds and actually protect the damfrom the toxicity of these compounds, e.g. methylmercury (75).

Importance of Abnormal DevelopmentThe obvious impact of abnormal development is lossof the nonviable fetus. This presents two possible prob-lems for the producer: first, financial loss, through lossof saleable animals and the cost of retaining the damfor another year, in the case of cattle; second, thisabnormal fetus may herald an outbreak of similarlyaffected fetuses if the whole herd has been affectedby an environmental teratogen or if an abnormal genehas entered the gene pool of the herd.The severity of malformation in the offspring may

vary considerably. Unfortunately, the more monstrousthe defect the more attention it receives even thoughthe implications for the herd are mininmal, e.g. chromo-somal aneuploidy. More serious, and often over-looked, is a mutant gene that has delayed expressionwhich may become incorporated in the gene poolbefore much attention is drawn to it (76). Attemptingto define etiology is important, not only to alleviatethe farmer's anxiety, but also to prevent large lossesin livestock production and possible spread of geneticdisease in domestic animals.

SummaryAbnormal phenotypes are products of the genetic con-stitution of an animal and the molecular, cellular, andhistogenic environment in which they grow. Fornormal development to occur, the critical cellularmass, correct cellular induction, and movements mustoccur at the correct time and place. Veterinariansrequired to determine the cause of phenotypicalabnormalities must recognize these interactions.Mutations, chromosomal abnormalities, and environ-mental interactions with genes that produce abnormaldevelopment may initially produce abnormal cells andlater a phenotypically abnormal individual. Teratogenic

agents usually disturb temporal-spatial tissue relation-ships at the critical period of development. Theseagents may be teratogens in their own right or mayhave to be biotransformed to an active teratogenicagent. The most complex, and least understood,cause of abnormal development lies in the genotype-teratogen interaction.

AcknowledgmentsI gratefully acknowledge the advice of Drs. PatriciaM. Blakely, Gordon A. Chalmers, Mary A. Dignean,Cecil E. Doige, Eugene D. Jansen, George G.Klavano, Otto M. Radostits, Carl S. Ribble, H. BrunoSchiefer, and Sheila M. Schmutz in preparation of thismanuscript. I also am indebted to Gary Cody for theart work. Financial support from Agriculture Canadais gratefully acknowledged. cvJ

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