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uterine Receptivity, M~ten~al ~iti~ of ~ arxl Fatly .~liC Talc R. Michael Pits SUMP ~ - sly Chic 1~= may be of g~etimlly normal "Thrice that are lagging }xhirkl the uterus ~ their develc~nt. Frye transfer Gq~eri~ts have In ~ a variety of I that sage degree of dirty Nat be coved between the embryo donor arm He recipient. Emmys trzrE;ferr~ to racipi~ts are particularly prod to lilac. Since ~ may Nor as a rut of retard Ovulation, time of fert;lizati~ arm law ramp of cleavage, a certain Cut of natural embryonic wastage is anticipated. ;sible I; for such ~ryorlic lea= AL 1) He Hanging uterine m;1i-~ is Fly narrowly permissive, 2) Frye; fad] to signal their pr~3 ~ time to pr~rer~t a return to ovarian pyclicity, 3) the embryos are rejected in~logi~lly. He Have are dic~3 ~ relation to the skid ~ro1 of uterine s~tory activity arm the patio of lut~tr~ic and antiluteol~rtic Stark by the ~us. Ibe It discovery that interferuns are major products of pre~lantation cumulate c~r~h~ raises the Fusibility that thou Is may be important in m~ulatir~ He Is tiaras the feds allog~clft. Heir Flayed potion might, therefore, Striate to embryonic Yes. Magnitude of Embryonic Tom= considerable prenatal Mortality probably Ark; in all Ills. In the Inman, a Belies that exhibits Fly high Ate= of embryonic 1~=, a Foul pregnant ooours ally ~ abut 1 in 5 trial:les in Karen having regular interfere arm not practicing mxlt~ception (l). Unfor~n~atDly it ~ rot clear to Cat extent fertilization failure cxx~ri~ces to this law .~= Ate, although two skies have ir~icated that a is was present at scale tine between days 6 and 18 after ovulation ~ about 60% of huh c~1es; (2,3~. Of these, between Bathed (2) and Calf (3) came to term. Ire results smugly Fat that Nat Acrylic lo- crate surly in preens, peaceably socm after implaITtatic~n. In Cap (4) AL cattle (5), whom fertilization rates are very high, between 60 and 80% of c~ulatic=; give a;- to live birds. Last of these 1~- Car to Car Within the first two or three weeks of proud. With sham it IS also C]r that Wow ~~ than a sterile Gelatin occurs al Be ovary, "rbry~ic mortality Is signifi~rItly (6~. In litt~arir~ animals such as He pig, bets 30 arts 40% of Uses are lc~ at start during gestation, whereas fertilization failure ~ care (.~ 7~. For enable, a mate scar Is 15 to 16 Ova, all of whim generally become fertilized. Abut 30% of these are 1~t before day 30 of prep arm a further 10% before day lOO. Us only 9 to 10 piglets are born. 319

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Reprobative failure is one of the Drx3t cry arx] lintitir~ promotion factors In ~ li~res~k ir~try. Me epic loss to Me liv~k irk ~ to repressive failure ~ difficult to estimate with a high He of Staid ~ ~ ir~le1:e records arx] Affirm effects al our ~tion Ants. To: due to Adaption failure arxt Acrylic mortality in swine alarm have been estimate to total apply $200 million anally In to Ihlit~ State= (8). In He case of the Moan repeated failure of EASY c~i~; a health topic of cansiderable urn arm often of ~1 Tic tub. In He next section we shall briefly review sad of the causes of sad early par f;~;lure C~ of Chronic To In the cam of fan animus, Caky practices and ~i~tal factors suds as heat stud;, high nutritional plane; severe Nerving, specific r~riti~al clefici~:ies and intrauterine infections have Ben fad to Tease d~nibryanic mortality. Hover, in well Unaged herd; these factors am not gel~al~y ~& ~ ~ i - I, and Qua ~pl~ti~ At ~ Apt for the majority of pow basses. Genotypic abnormalities in the fertilized egg can uracubtedly he lethal. Two major types of genetic lesions can be anticipated. First, lethal genes may be expressed in embryo early development upon activation of the embryonic genome in pigs. Evidence for embryonic I~== ~ ~ to the presence of lethal genes incus sire differences as they relate to -echoic mortality rate (9) arm a mark dose ~ eD~ryc~ic survival rate associate with increase iribr~li~ (10). parallel observations have been made in char species including the muse, arm ar~ctally, in man. Ire set type of abnormality is in due number and grass structure. certainly in humans there is a high incidence of d~1 a}~rmalitic: associated with pponta~s abc~rtions~n the first ar~s`3corx]tri~ster (11~. E~ver, informatioa,~s nicely arx] ~ictir~ for very Ally embryos won 1~- are highest. ~1 analyses of axis embryos in a variety of species have Feared that ~ru~1 abnormalities, particularly polyploidy, exist kilt Her at a relatively Ian rate (Free i2) . Although Bishop (13) has argued that much of the 'Sal" prenatal in== is of genetically abnormal "embryos, it seems fair to assume that a significant fraction of a~Hryo6 are 105t not Scram they are genetically abnormal but for carp other reason. In species where only single young are normally born this would I^~d to termination of the pregnancy, while ~ litie~earina anomies the number of young would be reduced overall. . ~ _= Bug aver reasons that have Ben pry ~ amount for early By I~= we shall cakier anly those Cat may be related to the fact that the uterus arx] is may beaned out of phase with each cuber. Specifically we shall H;~ the pcssibili~cies that a) the uterine i~t can be inanimate or even Fabric, b) the ~ fails to signal its ED to the =*her so that the pry in nat reknit, arx! c) the is is rejects i~lc~i~lly. Although tl~;e Stabilities have bed partition for corpus of diluvian, it will bare quite clear that each of these subjects averiap. - 320 -

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plar~cation arm Placentation it-fore ply f~ with this ~;s~i~ it ~c] be razed bat the ~ of p~;iological ate ~rpologim1 events that pz~ ~plantaticm in different gram of Pals ? }3ewil~ingly diverse (14~. Consequently it is difficult to conjure up g ~ rarities ~ at will apply to all species. Implantation and the establishment of a placenta are clearly crucial for continued development of the -embryo. Similarly, the pregnancy most be ~rec=grized" by the mother if she ~ to respond appropriately to the conceptus. However, the manner ~ which these processes oume about ~ different species As by no means uniform. I his point is illustrated in Fig. 1 where the range of events that precedes implantation in eutherian species is preset ted An olagramatic form. Be first cleavage division usually tales at least 24 h and 5obsequene civilians t' h or more. The ccrcEptus enters the uterus on about days 3-4 and blas*ocyst formation begins. It is around this stage that different species begin to show diversity in the way the ccoceF*uz develc. :En man and In a Or of rodent Dies the blast In an a~prmtely reptile uterus hatches Bite Orgy, attain; to 03 uterine epithelium arm subtly begins to i - lant. In other species, =*ably the rabbit, the awls of the blastocyst undergo fury rc~s of division, the blast ~ st enlarges, arm only ~ en ~ ; the prnn-~= of implantation begin. Implantation is a complex and variable process that begins with the apposition of the trophec$oderm to the surface epithelium at an appropriate and usually favored site for negation. In many species, the initial attachment is followed by limits spreading of the trcpheaboderm over the surface of the implantation site. Often the concaptus becomes partially or almost oomplet~ly enclosed by the endometrium in response to a synchronously occurring decided response. These stages are followed by penetration of trqph~bl~=t bells through the epithelium and the eventual establishment of the placenta. Placentation has been classified on the harts of the numbers of cell layers that separate the blood supplies of the mother and conLeptus (15~. In the come of the human and rodents the absorptive surface of the tmphc~last quickly C=le5 into dint contact with maternal bib and is said to be h~rial. Thus a reliance on the uterine milieu for rn~riticx~al or even endocrine sort may be relatively ~rt-lived In sub sties. The blast ~ sts of cattle, cheep end pigs hatch relatively late but then contirme to enlarge without implanting or even attaching firmly (Fig. 1~. In the sheep, for example, the hatched blastocyst at days 11-12 is Approximately 2 mm in diameter. Ey day 13 it ha= enlarged and begins to elongate into a thread-like form. At day 14 the elongated blastcayst reasures 3 to 5 cm in length, whereas by day 16 it can reach up to 20 cm and extend into bath uterine horns. True implantation with placenbome formation begins moth late', between days 20 and 30 (15~. Events ~ the cow follow a similar sequence but -~= slightly later ~ real time, with elcnuation beginning around days 15 to 16. The situation in the pig is even more curious. Here spherical conceptuses at day 11 average about S-10 mm in d;~-rt~r but can reach over one meter in length three days later (16)e IN this polyp - BYTE= species, eicNgate~ conceptuses arrange themselves end to end, each occupying not more than 10 to 20 cm of uterus ~ they follow the con tours of the v.;1lous folds of the endbretrium. Mbreover, the uterine epithelium is never eroded throughout pregnancy. All the su}stanY~s required for fetal and placental sustenance

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Nate therefore! ~== across this intact ppithelium. It Is for this reason that uterine secretions (or hi~Wcr~e) are ~3ht to play a marital role in of the pig are In War bevies Were an irrvasive type of i~lantati~ either ~ ret over or Taxer'; relatively late in pry (17) . Any of Embryo and ME is Palated to Folly F,rbryonic Sac It has Me Clever Mu embryo trarr;fer ex:ri~s In all species Emil that a~r~ between the transferred Oryx and We stage of We ~3evelc~ of the recipient's uterus can 1~ to tic death. In Gerald every=; transfer to 1~= all recipients are tolerate better than We reprise. Ever, bemuse We are ~ i~tim differences bet species arx] be- the effects of By a, the intonate `~vel~nt of embryos can also differ, it lo worth minim scan e~ri~al res~4cs ~ Ire mu. ~ Eats 24 h Ova Box survive as ~11 as Sly devel~ir~ entry=;. Hey Ryan in delay until He uterus catches A?. H~everl 24 h retard Kayos survive ;~ early (~c fief. 18~. Gates (18) that muse ~ Cat were cleaving Ore slowly in vitro had a poorer survival rate after transfer than arm; that had been dividing rapidly. ~~= of say embryos; trareferred at He blasts stage seemed to char at He immediate Ex>6t-iT~la~atic~n Orion. ]~ c~ervati~s have been ~ by Warner and her Colleagues (19) Ho have defined a specific gene (the ped gene) Cat appears to have an influerxx on controlling the rate of ~11 cleavage In philantaticn Ruse embryo. 1~ have been ir~icatic~ns that an alkali gene exists ~ Bar Dies as well as the ~se. Rabbit Buses also tolerate aurora poorly (20~. Ibis has been sham bath by trarmfer to p~r~nant ~ or }fly either delaying or a~leratir~ the passage of the embryo thrum the fallopian tribe of pennant OCR for page 319
One final observation pertinent to embryo transfer in the sheep has come from the experiments in which prcg}sterone was injected into ewes an days 0-3 of the estrous cycle to cause an early, although artificial, luteal phase (26). The uteri of these ewes at day 6 provided a suitable en;ircnGLnt for the survival of 10-day old embryos. Thus these aresults are indicative of the likely importance of uterine secreticos in selecting against asynchronous embryo;. UhfortLna+^ly, in the majority of experiments testing asynchrony in the sheep, the precise tote and stage of embryonic development at which death occurs has not keen accurately established. For example, it ~ of considerable interest whether the Ryan die before the period of maternal recognition of pregnancy or whether they continue to develop but fa;1 to pro an adequate signal. Alternatively, they may signal the ~ presence to the maternal so but die at a later stage. Ail rely Are have been relatively few studies cn He effects of any in pigs. flue results of such studies have generally confirmed c";ervati~ Dade in other Techies, namely that older embryos transferred to ye uteri often thrive even if He s~pazzltion in "age" Is as fang as 48 h (25,27~. Aver, the reverse situation ~ again poorly tolerated. EN Havoc were significantly z ~ when embryos were transfers ~ to red ipients that were only 24 h ahead of the donors. In addition, only one of 22 animals became pregnant of these that come into heat two days before the donors (27~. In this particular animal the total embryonic survived WAS also low. This study gave similar results whether donor embryos were tested from the early stages or at the hatched blasts cyst stage. However, it was not determined exactly when the embryos died. Attempts have been mace in pigs to advance the uterine environment during early pregGYrcy (28). However, injection of pregnant gal ts with progesterone in the early luteal phase increased circulating levels of progesterone prematurely, but did not induce an advanced eabryoci~k] uterine environment. Rather, e~brycnic mortality was unchanged. an the other hand, it has become clear that pig embryos theme elves cause a major alteration of the uterine milieu at about day 11 when they first begin to synthesize estrogen (29). This effect can be mimicked ~ non pregnant gilts by injecting exrgencas estrogen (30) and lark= to a Ad Increase in the teal City arxt a charge In the q~ali~, of proteins In the uterine s~icr~s. calcium arx! pr~aglar~in levels also bed elevated. P - e and First (7) ream at excuses estrogen Alpinists on days 12 are 13, the stage when abbey=; are pyr~esizing large As of estr~cn, c3i~ not interfere ~ th ~ or - . ~ ever, es ~ iol 17-' tr'3a ~ no on cays 9 ark 10 was embryocidal. Further studies by Mbrgan et al. (31) have confirmed that estrogen treatment at day 9 or days 9 and 10 advanced uterine secretion of calcium and various proteins and was highly a~bryocidal. Recent work fain the came Lavatory has shown surprisingly that -embryonic death occurs after elcogation at about day 14 and not at a timP i"~P~iat^1y ocincident with the estrogen rise OR.D. At, unpublished results). DieRman and Long (32) have reported similar Cryptic effects fmn fading the tic At, zearalenone, to pregnant gilts prior to bluntest elc~tion. ~ an artier study Pope et al. (25) so Bat when day 5 ~ryo6 were transferred into crm uterine ham and day 7 "rhryas into He over uterine horn of recipient - 323 -

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gilts ply 6 days after Thea preview= esters (day O), a high pin of the I Aryan survived while the majority of He act "ri~ryc6 died. qua ]~= ~1~ Ire I after day ~ }it was rat accurately pinpoint - . }tabby, the prelature Men pr~ti~ }7y the Ire "hryo6 led to Me In; of bee bat were ]~= <]evelc~ed. It is clear, therefore, that the ~n:us embryo, particularly cone Mat is delayed relative to the uterus, has a poorer crane of survival than one In i. What Me basis of its dean might be Is in it Mold ~11 be ~m to multiple factors, ~ of whim are did In Me subsequent three secticr~s of this paper. Me Nec=;sit,, of the latrine Errant It has been well ~t~ that the epithelium which line; the surface ad glares of the uterus ~ active In secretion, that these secretions contain protein ~5 different in those In place, arm that the temporal patterns of preteen syrups are oorrelated with the cir~atir~ slid hormone ~ntratic~s of the aider. E - ever, curly a limited amber of these logical s~tory proteins have been pacified. Here a few of the better characterized pry AL Men r~;ive Is will be disabuse in order to illustrate their rape of f~ions. B~tri~1 protein 15 (EP 15, 'spry associated 2~1c~ulin" or ~p~ pacific protein 14", d~i~ USA authar) of the human is a pit of the uterine ppithelium during the secretory phase of the chicle arm airing the first tri~ter of pro. EP 15 has significant may s;~;lari~ to proteins of the 9-lac~l~n gene fairy whit include its that bind tiny arx1 a variety of the Molar ligates (34). Aver, no pacific furrier for EP 15 has yet boy evident. -Uteroglc~in, historically the first pair pratem to be characterized in goals, is sol by We uterine ppithE~ium of the rabbit in sly prey are ps~r~ (sac 35). Int~ti~ly, it is an examine print of several organs, incline the 1~ where ~tru1 }:y oortia~id rusher than pr~e is evict. A varied of functions have been ascribed to u~glab~n. the Ant ray is as an anti-inflamnatory agent whim acts to inhibit ph - Fholipase C arm the gereratior~ of arac~hidon~c acid (35~. We muse glandular epithelium has recently been In to be a source of growth factor;, including ppid~1 gray factor and coldly stipulating f - :to~1 (~-1). she latter is sy~iz~ in ~ to pr~e ark has been plated to be important in c=`Lrulling prolif~ati~ of We placenta (36~. lax pig, Me uterine se~ticrm are probably the best characterized of all Is, Em a diffuse epithelio~=r;~1 tape of plac~a~ci~ where the uterine epithelium ~ roar invaded arx] wore the blood sallies of the Muir arx] Is rain Maraud by several ~11 layers. We c~s Thieve to have a lasters r~iarxx a, material rely as secretions into the uteri luminal m; ~ ieu. the first story protein of the pig to be stied in detail was ferric whim, alto an acid pitas, clearly livers iron to the -is (37~. P~tly a fondly of retir~ol~irxling proteins have also been Gibed (-em 17~. IN uten~ferrin, these proteins are Size in r~ ~ pr~e am air to be res~;ible for 324

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transplac~al transport of a water irx;oluble retrims. Other at proteins fat ~ porcine *Erie secretion Uris pry include several pla~in,ttry;~;m inhibitors whim cay act to protect the uterine n~1 surface fmn ~ action of Is protest, art lysozy~, an enzyme I= r~ as having antimicrobial activity (17~. As in the I, porcine uterine sureties here been ~ to be a statue of grv~ facto=; (38). In icier; ~ ~ ~ icky ~ ~ uterine wall any reliance In ~ithelial dices may be Shorter liver man ~ the pig. In ~ ~ ~ in, ~ ~ Blast q~ic~y }as ITS decider ;. A lambs of pr~ter~re~;ive secretory predicts of me man and balm decider have teem Prim. Than; the At Irwin ~ EP 14, a protein whim is i~ti=] ~ me IGF-1 bit protein of plum (39), arx} ~ likely to be id~tic~1 with PP12, =;e, <-2-PEG and several offer acnx~ms (Ref. 33). due are several uterire secretory proteins that rum to or are pr ~ in r ~ e to ~ t ~ (see 40~43). Among these are ~ rine lactoferrin (40) and the so-called COPED glycoprcte~n (41), a high molecular weight glyooprctein ~ the cat, whose function remains unknown. In mention, there is now evidence that a range of carrier proteins for water soluble vitamins such as riboflavin, Violin and thiamin are produced by the liver, and risibly by the uterus, in response to estrogen (43). Although these vitamins are water soluble, the presence of such carrier molecules may be important in transporting such vitamins to the conccp*us. Active or passive immunization of females against these carrier molecules appears sufficient to ca`~- abartion but has no nutritionally deleterious effect on the nether. Adiga et al. t43) have speculated that the need for estrogen in implantation of same finals may be In part ~- to a req~nt for sop carrier proteins for nutritional short of ache embryo. hat ~ particularly intrigue Is that hose proteins have been remarkably cxx~red in evolution f~ a~riparity to viviparity and have been pertly identified in he hen. It thus appears that the major pains surety by he ~triurn r~lrirlg early p ~ p, itch are ~ sive to p ~ esterane arxl estrogen fall into a number of categories. These categories include nutrient and hormone transport molecules, growth factors, pro tease inhibitors, antimicrobial components and ~ restive agents. Others may be involved in pro meting implantation or attachment. Many of these proposed roles are at best speculative and may have to be revised. Mbreover, the pa==ib;1ity should not be ignored that there may be a get it for prctem in he I~1 ernri~c of the embryo to fulfill nonspecific Figaro binding, o~regulatory and Bufferin rules similar to he functicms of akin in plan. certainly in bane species exhibiting an invasive type of pla ~ titian, any mltritim al reliance upon uterine se ~ tians might be expected to be Short-lived, since the trephoblast quickly comes into close. contact with the maternal broad Pearly. Only in species such as the pig where the tropboblast invades late, or not at all, ~ it anticipated that uterine secretions have any long-term function in support of the embryo. Even though so little is known of the preteen nd~ieu, even l-== is known about the concentrations of major ions, the amounts of sugar, lipid, amino acid and m~crcoutrients, the levels of ~;==olved gases and even the pH in the 325 -

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uterine fluids bathing Me early Titus. It Am; likely that lcrw molar weight its are present at ~tratians that are different ~ thee ~ plum, arm Hat Rein relative ~sitic=;, like Doe of the Reins, fixate in rehouse to maternal hinges. Our lack of kr~l~ge in these areas is nafl~ in current wagtail abcut the Bet aerate media am venture Titian Eat dhalld be use1 to Tort early Magyar viler. A1~ air Kene of the c~ar~ir~ Posits of Be uterine vi~c is very limited, it ~ clear that a~n~liti~ cold Lily car as a rot of ovarian pysf~ticr~ or Formal u~rine Rae to Groins that scald place the is at odds with Be mother. Ire 1~= of bus embryos might well result f`~ an ina~r~riate Halite, quantity or even tactic nature of uterine sureties. Even Hen brat Troy exists between an Kayo arm the Other, a hormonal profile similar to that conserved c3urir~ a normal pregnancy mast be Attain if _: are to survive In a Other be Caries have been roved. Al~h the timing of ache rise In luteal proges~ne Is variable arm ~ ultimate levels reach not uniform, the pattern of pm relax is clearly important for granary a. Also an Deviation of lower Pie Nitrations _ _ . . . . ~ . with a failure to Derive has Ben rote in sheep as w~1 as cattle. So far, hover, few ~r~herE;ive shim ~ any species have ~ that inis~ation of price In the luteal Pam can pride a significant i~?m~r~t in fertility (see 12). It is possible that sane of the differ In pry corx~tration between pregnant arm bred but r~pr~nant animals may be related to the lut~cr~ic effects of scne ~ yonic products. Mat Cognition of barb arm barb Pa;]ure R~ysiologica' monition of the probe of an embryo ~, the Tier results from the probation of bic~ni~1 mediators fly the Rye. Ire Diators ~itic~1ly intervene ~ the norm pr~ressi~ of He mat is or Dual cycle such that the embryo is Pigtail in an end ~ucive to continue grouch arm develc~ent. In Bet Italian spies physiological reposition of Prague ~ associate with extended luteal furx~tic~n, arm this pa; mist Car either }fly Dot lu~trq~ic short in primate species where luteal fur~ti~ Is promoted fly Be probation of Periodic g~adatr~in (44) fly pr~enti~ of lut~lysis as Is son in Tic Cites arm swipe (45) or fly a c~binati~ of sub events. In swine arm Hectic rim, the uterine pr~tic:,n or recluse of a lu~lytic Dab ~ reed. ~ da~;tic cheep, the =1~ of He Acrylic signalts) critical for maternal rendition of pro first fixer'; beaten day'; 12 arc] 13 pcst~atir~ (45~. He active Stab has been sin to be pruteina~, pr~xxd for only a liming period astir pro (46), arm is Ohm to be a Icy Tear weight acidic At 1~ as chine tr~last protein 1 (or al - 1~. o~1 arbors; to act as a passerine horn did to Be uterus (45~. Patently depot has bum shown to be closely relays spirally to interferes of ~ so-called IT clan-== (47,48), a result Cat is of partial i~t since interferon; not only are An to affect pr~taglar~in metabolism in their target tissues hat also to have patent 326 -

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i~ato~r properties. Me i - lipstick of the latter pa Drill be ~rms" f~ ~ the later d;~=ion of i~n~rejectic~n. ~ a, similar I; of peridots, an Incus protem identified as bovine Blast pr~eir - 1 ~1) has bum inferred as a crick factor In maternal ~itic~n of pro the bovine. b~1 has also been In be interf~liX`3 in }x~ its 5~ arx} prc~ertie~; (49~. He active it ~ by porcine embryos believed to promote F~tia~ of corpora lutea ~ lu~lys~s has I~ been pry to be Ben (~ 45~. Kirby Finish to gilts between days 11 arm 14 of Me exodus Cole id - = ~ prol~ lu~ linden. Her, it ~ of Cat porcine Aryan also begin to sedge ir~erf~s daring this period (J. Cross, R.M. Rc~rts, Publish results). In bath primary and ~ the domestic species d; above, he timing of the reline of the active Satan, Nether it be a gonaclcrt~pin, an interferon or art I, begins very cay to the time when corpora lutea b - in Heir normal cyclical lc - = of fulgid. Rescue Ire; just prior to Hen the corpora lutea are irreversibly unit to Asian. Clearly Boos Played ~ their develc~t or pr~ir~ the active Bent in 1 Arcs might fail to signal their prude say that Hey are 106t as luteolysis proceeds. Nether this inability to Fornicate Lately with the mother contributes to prearm failure is net In, kilt it clearly most be r~ as potentially important in view of the earlier ~sion ~ the ire of Army between `3~ibryo art Her. Ideological Rejection of Embryos ~ a nook Ambled pc~lation it is improbable At any rar~anly mated male or female or any embryo or its Other will share ~ same transplantation antigens since the genes Extolling these loci are highly polymeric. He embryo, tl~fore, can be Insider to be an all~aft, ark, like any organ or ti~ graft, shalld normally be rejoin. In odder to survive, allogrufts Nat either be placed at silk that are not Gaily penetrated by calls of the ~ipient's in system or else oust be p~t~ by treating the ~ipierrt with is that are briefly passive. Excuse the uterus ~ no an Ike privilege site arm Use in factions of the o~ is not generally deprave durir~ prearm, the fetal h~iallograft mist either behave or be organized differently than a surgically play allogruft (am 50,51). By most Oryx; eke illogic attack arm Nether or not immune rE jection caprices ex0E;ively to embryonic 1~-, particularly in early E~, = una~ questions. Unfor~at~ly, that limited X~wl~ge that alrrmdcly exists has largely bun derived fm~ Do, a series ~i may not be an a~roprmte PI for Canals Cat coo scat have an invasive type of pla~aticx~. He rejec tian of embryos by the maternal imp Item as a cause of infertility ~ rat a well ~ Ed singe it is difficult to t=1 He infix ratio of lye into the "graft' is the basis or of F*~zyonic failure. It has been Elate ~ nr.~1r Purim rejection of i~ific hybrids and kirks (52) arm ~ cases of Stan abortion ~ ce (53) arx! in hlmans (~ 51,52), kilt even in these it the data are not clear art. 327

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Me multiple hi~tihili~r antigens, whim are belied to play Me major kilt pliably Tot Me sole role in gaverT~ the a~x or rejection of grafts, exist as the cl--- of ~11 surface protein;, each prints of closely lied ger - ;. Only the clad I type are lawn to be pr~t in pla~xntalL tissue, arm there is considerable c~versy as to }we wily in pi hey are expel (19,50). Al~h C1~== I antigen; he been report I: on blast~sts arm on the Idly invasive blast of the ~se, no mica are available for the tic anion Species. Never~el~=, singe other antigen; may c~tri~te to the "foreignress" of a graft (54), the early 6ryo may tic be i~logi~3ly irrupt. Certainly in It defies the bluntest I: Able of initiating the ~i~atic~n and prulif~a~ci~ of blood capillaries and We aa~laticm of fluid and serum proteins claw to the zone of aback:. Chewer there is auction of maternal in Ails to this site is unclear. Embryos Mainly do not remain iT~logimlly neutral for very long. Foreign antigens are expressed and are In to be Sized by the Seer (50,51). ~so~wrcly, considerable rearm has gone into defining ..i~ressive" Irk produced either by the - - ryo itself or }A the er~trium ~ rue to pr~e that might blunt maternal Ike activity at the fetal~aternal interface. Ally, Mere ~ also limited, arm a~nitt~y Chat anecdotal, evader that scan sort of Ike Apse ~ redry for a pry to ~ (~ 50~. If these reports are correct, the fetal allagraft on the me hard At print itself against in attack yet ~ the other be sufficier~y foreign that its presence be Size. His recognition may serve ~ gestate rekey ly~ki~ or g ~ fac Cars at the maternal interface. in this regard, a particularly exciting result f`=u cur laboratory has been the discovery that early embryos of domestic ungulates produce alpha-~nterferons in substantial quantities (47,49~. We have suggester that these sobstanos are responsible for maternal recognition of pregnancy. However, these proteins are also potent negators of the immune system and can delay the rejection of artificial grafts (53,54~. Dew effects an Ells of the inane system are Telex; they are rat simply ~=~ressive in a broad sense. For example, interferans do have the ability ~ ir~ibit the proliferation of Ply ~ r~ ~ a Valerie by antigen and Ably inhibit the in~rparati~ of [~IJ-thymidine into misers Ate Ins or into lye stin',lated with mitogen (55), tic, An are probably averse tests for Ingression. OR Me aLher hard, ~eY str~lY Pate the exores~;i~ of _ _ : . . . . . ~ cleric I TIC genes am have been reportm to activate nab Viler Ills. 1` Acyclic interferes of Reid am first pry by Be tr~lerm coincident with the t:i~ that the Lyrical blast~sts begin to ~ (45,46~. IFN's are rel~ by pig Aryan at an equivalent period of their devel~nt, are we have preli~ esriderxx that the Norse embryo also produces IFN and Me tin of implantation (J. Chess, C. E arm arm R.M. Pus, ur~bli~ relics). -there are several other reports of later stage placental tine Staid He's (ad 48~. It is to to surest that He prcx3ucti~ of It's }I e ~ta~m or later stage placental tissue may p~ride one Aim wherry the Frye evade= ~str~tic~n as a gruff ~ liming larval adjust of the matinal ideate system. We also speculate that a failure to produce I:FN's at an appropriate time or in - 328 -

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ansufficie~t Cities might cxDpr~se Hat "rhryo. ~us, late Empire or sI - r ~ "Thryo6 will agate be plan at a ~ - ignoble did in the face of an agrmisive in~logi - 1 cadre. AM at. Epic TIC It Em: i~ble Bat Me uterus ~ ly narrowly pensive to the early preil~laDtati(= ~pb=. Even fo Size the models Is ~va~irlg rapidly ~ its devel~It aloud the uterine ~ idea ~ si~tar~sly u~ir~ rapid Dame as He ~ium to mat s~ic3.s and to the 10~ pa of a I. C~s do slowly or ot~ise alt of phase with the Drawer may not be table of expire with Muse charges and will be Ic~t for a varied of reasons as d; earlier. Ike uterine It I; likely to place straw -elective prep can "rhryo6 sup bat only type keeping pace with the endare~cri~ will survive. This r~xe~t for Icy may be ache pans ~by genetically a}'nor~1 embryos, whip cat keep pace with events with the uterus, are discard. Ever, retardation of ~ryo6 may also ~fir na~ly as a ~t of at least three different can (18~. Fir=, the timid of ache fit Biotic division may lead to sad of; laggir~ in Ear maturatic~n. Ungainly Cation in ~tipan~s Belies ~= ger~ly ~t a ~ s pr ~ as and can n-~]r aver several hairs. acre et al. (56,57) have provided strong evidence that the variability ~ embryonic development seen at days 11 and 12 in Western breeds of pig is the result of late developing eggs giving rise to 1~== developed embryos. It is these immature embryos that subsequently appear to be lest. A second natural can-== of retardation in embryos may relate to the time of fertilization and the completion of the secorxt Biotic ctiv~sioa~. ~ mom, for eagle, fertilization of all shed Ova ryes several hairs (see 18). Finally, as mention earlier, in relation to the pod gene (19), Rang cleave at different rates. Even within inbred Moe strains, hover, ~velc~nt of all e Lyon is not ~ ual. At day 3 V2 m Use embryos have usually undergone anywhere fram 4 to 6 cleavages, resulting ~ a theoretical developmental separation of 24 h (18). There is even greater variate ~ ity following superovulation. Clearly all the above events could lead to wastage if the uterus selects against the 1-== advanced but otherwise normal -~Hryo6. It is perhaps worth canting upon the fact that embryos true many species, once they have been coaxed past an "wily developmental block (itself probably He result of inappropriate culture Tuitions), can thrive in Culture arx] densely to the blast~yst stage Al beyoK] in m - ;a only slightly modified from ones that were Avery Blearily for fibr~last quash. Such c~;ervations sagest that urine milieu, rather than canstitutir~ a rig ~ bryotrophic vellum, provides instead a nary ply pen missive Sari ~ t praratir~3 tile Deprival of only those e~ryc6 Hick can develc~? at a rate Cat 1~; them a;~r~riat~ly in phase with the mat ~ r. Acknowledgements. Support was prc~ided by grants bran the National Institutes of Health tHI21896) and the United States Department of Agriculture (87-CRCR-1-2543). 329 -

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Referees So, R.V. 1984. Species differs In reprobative ~i~, lo. 24~61. in R - ration in As: 4. P - regive Fitness, C.R. Austin arxl R.V. Chart, ems. Cambridge Uhiversi~ ~ass. 2. Ems, D.K., AS. Lindsay, J.F. Miller, E. Williams ark P.~. Am. 1982. Folly Physic mortality In An. Fert. Steril. 38:447-453 3. Smrt, Y.C., L.S. Fraser, T.K. Roberts, R.L. Clancy and A.W. Coo;. 1982. Fercilization and Ally prearm 1~= ~ healthy An at~ci~ in. Clan. Repro. Fert. 1:177-184 4. ~y, T.W. 1979. Erdbryo ~rtality, ~. 315-325. ~ Sheep 8r~i~, G.J. ~;, D.E. ~tson, R.J. Lightfoat ar~ W. Haresign, "c., B^er - ~, ~on. 5. Ay~lon, W. 1978. A review of erbry~ic ~rtality ~n ca~le. J. Repmd. Fertil. 54: 483-493 Doney, J.M., R.G. Onln arxt W.F. .c~ith. 1973. ~rine migratim arx] ~r~ suz~rival in sheep. J. Reprul. Fertil. 34:363-367. 7. ~e, W.F. ar~ N.L. Firet. 1985. E actors aff~ting the survival of pig e~ryos. Iheriagenol<33y 23: 91-105. Gerrits, R.J., T.H. Bl~r, H.G. P~a~, C.E. lerrell and E.J. Warwic~k. 1979. Eoor~anics of iT~pr~ing repr~:ive efficierx~y ~ farm animals, p. 413. ~n n~ltsville Sy~6la ~n Agri~~l~ral R~ar~. 3. Ar~1 Pepr~tion, H.W. Haw~, ea., Jchn W;ley & S~;, N~w York. 9. P=ry, J.S. arxl I.W. R~lar~s. 1962. ~'ly pr~r~y in t~e pig. J. Repr~. Ferti] . 4 :175-181. 10. S~ires, C.D., G.E. Di~ ar~ D.T. M~yer. 1952. ~flue~ of irib~g, age arxl gr~ rate a, s~'s se~mal ma~rity, rate of avulation, fertilzatian ar~ "bry~ic survival. Res. nlll. - . Agric. Exp. stn., Nd. 494. Hassold, T., N.J. C~en, J. E~r, T. Jc~, B. Ma2mel, J. M~tsmra, A. Mat~ar~, C. W;1son, J.A. Yar~ and D.A. Ja~. 1980. A c~tic s~ of 1000 ~t~3 abortia~s. Annds. H=. Ger~t. 44: 151-178. 12. Wilmlt, T., D.I. Sat~ arx} C.J. Ash~r~. 1980. M~ternal arx! "bryanic factors ;~=ted with p~atA1 1t~= in ma~als. J. Peprod. Fertil. 76: 851-864 . 13. Bishc~, M. 1964. Paternal ~tribution to ~br~iC death. J. P~?r~d. Fertil. 7: 383-396. 330

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14. molten, A. 1982. me Frye, }I. 1-25. in Pep~i~ in is, Vol. 2: B~2ryc~ic are fetal c3evel~, C.R. Austin arm R.~. Short, echoic., Prime, Bridge Uhiv~ity mess. 15. Kirk, G.J., B.A. Atkinson ark H.A. Fs~t~n. 1982. Explanation ark wily pla~atic~n In chic Balm. J. Peprcd. Fertil. (Supply 31: 17-30. 16. At, L.L. 1978. Grm7th, protein c~nterlt art distribution of early embryos. Anat. ~c. 190: 143-154 . 17. Rc~s, R.M. art F.W. Nader. 1988. he fur~ic~n of u~rine secrecies. J. Coped. Fert; ~ . 82: 875-892 . 18. Gate, A.H. 1965. Rate of Ocular develc~rrt as a factor ~ ryonic survival, I. 270-288. in Reimplantation stages of E~a~, G.E. W0lsterho~ are G.E.W. O'Connor, ecis., Cub F~ation Sy~;iurn, J.A. Will Ted., ~on. 19. Warner, C.M., M.S. Bucknell and M.A. Ewoldsen. 1988. ply aren't - Frye Ecologically rejected by heir =*hers? Biol. Reprod. 38:17-29. 20. At, C.E. 1965. he influerx~e of maternal Trite con Reimplantation stages of pro in the ra}~it, ho. 345-373. ~eimpla~ation Stage of i, G.E.W. WolsterholmP art M.O. O'er, ads., ~ E~3ati~ Ilium, J.A. Quill Ltd., lion. 21. ~ore, N.W. and J.B. Shelton. 1964. EM transfer ~ she. Effect of degree of ~ization between donor arx] recipient, age of egg are site of transfer can ~ survival of transferred ~5. J. Repro. Fert. 7: 145-~2 . 22. Ran, L.A. am R.M. ~or. 1966. Fryo transfer In the Am: me significar~ of isle Litmus ~ the dear ark recipient animal. J. Peprod. Fert. 11:207-212. 23. Wilmlt, T. ark Sales, D.~. 1981. Effect of ~ Avid on ~Lryc~nic develc~nt In Amp. J. P - ~1. Fert. 61:179-184. 24. Wilma, I., Cal. Ashwor~, Am. pprir~e~ ark Dig. Sales. 1988. Effect of variation in 6 - ryo age cn the establi~nt of pro, and Embryo survival ark growth in em; with ~ entry=;. J. Reprod. Fert. 83: 233-237. 2S. Pe, W.F., R.R. Maturer am F. Stornehak. 1982. Survival of porcine rhry~ aft anus trar~;fer. E=c. Soc. E~ptl. Biol. ma. 171: 179-183 . 26. ~on, R.A.S arm L.P. Cahill. 1983. ~ificatian of the emibryo~aternal relatic~ip in mu; }fly protege treatment In the Orgy tams cycle. J. Repmd. East. 67:473-475. 331

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27. Polge, C. 1982. Fnhr~o trarep~antatian arm preservation, lo. 277-291. in Strop of Pig Repr~tic~n, D.J.A. Ale arm G.R. Fc~xcroft, As., ~rth Scientific, Ion. 28. WilOt, D.E., A.A. Cuiver, C.B. ~r~zrb arm W.R. Hi. 1976. Effect of piers Cal litter size in pigs. J. Reprod. Fert. 48:209-211. 29. Geisert, R.D., R.H. Cougar, W.W. Abaser, R.M. Pus ark F.W. Parer. 1982. E~tablislnrent of pry in the pig: I Ji*~rr~laticxlshipc; between prei~plantation devel~t of He pig blastoff arm uterine er~trial sec~retic ns . Biol . Reprud. 27: 925049 . 30. Geisert, R.D., W.W. Impair, R.M. Rc~s arm F.W. Moser. 1982. Fstabli~m~t of pi in the pig: 111 ~danetrial s~tory rinse to estradiol valerate administer can day 11 of He estrcus cycle. Boon . P`eprod. 27: 957065. 31. organ, G.L., R.D. Geisert, M.T. Zavy and A.T. Fazleabas. 1987. Develc~t and survival of pig blasters after estrogen administration an day 9 or days 9 am 10 of pr~Funcy. J. Reprml. Fert. 80:133-141. 32. Diekman, M.A. arm C.G. I=r~. 1984. Termination of pro ~ gilts snip z~ralenone on clays 7-10 po6~atir~. J. Artim. Sci. 59 S~ppl . 1) : 123 . 33. Bell, S.C. 1980. S~tory~etria~ ar~ldeciclualprateins: Shamir arm clinical significance of a maternally~erived gray of pr~- ass~xiat~ser~npr~eins. Hen. P - rod. 1:129-143. 34. Hulas M.C., N. Ka~i~, P. Palcx~a}ci, M. Julius, H. Bun arm M. Splat 1986. Amine arm so similarity beaten placental protein 14 arm -lactogid~ulins fun variers Specie. I~r Biol. 7:273(A}=tr). 35. Miele, L., E. Cordella~iele arm A.B. ~erjee. 1987. U~g1~n: sure, ~lea~lar bio1Ogy, arm new lives on its bunion as a ph~pholi~ A? inhibitor. Enshrine Previews 8:474-490. 36. Pollard, J.W., A. l~rt~i, R. Ar~i, A. OriofE~y, M.B. Ia~r arm E.R. Stanley. 1987. Ant role of the Package girth factor, C~F-1, pla~ta:1 development. ~=re.330:484-486. 37. P~:s, R.~., T.J. Rabb, ark F.W. Bazer. 1980. Pole of u~ferr~ transpla~tal ion t~an~ort in He pig. Red. Ed. 45:2513-2518. 38. Sicken, R.C.M., Y. Kin, X.H. Liu, M.H. Wiggle, W.~. P=e arm F.A. S;~r~. 1988. A uterine ~11 mitten distir~c fun ~?idernal growth factor in porcine uterine 1~ fluids: ~c~rizatioaa ~ Dial purification. Biol . Ramrod. 38: 551-561. 39. ~Kbistinen, R., W. i, M.-L. koala, M. Sheila, H. Bun and Eye. moaned. 1986. Pleural piker s a decider protein that birds Stalin arm has an identical N-t~minal amino acid sauce with SO=t~; bird protein fun Oman amniotic fluid. E~rino1. 118: 1375-1378 . - 332

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51. } - ers, J.C. are B.L. Drake. fir. Scientist 75:51-57. 1987. Me enigma of the fetal graft;:. 52. Art, G.B. 1988. Inter~ific priorly: Biol. Repro. 38: l-16. b~iers ~ prims. 53. fig, L.H. 1985. Ferns: ~facture art a~lica~cion ~ Medicine, pp. 451-462. in Biot~logy: A - licati~s at Prearm, P. a~isinoff art R. Ouell.e~e, ed.c., ~c, I, Mania. Friedman, R.M., T. origin am T. Sreevalsan. 1985. interferes as ~11 gram inhibitors art antiquer factors. WL synvia canlumbar art cellular Biology, New Series;, Vol. 50, Alan R. T.; - C, New York. 55. Fri~n, R.M. and S.~. Vogel. 1983. ~erfemns with Special con We imp In. h3va~ in ~1. 34:97-140. 56. P - e, W.F., M.H. Wilde arm S. Xie. 1988. Effect of electrocautery of Uvula day 1 follicles ~ ~t D=rpologi~1 variation day ll porcine Mayor. Biol . lid. 39: 882-887 . 57. E=e, W.F., M.S. lawyer, B.S. New am N.L. First. 1986. Effect of ~rur~s s~erirr~ion on er~ryo sunrival arx] range of blasts Revel Tine. Biol. Prod. 35: 133-137. 334 - 1

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mg~ Fig. ~ ~=ly~of ~~ ~~U of i~katia1 (Maps" ~ Fig. 1.1 of Pef. 14). F - lazed Blastocyst Enters~uterus Zone pelucida ~ Trophectod~ 1 war cell mass I,, Hatches, Implants (some rodents, bats and man, Endoderm ~ Expands \ I,,, Hatches, hydrants (borne bats, hsoctnrores) /; Hatches, elongates, ~ Replants (artbdacty~) (scab Breath reduced) Itches, Its (rabbit) 335 -