Fetal Programming of Stress Responses AMY. WARD aad DLW, FHILLIPS* Rn, Sahrgn Gin Hep Tron Pad een S60, ected 9 Ne 20 Re 2 Samay 20 form 9 Ma 9) Ems sas ane shown ht lize i sit! with a inte ‘ik ovary bea ene dei acer aca yeeros Type 2 dete. Tessas ht hs seas inking ou Nthweg wih dese el fe on inline beter rate and dap. Thine ols tt rd ‘screw fee he en nt ae ey os fel pha increasing fet avai Pr he ogee ey ae alae aga tes ‘kof cones eat esse Experi daa hain a ee hana Sse es ‘ove sugges hat ans i hee pit fhe Bypass -aea as ad smptcadetal gt re npn ge chops ht xe in axa With reed al orth These a sgn ha he tre anand fe Ss es ay be dtm by bate ace eons: Fetal gwd HPA ais Progannia: Stes tsps: Symposia |LBACKGROUND. 1.1 Fetal Growth and Adult Disease “There is now substi evidence that smal size at ie snk with a higher prevalence of coronary Fart eas in ad fe Tn longer flow study carved ot in Herons, UK, death ates from connary heart disease el almost wot from the lower to the upper ends of the binweght istibtion (Barker, 195). Allowing for gestatoal ag, it has besa shown hati i growth retardation rater than_ prematurity that accounts for these findings (Maryn er al, 1996). These ndings have ‘eon confimed extensively ia stalies fom Filan, ‘Sweden andthe USA and have been demonstated 0 te independent of adult ewyle fctrs sch as ‘woking, aloo consumption, exercise and scio- ‘conamie satus. There are ako compeling data hat low imhueight is associated with an increased prevalence of isk fst fr art dase especially "Type 2 (no-insulnependet diabetes and byper- tension. For example ina stdy of 370 men boe in enfordhice, the prevalence of Type 2 diabetes and -tlicose itlerance fel from 40% among me who ‘weighed Sb (25ky or les at bith o 145i thse who weighed 9.51 (4.3k3) 0 more (ales eal, “are te: oD TI6,Fa-44.2070N al: npc aon1991: Law nd Stell, 1996). These tis ud ut cent bly mass index (BM, Ky) and sci economic status at possible confounders. The netboic or inulin resistance syndome (gc inokrance in combina wi byperesion and lpia) is alo srogly asocsed wit ‘ced fet gronth In Heron the pevalense ofthe metho symome was six times higher in mn aged 65 who weighed 5516 (2Ska) or les at rth tas ia thse who weigh 9318 (8.3K) or ne (Barker ea, 1998). ALa metabo level ow! ‘inivelght hasbeen shown to be aseited with inoin resiane in exer diferent populations ‘ing a arty of techniques, inclaing the ype lnsalimenic el caemic elanp an he inkanens ‘coe tolerance test wich minal del salve (Philips raf, 199; Pagan ea, 2000, 12, Fetal Programming “Te growth of fet is gly deri by the sue and exyaen ic receives, and ths these brains inking ow eal growth rales with sisene have Been interpreted being de ofa ‘demain. is suggested that nmin pean ie for a varety of reasons, thee i an imbalance eteen feta sent demand and spp. Tht Imbalance res in metabolic and eedocine dations which hee he fet nthe sr tom by reducing feul giowh and increming ful vali, btn the loge er thse adspations ne malate leading 0 a creme ik of the raeabolle syadrome snd cindoraclar dese (Philp, 1996) Underlying this the conept of ropaaing whey a simul cei tial sage ia deekpment bas lasing sigan. Tae underutiion hypothesis is sapped by ses hic show hat animals expe ow tein ts ing gestation deep metabolic abnoemais (Sugden and Hens, 198: Bars ea 1997) and bya Follow-up staly of babies bor following the Dutch Hunger Wine (Ravel eta, 1998, This study of mea and wont, gu 80 yes, ho were ‘om uring ater th Dutch wie famine of 1944 ows hat uedematon at ary sige of estion is Hake with ced laste oerane an viens of inelinesistace ithe oflrig. Inthe search for posible mechanisms of the ng term effects of uniemuition, many imesgaors ave focused onthe hypotaamic—pititary—ate- al HPA) ais nd sympa nerous ster. The Noogicaly potent sess hormone contol can increase Noe pesue 2nd ipa slucse lene and thus, if preset i increased culating cocen- tains, may cone fo the pepsin to he metabolic symirome in Tow binhweight ofpring (Philip 998 Likewise, he activo the sympa ters ining recognise tn imporast derma of cadioascula hai ‘nd shores of sympathragal bance ave ho en lined ith the metabolic syndrome (Pacchin) ef al, 1936), hee is test in the incace of erly fe on this aspect of the sess respome, These ew daa suggest that intaeine factors uy alle the nature an mnie oan insists sponse, 2, PROGRAMMING OF THE HPA AXIS 24. Ontogeny ofthe HPA Als Glucocecoid ae prota hy the aaa cortex der th predosinan replton of the hyp Jno-piutay ais tate pact play ‘key fe in physio. pica in meting he ‘as’ oiponse tose. fetal fe slacooricid levels re Jobat in many pis ie war tem when they nine sue matron in repeat exsaterine exience The fetal HPA as well velo an factional in ne gsstion i may species including humans (Fisher, 1998). The evelopment ofthe marlin HPA ans has been exesvely sted in sep (Mathews and Chal, 1996, Prapionslnocorin (POMC) mRNA resent inthe pity from the earest stages of esate. The bevels of POMC mRNA in the pas sulis of he pituitary, wich conte ell with relating fetal adenocorictophisormone(ACTID, incase progressively dering the second ‘nif of gestation, Cnicotpin lesing bormene (CRED nd apne vasopressin are the primary ‘actors coming spe and secretion of ACTH ‘onthe prt distal a hy re eh ou he hypothalamus feom mid gestation. Ie is well stblhed tht the eal HPA as espe 16 steal sma In late ovine gestation (ay 135) experimen fetal hypoxia inducing a 0% redo {net atv PO, rods rob nese i tal ‘Pauma ACTH and col level, wich apps o be ‘eine by rca of rsopesin am CRE ito he spon portal stm (Mathews and) Chali 195), 2.2. dence fr HPA Programming ia Animal igerimeats “There growing evidence that export tes in prettal stcaty pot fe ie able 0 aller Permanently the bolo an behav esponse totes inthe ada ofsing. Gvecorcois appt tobe central w thse igs. Ra ars enpond 0 tmpedicuble noise and ight ses thoughout Premnney produce ffping with greater ction Ay on expres mc etn (Welk (rl, 1982) mature female oping hi is ‘feta wit incre taal coniconerne level and 2 prolonged rie in coricoserore sereon Tetowing open Hell tes. Injection of human ‘lod eels (HRBC) or ligoplyscchuse «LPS) induces an immune rosponte im progant rat insfccnt wo cause aber. bt sith ng ing fel eects, Baal cortcrtrone levels were raised 1229 in offing of te HRBC-eated group aad (6% in ae vo medhers wee exponed to LPS ‘eu era 198) aden sessindvced ACTH. ‘sndconiconterone levels wee sett inthe fone ‘rep. Petal ethanol ae duces MPA a ype ‘esposivenesstoa aie of sessr inthe al at, ough the eet vain at ferent sages of ‘maturation and byperspoasivnois 0 the same ‘rewor may be sen when the offering ae teed ‘ior to pubery (Lee and River 1996), Sox iterences ae apparent in sme rat models with female oigring tending 10 show rear diferences IW HPA tation compared ith cots following ental ses than hei male counterparts (McC Ick a, 1995) Sti footing diel at maternal underuion have aio iented pertrtatons ofthe HPA ani [ngley-Evans and ‘colleagues fave shown tht ofpring of rt fed. a low protein dit daring prepany develop ifetong hypertension an that hs ‘an fe abolished by pbarmacolgiat Blockade of ‘ovcoteene ste Langley an Jackson, 199). ‘Atcom anda weaning ce fing mee fou 0 have elevated levels of certain gloscoricod inducible enzymes in the bain abd the live. we ‘he ates of lacoronicidmeenstine emymes ‘wee une oowerd- a ado four weeks oF age they exhibited bled cra pater of ‘ACTH secretion and eed binding of lalid conicosrone to licoconisoid receptors (GR) (angley-Brane a, 19640. Ina ganen pg 88 ‘of mien restriction ty 50 of setatin seed tbe meral HPA ais which red fea con levels. The following dy GR MRNA expression was ‘ced in the developing ypetakmas and Hipp ‘campus, finding tht may hve lasing significance forthe tt pon ofthe HPA ane pot Linas etal, 199). Tis tough ht thse stesso at vis econ fetal expos to glucocorticoid bamones sling eset aheaions ia HPA atv. The exgpereed ‘tes indced ein cocetrone sci nas ‘whose moter a experienced estat stesso he nal weck of pregnancy i me seen when the mother as previosly andergoneadealetomy, bat ‘mimicked when an excenive replacement done of Ssemionetone is wed post adenlsctomy Bach {anges el, 1006) Furthermore, penal tea! fof rts with devanehasone, whith faces fetal lucoconiaid exporre, leads 10. permanently foceased acuity of the HPA ais Levitt al 990; Manco ea, 1987). These elect 0 ot seen inal ses and appear wo be depen! o the dove andiming ofthe administered luce. Ia ‘primate sty pregnant ewe makes ihesametasone pode oiing with elevated ‘acl and ses nce coon ert and Sanat ditferences in hppcarpal sractre (Uno ral 1998). ‘Some ses of prenatal dexamethasone expose use lees measurement of gcc ep ts he hippos which san imprint of ‘pate feedback ofthe ais Inthe rt aedutio in tn GR snd minerlocricoid ee mines at found and may pay expan the hyperactivity of te ss (Levit te, 1980) However. the Badge ‘ui pig model were ess stihorward with incemsd GC mae tring and rece Gn Female oloring following penta shcoceticc ‘Mathews, 200) lea tess ad programing ofthe HPA ax te fous is mee by fel of mata eee Placena, he feus tas much lower levee of lsweoricoids than the mother, Ths gradient achieved fy placental spdoxpteroiddeyo- ‘sna (LIB-OHSD) Type 2, which catalyse Ptaolam of ate ghnoconicoe cha ota (oir inne Ite Frm The petal baer Iseticint and ensures at os tt al teres conisl is iaactated upon reaching the fal ‘rutin, Edwards and coleages ve proposed {hat ow placenta 119-OHSD-2 sci my low Imtemal cost to ramming (Langley Evans ea, 1964). Programming oe HDA aus mot rested 10 ‘the prenatal period, parically ia ats whee the ‘Sen ervons eps ey tte th Meas e (1956) hae sown tht hang at psi hit to worries ese eapome t2 SStnequat rorait al incemes derameihnone Sires ofthe ais dings asecated th Increased hippocampal gacoconicoid receptor ‘expression (Meaney «t aly 1986) Conver gate snail at his time, sch at mater SSouation, physical Wound nto dias ron, enhance HPA responay em 2.8. oldence for HPA Programming in Humans Despite the body of evince fom animal exper: mens, there have een few studies of this phenomenon human populations. Fetal expose Ioglucoseotd eres south ant ow ithe abies have reise cori ences nub ‘ont blood an raised wimy coil excretion In ‘bool (Ritch 178; Cake a, 1986), No sodis have been cared out aes HPA ais funcon in hilren or young ads torn to mur ho recived gloccortcotds dung. pregnancy Giewcricoids re commnaly given 1 ther where thre i «sk of peer bor w spd maturation of enain vit ses. especialy the Tings ASimay of these etsy re ber ea tay ofthe behavioral Sequels of the glcacoicold ‘weamest is tampered by their isenod rk of evelopment pienso pemsrty (Eco ides a, 1988).Fasting cortisol (nmol/!) id ao zs Free cortisol (nmol/mg) 23 ae ae eu aeReceitly, we sowed ht brinch as eed vo fang oming coil concetatons in men ‘gd 8 yas bor in Hero. Figue 1 shows "tte fst lama cots concent el om ‘Sem ins wh weighed Sb 2 Shy ores. te Arm among toe who weighed mae th 950 @3kg) (Pips ofa. 1998. These wends ver parleled by the concennsions of “ee Catia estimated by the rato of eorsl 10 ‘oie ning globulin. The sceiation Wat ‘depen of he cent oes. AO sine Sung com measuenen as sibs imi ‘sins, this ebseration sgpeted the pity of fn portant ink owen size ad ac ‘ial mone atin da fe, We ore Ping apps saps of 165 en al were ‘orm in Ati South Aust, om 1975-76 19 ner an women torn in Presen UK, from 1935 1943 and 308 women bom in Eat Henodtie, UK, fro 1923-30 (Pilione a 200, Low wei tras soci wih aed ating plums conta oncetaions In all three populations and. a ombined analysis which allowed foe deems it the gender composton. age and body mis inde Iatwcen th stiles showed that cao! concen. fron fel by 289amci per Rg inctene in ‘inca (SEC, 916-882, p< 0001: Fi 2. ‘Schr eid en ae pute emcee ce sr Sey Step sa We extended these preliminary cberatons by syngas of 203 men fom te iia entries. Thy andereot anor ow ose (025mg) desaricthawone suppression test foowed by low dove us ACT > tinal teu eyo ef, 200) A 24h ain amp wat ‘alle or aay of corsa metas by ab ‘homaopripllecron pct as Spectmey ‘Men wih lower bite bad eabanced plana come spoons t@ ACTH, 2 = GA: Fg 3) Incrned tl aia coriol metabolic exceioe {Gtr aumento confounding tes isteed ‘hey ni nbc mas ps that meh, Tout no. iffernce in plasma comtsol after mars thre are fe dt om the eaters mechani response ortee aerate. There ntoneny av to wheter the ae asiatons tween rttelaht and pacenalTIB-OHSD-2 levels Sten era. 195; Ropersan ef al, 197; £ Presa crt! mat LED) ‘Sent i arin THs ere ere UAC a ce fcoesa.Smgcume ot eng prac Sod+r esses vEPITEg ‘Sham cal, 198), However. i hs Bsn served ‘hr deleterious tans of the 15-0HSD.2 gore 9 aman are anit with low ici (Mane al, 1989) Many fetal tes au expos 1 (OHSD.2, which could sy a role in reglaing iconic fet lough he wmporaace of hie ieeotele |. PROGRAMMING OF THE. 'SYMPATHOADRENAL SYSTEM. 1 ely ta th programming ek of peas stress on the symputeaenal system ar clsely Inte wa thos 0 he HPA ai the tw sys ‘cin cose Caebolumineric pts mule the PX ans cma and lacoerbcis pte te fects ofthe fmpatsc nervous stem. In, Tet expnie to pacovericoie fet the ptr Aifeeninion of soncmic vere celle and the Aeelopment of abenetpe cep, together wth to couping Wo cll ance mater (Skt| al 980). Despite his ata ting tothe aye ataenese 1 ssmpatheaenal fantom ate mich seat ‘osstock ea (1982, 198) have sbown that at tee rt beet anders er opted i eared ‘hie nine and ligt steve ogo geste have {euaggerated norateaine response irmeitly ier foosioek (Weinstock etal 1998) A recent Study using werine any lean i at wat | Inumuerine prowth roto Found 4 secpeie sfc. In the female ofgring low bithvigh was seid wih pressed sympuhstinerous system aig menured by nonrenaline tape ion techniques at four moms of age dann and Lambert, 199) Ineresingly hi group alo had ‘levated fang Hood pcs eel ann response {01 glucose oad he asin eels were lower and slacowe levels were higher The sale ling owed an sigan bith I humans well copa ha Fetes with ‘nueie growth eardation ave higher pus ator ana higher catcolamine concent i ard ond Raion of al, 1981) Ta tay of 266 men and women aged 50 years esting pulse te was inverse Rha tn in ple rat er ky cease in btheigh = 27, 95% CT 05- ‘{Rbeas min") Pili and Baker, 197). Thin ‘ing wasndeerdet of esatonl gs, a BM orwas hipaa mained afer cnet tose {nda with Know caovsele dene. Thit ‘nding hs eon confirmed in 2648 Afi sh shin who aso dembrerated an mere tli ship twee ithe an Hao! posure Lengo 4. CONCLUSIONS. “The data presented suggest that event i tere and ‘ely postal if programme te evel fatty of the two mujor neuendceie tess anes and that, thee eno penis tooghont he Hie of the individ Those Hinings may. Aste import Ingato for fare Peal bh physically and reysnegialy. Fo, example, we found that ated eso! concentions were asec wa ier ‘od pete and inp pice flere nn population sample ia Henfoative (Pulp 1958, Farther work is seeded t determine the exist sate of the erty Iie effect on MPA and ‘Symputoasrena fonction and to elucidate {ulin ht exit with alt Belson and Stress. 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