Differential effects of prenatal stress and glucocorticoid administration on postnatal growth and glucose metabolism in rats

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1 319 Differentil effects of prentl stress nd glucocorticoid dministrtion on postntl growth nd glucose metolism in rts K L Frnko, A J Forhed nd A L Fowden Deprtment of Physiology, Development nd Neuroscience, University of Cmridge, Downing Street, Cmridge CB2 3EG, UK (Correspondence should e ddressed to A L Fowden; Emil: lf1000@cm.c.uk) Astrct Glucocorticoid dministrtion during pregnncy progrmmes crdiovsculr nd metolic functions in the dult offspring. Often, the control procedures re stressful per se nd rise mternl glucocorticoid concentrtions. This study compred the effects of mternl injection with dexmethsone (dex, 200 mg/kg) or sline with no tretment from 15 to 20 dys of rt pregnncy on offspring growth nd glucose metolism. Ner term, mternl corticosterone concentrtions were higher in the sline-treted dms nd lower in the dex-treted dms reltive to untreted nimls. In oth mle nd femle offspring, growth rte ws mesured for 14 weeks, nd glucose tolernce ws ssessed etween 12 nd 13 weeks together with ody ft content nd plsm concentrtions of insulin, leptin, nd corticosterone etween 14 nd 15 weeks. Offspring liver ws collected t different ges nd ws nlyzed for glycogen content nd gluconeogenic enzyme ctivity. Compred with untreted nimls, oth dex nd sline tretments ltered postntl growth lthough dult ody weight ws unffected. The two tretments hd different effects on dult insulin concentrtions nd on heptic glycogen content nd gluconeogenic enzyme ctivities oth pre- nd postntlly. Reltive to untreted nimls, dult glucose tolernce ws improved y mternl sline injection in mles ut not in femles, while it ws impired in femle offspring ut not in mle offspring of the dex-treted dms. Adult glucose tolernce ws relted to mle ody ft content ut not to femle ody ft content. Dex nd sline tretments of pregnnt rts hve differentil sex-linked effects on the growth nd glucose metolism of their offspring, which indictes tht the progrmming ctions of nturl nd synthetic glucocorticoids my differ. Journl of Endocrinology (2010) 204, Introduction Humn epidemiologicl studies hve shown tht impired intruterine growth is ssocited with n incresed risk of crdiovsculr, metolic, nd other diseses in lter life (Brker 1994). These ssocitions hve led to the concept tht dult disese cn originte in utero s result of developmentl progrmming of key tissues nd orgn systems during suoptiml intruterine conditions ssocited with poor fetl growth (Gluckmn et l. 2008). Experimentlly, prentl progrmming of postntl metolism hs een demonstrted in numer of species using rnge of different techniques to induce intruterine growth restriction (IUGR) including mternl stress nd glucocorticoid dministrtion (see McMillen & Roinson 2005, Fowden et l. 2006, Seckl 2008). Similrly, in nturlly occurring IUGR in polytocous species, low irth weight is ssocited with dult glucose intolernce nd ltered ft deposition (Poore & Fowden 2002, 2004). In oth nturlly occurring nd experimentlly induced IUGR, the progrmmed ltertions in postntl glucose hndling re ssocited with functionl chnges in rnge of tissues involved in growth nd glucoregultion, including severl endocrine systems (see McMillen & Roinson 2005, Fowden et l. 2006). In pregnnt rts, mternl tretment with the synthetic glucocorticoid, dexmethsone (dex), vi numer of different routes leds to IUGR nd glucose intolernce of the dult offspring, ccompnied y chnges in the liver, ft, nd skeletl muscle, nd in circulting concentrtions of insulin, leptin, nd corticosterone in the dults (Muneok et l. 1997, Nyirend et l. 1998, 2006, Smith & Wddell 2000, Sugden et l. 2001, Clesy et l. 2003, O Regn et l. 2004, Wyrwoll et l. 2006, 2008). Similrly, stresses during rt pregnncy tht rise mternl glucocorticoid concentrtions, such s restrint, noise, nd isoltion, induce IUGR nd lter glucose hndling nd hypothlmic pituitry drenl (HPA) xis function in the dult offspring (Brznges et l. 1996, Vllée et l. 1996, Mccri et l. 2003, Lesge et l. 2004, D mello & Lin 2006). Indeed, in pregnnt rts, procedures such s sline injection, often used s control in studying prentl origins of dult disese, led to elevted mternl nd fetl corticosterone concentrtions, which my progrmme tissue development per se (Wrd & Weisz 1984, Brznges et l. 1996). Consequently, the stress of injection my mimic, Journl of Endocrinology (2010) 204, DOI: /JOE /10/ q 2010 Society for Endocrinology Printed in Gret Britin Online version vi

2 320 K L FRANKO nd others. Glucocorticoid progrmming in prt, the progrmming effects of synthetic glucocorticoids nd my men tht the comprison of offspring from dex- nd sline-treted, or vehicle-treted, dms my e exmining different types or degrees of intruterine progrmming. However, little is known out the effects of commonly used control procedures, such s mternl sline or vehicle injection, on glucose metolism of their offspring. The current study, therefore, compred the effects of mternl injection with dex or sline with no tretment during rt pregnncy on the growth nd glucose metolism of their mle nd femle offspring. Mterils nd Methods Animls A totl of 32 virgin femle Wistr rts ged etween 12 nd 15 weeks were used (Fig. 1). They were mintined t 22 8C in 12 h light:12 h drkness cycle nd were fed stndrd lortory chow throughout the study (Stndrd Breeding Diet No. 3, Specil Diet Services, Essex, UK). Femles were housed overnight with mle Wistr rt (minimum ge 15 weeks) nd were checked dily for the presence of copultory plug. The dy fter mting ws tken s dy 0 of pregnncy (term is dys). Before mting, ll femles were housed in groups, wheres fter mting, they were housed individully to llow the mesurement of dily food intke. Dms were weighed on dys 0, 15, nd 20 of pregnncy. Experimentl procedures All experimentl procedures were crried out under the Animls (Scientific Procedures) Act On dys of pregnncy inclusive, 22 dms were injected sucutneously with either sline (400 ml, 0. 9% w/v, nz11) or dex (200 mg/kg, dex 21-phosphte sodium slt, Sigm, in 400 ml sline, nz11, Fig. 1). Administrtion of dex to pregnnt rts t this dose nd stge of gesttion is known to progrmme crdiovsculr nd metolic functions in the dult offspring (Nyirend et l. 1998, Clesy et l. 2003, Drke et l. 2004, O Regn et l. 2004). Ten dms cted s controls nd received no tretment (Fig. 1). Between 0800 nd 1000 h on dy 20, suset of ech group (nz6 control, nz7 sline, nd nz7 dex dms) ws nesthetized with mixture of sodium pentoritone nd chlorl hydrte (equithesin, 0. 6 ml/100 g ody weight, i.p., nd 9. 6% pentoritl sodium, BDH Chemicl Ltd, Poole, Englnd; 42. 6% chlorl hydrte, Sigm Aldrich Co). Once nesthetized, ventrl incision ws mde in the domen nd 2-ml lood smple ws collected from the uterine vein for the mesurement of lood glucose nd plsm corticosterone concentrtions (Fig. 1). Fetuses were removed individully from ech horn, weighed, nd killed y decpittion immeditely fter delivery. A smll lood smple (!20 ml) ws otined from the severed vessels in the fetl neck for the mesurement of lood glucose concentrtions. The fetl liver ws removed, weighed, nd then flsh-frozen in liquid nitrogen for susequent nlyses of glycogen content nd gluconeogenic enzyme ctivities (Frnko et l. 2009). When ll fetuses were delivered, the dm ws killed with lethl dose of nesthetic (200 mg/kg sodium pentoritone, i.v., Dolethl, Vetoquinol UK Ltd, Buckinghm, UK). Mternl lood smples were centrifuged t 4 8C,ndtheplsmwsstoredtK20 8C until the mesurement of corticosterone concentrtions. The remining four dms in ech of the sline nd dex groups received nother injection on dy 20 nd were then llowed to deliver nturlly without further tretment, Figure 1 Schemtic digrm of the experimentl protocol indicting the sequence of experimentl procedures nd the numers of dms nd offspring involved t ech stge of the experiment. Journl of Endocrinology (2010) 204,

3 Glucocorticoid progrmming. K L FRANKO nd others 321 together with the four remining control dms (Fig. 1). On dy 1 of postntl life, ll litters were culled to eight pups so tht four femles nd four mles nerest to the medin weight for the litter were rered y their mother (Fig. 1). The rest of ech litter ws killed y decpittion (Fig. 1). A smll lood smple (!20 ml) ws tken from the severed neck vessels to mesure lood glucose, nd the liver from culled neontes ws collected into liquid nitrogen. Rered pups were weighed weekly until 21 dys of postntl ge when they were wened, nd then on dy 22, hlf of ech litter (two mles nd two femles) were selected rndomly for culling y cervicl disloction. A lood smple (!20 ml) nd the liver were collected from ech of the culled wenlings (nz16 controls, nz16 sline, nd nz16 dex offspring from 4 dms per tretment, Fig. 1). The remining two mles nd two femles from ech litter were individully mrked nd fed stndrd lortory chow (Stndrd Breeding Diet No. 3, Specil Diet Services) until the end of experimentl procedures etween 14 nd 15 weeks of postntl ge (Fig. 1). They were housed in groups y sex with control, sline-treted individul, nd dex-treted individul in ech cge. Offspring were weighed weekly from wening to 14 weeks for the clcultion of frctionl growth rte (FGR). Between postntl weeks 12 nd 13, glucose tolernce test ws crried out fter n overnight fst (nz14 control, nz16 sline, nd nz16 dex from 4 dms per tretment, Fig. 1). Glucose (0. 2 g/kg s 20% solution) ws injected intrperitonelly, nd lood smples (!20 ml) for the mesurement of lood glucose concentrtions were collected from single nick in the til vein t K15 nd 0 min efore nd t 15, 30, 45, 60, 90, nd 120 min fter glucose dministrtion. At the end of the glucose tolernce test, the rts were returned to their cges until etween 14 nd 15 weeks when they were weighed nd euthnized y cervicl disloction in the fed stte for the collection of lood (2 ml) nd liver smples (Fig. 1). After removl of the liver, the ft content of the dominl region of the crcss ws mesured using dul emission X-ry sorption (DEXA) scnning (LUNAR PIXImus Densitometer, GE Lunr Corportion, Mdison, WI, USA). The scn included peritonel, omentl, mesenteric, perirenl, nd sucutneous ft deposits in the dominl cvity. Therefter, the discrete peritonel nd perirenl ft deposits were excised nd weighed. Biochemicl nlyses Blood glucose concentrtions were mesured using hndheld glucometer (Lifespn, Ortho-Clinicl Dignostics, High Wycome, UK). Concentrtions of insulin, leptin, nd corticosterone were mesured in dult plsm y RIA using commercilly ville kits (insulin nd leptin, Linco Reserch, Sint Chrles, MO, USA; corticosterone, Immu- Chem, Orngeurg, NY, USA). For ech hormone, ll smples were nlyzed in single ssy. The lower limits of sensitivity of the ssy for insulin, leptin, nd corticosterone were 0. 1, 0. 06, nd 10 ng/ml respectively. The intr-ssy coefficient of vrition ws %10% for ll three ssys. The heptic glycogen content nd ctivities of glucose-6- phosphtse (G6Pse, EC ) nd phosphoenolpyruvte croxykinse (PEPCK, EC ) were mesured in the liver from the postntl offspring nd from, t lest, four fetuses from ech litter (two of ech sex) using estlished methods descried previously (Frnko et l. 2007, 2009). Briefly, G6Pse ctivity ws mesured s phosphte production from glucose-6-phosphte, while totl heptic PEPCK ctivity ws estimted y mesuring 14 C incorportion into mlte (Fowden et l. 1993). For oth gluconeogenic enzymes, tissue ws homogenized in ice-cold sucrose (0. 25 M) nd ctivity ws mesured over 10-min period t 37 8C. Heptic glycogen content ws mesured s glucose produced y myloglucosidse ctivity in 10 min t 55 8C (Frnko et l. 2007). The inter-ssy coefficients of vrition of fetl liver homogente in the glycogen, G6Pse, nd PEPCK ssys were 9, 11. 8, nd 5% respectively. Heptic protein content ws determined using the Lowry ssy. All tissue nd plsm nlyses were done in duplicte. Mesurements of the ft content of the region of interest y DEXA scnning were vlidted iochemiclly in ten dditionl Wistr rts using the chloroform/methnol method of ft extrction (Folch et l. 1957). Body ft content mesured y DEXA scnning ws linerly relted to the ft content determined iochemiclly s follows: yz0. 79x C1. 11, nz10, rz0. 955, nd P!0. 01, where y is the percentge ft content mesured y DEXA scnning nd x is the percentge ft content determined iochemiclly. Sttisticl nlyses Mens (GS.E.M.) re presented throughout. Tissue nd lood smples were collected t four ges: fetuses, neontes, wenlings, nd dults etween 14 nd 15 weeks of postntl ge. The effect of tretment in the pregnnt dms ws ssessed y one-wy ANOVA with the Holm Sidk post hoc test (Sigmstt 3.5; Systt Softwre Inc., Point Richmond, CA, USA). For the offspring, the effects of tretment nd sex were ssessed y liner mixed model using the Sidk post hoc test using the dm s suject with ech offspring nd time, or ge, s repeted mesures s pproprite (SPSS 16.0, SPSS Inc., Chicgo, IL, USA). When sex of the offspring or n interction etween mternl tretment nd sex of the offspring ws identified s significnt influence, mle nd femle dt were nlyzed seprtely y liner mixed model using the Sidk post hoc test. Associtions etween the dult vriles were ssessed y liner mixed model using generlized estimting equtions clustered on the dm to llow for nonindependence of littermtes (Stt v10.1, Sttcorp., College Sttion, TX, USA). FGR from irth to wening nd from wening to 14 weeks ws clculted for ech niml s weight increment over the entire period expressed s grms gined per week per grm strting weight t irth or wening respectively. Journl of Endocrinology (2010) 204,

4 322 K L FRANKO nd others Results. Glucocorticoid progrmming Pregnncy outcome Dm weight ws not significntly different etween the groups on dys 0 nd 15 of pregnncy, ut y dy 20, it ws significntly lower in the dex-treted nimls thn in the control nimls (Tle 1). Mternl weight gin ws, therefore, similr in the three groups from 0 to 15 dys, ut reltive to the controls, it ws significntly less in the slinend dex-treted groups during the tretment period (Tle 1). Weight gin over the tretment period ws lso significntly less in the dex-treted dms thn in the sline-treted dms (Tle 1). Mternl food intke did not differ etween groups efore or during the tretment period (Tle 1). Litter size ws lso similr in the three groups (Tle 1). On dy 20, mternl concentrtions of plsm corticosterone were highest in dms treted with sline nd lowest in those receiving dex (Tle 1). There were no significnt differences in mternl lood glucose concentrtions with tretment on dy 20 (Tle 1). Offspring growth nd morphometry Compred with the controls, dex tretment reduced ody weight of the offspring in utero, t irth, during suckling, nd for 4 weeks fter wening (P!0. 01, ll cses, Fig. 2). Body weight of offspring from the sline-treted dms ws similr to tht of controls in utero, intermedite etween the vlues of the control nd dex-treted groups t irth (Fig. 2A), nd significntly less thn control vlues during suckling nd from wening to 7 weeks (P!0. 01, ll cses, Fig. 2B nd C). Tle 1 Men (GS.E.M.) food intkes nd solute nd incrementl (D) ody weights t different periods of pregnncy, litter size, nd concentrtions of lood glucose nd plsm corticosterone on dy 20 of pregnncy in untreted, control rt dms (nz10 dms or for corticosterone nd glucose nz6 dms) nd those treted with sline or dexmethsone from dys 15 to 19 of pregnncy (nz11 dms or for corticosterone nd glucose nz7 dms in ech treted group) Control Sline Dexmethsone Food intke (g/dy per rt) 1 10 dys 21. 1G G G dys 25. 0G G G dys 24. 9G G G1. 2 Body weight (g) Dy 0 260G11 258G10 268G10 Dy G11 305G12 315G13 Dy G10 364G14, 347G15 D 0 15 dys 52G6 47G3 46G4 D dys Litter size 76G G G G G4 c 14. 3G0. 7 Corticosterone (ng/ml) Glucose (mmol/l) 652G59 818G G G G25 c 4. 33G0. 42 Vlues within rows with different letters s superscripts re significntly different from ech other (P!0. 01, one-wy ANOVA). Journl of Endocrinology (2010) 204, Figure 2 Men (GS.E.M.) ody weights of the offspring of untreted, control rt dms, nd dms treted with sline or dexmethsone from dy 15 to dy 19 (fetuses) or dy 20 of pregnncy (ll other offspring) (A) on dy 20 of pregnncy nd t irth (Con, open columns; Sl, stippled columns; Dex, striped columns nz4 7 l per tretment t ech ge), (B) during suckling from irth to wening (Con, open circles; Sl, tringles; Dex, filled circles, nz4 l per tretment group with four mle nd four femle pups in ech litter), nd (C) in mles (solid lines) nd femles (dshed lines) from wening to 14 weeks of postntl ge (Con, open circles, nz7 mles nd nz7 femles from four dms; Sl, tringles, nz8 mles nd nz8 femles from four dms; Dex, filled circles, nz8 mles nd nz8 femles from four dms). At ech ge in (A), columns with different letters re significntly different from ech other (P!0. 01), while columns shring common letters re not significntly different from ech other (PO0. 05, liner mixed model). In (B) nd (C), significnt effects of mternl tretment ( P!0. 01) nd/or sex of the offspring (*P!0. 01) re shown y liner mixed model. There were no significnt effects of sex of the offspring on ody weight in (A) or (B).

5 Glucocorticoid progrmming. K L FRANKO nd others 323 By postntl week 8, mternl tretment no longer hd significnt influence on offspring ody weight (Fig. 2C). Body weights of mle nd femle offspring from the slinend dex-treted dms, lthough still numericlly smller, were not significntly different from those of the controls t the time of the glucose tolernce test or t tissue collection (Tle 2). Sex of the offspring hd no significnt effect on the ody weight of fetl, neworn, or wenling pups (PO0. 05, ll cses). However, y postntl week 4, mles weighed more thn femles nd remined hevier therefter (Fig. 2C). There ws no interction etween mternl tretment nd sex of the offspring in determining ody weight t ny of the ges studied (PO0. 05, ll cses, Fig. 2C, Tle 2). FGR, clculted s weight increment from irth to wening, ws unffected y mternl tretment or sex of the offspring (PO0. 05, oth cses, Tle 2). In contrst, FGR from wening to 14 weeks ws influenced y oth mternl tretment nd sex of the offspring (P!0. 05, oth cses, Tle 2). Over this period, FGR ws significntly less in femles thn in mles (Tle 2). In mles, postwening FGR ws higher in offspring of the dex-treted dms thn in the other groups with no significnt difference etween the control nd sline-treted groups (Tle 2). In femles, mternl tretment hd no effect on the postwening FGR (Tle 2). In dults etween 14 nd 15 weeks, the ft content of the dominl region mesured y DEXA scnning ws influenced y oth mternl tretment (P!0. 02) nd sex of the offspring (P!0. 001). Femles hd less ft thn mles irrespective of tretment (Tle 2). In the mles, ft content ws significntly lower in offspring of the sline-treted nimls thn in the other groups (P!0. 05, Tle 2). A similr trend ws oserved in the femles, ut this did not rech sttisticl significnce (PO0. 05, Tle 2). When perirenl nd peritonel ft contents were clculted grvimetriclly, the vlues were influenced y mternl tretment (P!0. 02) nd sex of the offspring (P!0. 05), with significntly lower vlues in the dex-treted group thn in the control group (P!0. 02). This effect of dex ppered to e more pronounced in mles thn in femles (Tle 2). When dt from ll dult nimls were comined, there were significnt positive reltionships etween the DEXA percentge ft content nd postwening FGR (P!0. 001, nz46 offspring from 12 dms) when differences in current weight were tken into ccount. Percentge ft content clculted grvimetriclly ws not relted to postwening FGR (PO0. 05, nz46 offspring from 12 dms). Plsm hormone concentrtions Between 14 nd 15 weeks, plsm leptin concentrtions were significntly lower, while plsm corticosterone concentrtions were significntly higher in femles thn in mles irrespective of tretment (Tle 2). Neither of these hormone concentrtions ws ffected y mternl tretment (Tle 2). In contrst, plsm insulin concentrtions were influenced y oth mternl tretment nd sex of the offspring with lower vlues in femles thn in mles (Tle 2). Insulin levels were significntly higher in the sline-treted group thn in the dex-treted group with intermedite vlues in the controls (P!0. 02, Tle 2). When dt from ll dult offspring were comined, plsm leptin concentrtions were positively relted to DEXA ft content (P!0. 016, nz32 offspring from 11 dms). Conversely, plsm corticosterone concentrtions were inversely relted to DEXA ft content (P!0. 012, nz40 offspring from 12 dms). In contrst, insulin concentrtions were unrelted to DEXA ft content (PO0. 05), ut were positively relted to postwening FGR (P!0. 025, nz35 offspring from 12 dms). No significnt reltionships were oserved etween ny of these hormone concentrtions nd percentge ft content clculted grvimetriclly (PO0. 05, ll cses). Nor were ny of these hormone concentrtions relted to ft content (DEXA or excised) when mles nd femles were considered seprtely (PO0. 05, ll cses, nz16 20 offspring from 12 dms). Glucose metolism Glucose concentrtions At ll ges studied, lood glucose concentrtions in the fed stte were unffected y mternl tretment or sex of the offspring (PO0. 05). The men lood glucose concentrtions in the fetuses, neontes, nd wenlings were 4. 3G0. 2mmol/l (nz19 litters), 3. 9G0. 2mmol/l (nz12 litters), nd 8. 9G0. 2mmol/l (nz43 pups from 12 dms) respectively. Adult glucose concentrtions in the fsted stte were significntly less thn those in the fed stte nd were lso unffected y mternl tretment or sex of the offspring (Tle 2). Heptic glycogen content nd gluconeogenic enzyme ctivities Heptic glycogen content nd ctivities of G6Pse nd PEPCK were not ffected y sex of the offspring t ny of the ges studied (PO0. 05, ll cses). Mternl dex tretment influenced heptic glycogen content in the fetuses ut not in the other groups of offspring (Fig. 3A). In fetuses, heptic glycogen content ws highest in the dex-treted group nd lowest in the controls with intermedite vlues in the sline-treted group (Fig. 3A). A similr pttern of heptic G6Pse ctivity with mternl tretment ws oserved in the fetuses (Fig. 3B). However, G6Pse ctivity ws unffected y mternl tretment t ny of the postntl ges studied (Fig. 3B). In contrst, heptic PEPCK ctivity differed with mternl tretment t ll ges studied, lthough the specific effects of tretment vried t ech ge (Fig. 3C). In fetuses, heptic PEPCK ctivity ws significntly higher in the treted group thn in the untreted group, ut it ws not significntly different etween sline nd dex tretments (Fig. 3C). At irth, the sline-treted group hd lower PEPCK ctivity thn the other two groups, while in wenlings, PEPCK ctivity ws lowest in controls nd highest in the dex-treted group with intermedite vlues in the sline-treted group (Fig. 3C). In dults, heptic PEPCK Journl of Endocrinology (2010) 204,

6 Tle 2 Men (GS.E.M.) vlues of ody weight t the time of the glucose tolernce test nd tissue collection, frctionl growth rte (FGR) from irth to wening nd wening to 14 weeks, dominl ft content mesured y dul emission X-ry sorption (DEXA) scnning nd grvimetriclly, nd of plsm concentrtions of leptin, insulin, nd corticosterone t the time of tissue collection together with lood glucose concentrtions in the fed stte nd fter overnight fsting (sl) together with the mximum (mx) nd mximum increment (D mx) in lood glucose levels during the glucose tolernce test in mle nd femle dult offspring of untreted, control rt dms, nd those treted with sline or dex from dys 15 to 20 of pregnncy (nz5 8 mles nd femles offspring from four dms in ech tretment group) Tretment Control Sline Dexmethsone Sttisticl nlysis (P vlue) Mle Femle Mle Femle Mle Femle Tretment Sex Interction Body weight (g) At glucose tolernce 394G19 230G6 368G7 225G5 376G19 227G7 NS! NS At tissue collection 430G18 258G7 403G8 249G5 413G21 248G8 NS!0. 01 NS FGR (g/week per g) Birth wening 2. 93G G G G G G0. 21 NS NS NS Wening 14 weeks G G G G G G ! NS Ft content % DEXA scnning 29. 2G G G G G G ! NS Grvimetric 2. 9G G G0. 2, 2. 3G G G NS Leptin (ng/ml) 6. 75G G G G G G0. 45 NS! NS Insulin (ng/ml) 1. 86G0. 45, 0. 78G G G G G NS Corticosterone (ng/ml) 522G43 530G G21 608G67 360G53 591G91 NS NS Glucose (mmol/l) Fed 6. 4G G G G G G0. 1 NS NS NS Fsted Bsl 4. 8G0. 2* 4. 6G0. 1* 5. 0G0. 1* 4. 7G0. 2* 4. 6G0. 1* 4. 8G0. 1* NS NS NS Mx 12. 9G0. 4 D Mx 8. 0G G G G G G0. 9, 7. 8G0. 8, 13. 0G G G G NS NS NS NS For ech sex within row, vlues with different letters s superscripts re significntly different from ech other (P!0. 05, liner mixed model). *Significntly less thn the corresponding vlue in the fed stte (P!0. 01, pired t-test). Liner mixed model (NS, not significnt). Peritonel nd perirenl ft deposits. 324 K L FRANKO nd others. Glucocorticoid progrmming Journl of Endocrinology (2010) 204,

7 Glucocorticoid progrmming. K L FRANKO nd others 325 At ll ges studied, heptic protein content ws unffected y either mternl tretment or sex of the offspring (PO0. 05, dt not shown). Figure 3 Men (GS.E.M.) vlues of (A) glycogen content, (B) glucose-6-phosphtse (G6Pse) ctivity, nd (C) phosphoenolpyruvte croxykinse (PEPCK) ctivity of liver from the fetuses, neontes, wenlings, nd dult offspring of untreted control dms (Con, open columns) or dms treted with sline (Sl, stippled columns) or dexmethsone (Dex, striped columns) from dy 15 to dy 19 (fetuses) or dy 20 of pregnncy (ll other offspring). For the fetuses nd neontes, nz4 7 l for ech tretment group. For wenlings nd dults, nz14 16 individul offspring per tretment group with four dms per tretment. At ech ge, columns with different letters re significntly different from ech other (P!0. 02), while columns shring common letters re not significntly different from ech other (PO0. 05, liner mixed model). In (A), (B), nd (C), there were no significnt effects of sex of the offspring t ny ge studied (PO0. 05, liner mixed model). ctivity ws higher in the dex-treted group thn in the sline-treted group, ut neither of these vlues ws significntly different from tht in the controls (Fig. 3C). Adult glucose tolernce Adult glucose tolernce ws ffected y mternl tretment (P!0. 003) ut not y sex of the offspring (PO0. 05, Fig. 4). In ll nimls irrespective of sex, mternl tretment influenced the glucose concentrtions oserved 15, 30, nd 45 min fter glucose dministrtion (Fig. 4Ai). The mximum concentrtion nd increment in lood glucose differed with mternl tretment ut not with sex of the offspring (Tle 2). For ll nimls, the re under the glucose curve (AUGC) ws smllest for the sline-treted group nd significntly less in the sline-treted nimls thn in the dex-treted nimls with intermedite vlues in the controls (Fig. 4Aii). However, there ws n interction etween mternl tretment nd sex of the offspring in determining the time profile of the glucose concentrtion nd the res under the curve such tht the specific effects of tretment depended on sex of the offspring (P!0. 05, ll cses, Tle 2). In mles, glucose levels were significntly different with tretment 30 nd 45 min fter glucose dministrtion, nd AUGC ws significntly less in the sline-treted group thn in either of the other two groups (Fig. 4Bi nd ii). No significnt difference ws oserved in AUGC etween mle offspring of the control nd dex-treted dms (Fig. 4Bii). There were lso no significnt differences in the mximum concentrtion or increment in lood glucose with mternl tretment in mle offspring (Tle 2). In contrst, in femles, lood glucose concentrtions were significntly different with tretment t 15 nd 30 min, nd AUGC ws significntly greter in the dex-treted group thn in the other two groups (Fig. 4Ci nd ii). Unlike in mles, there ws no significnt difference in AUGC etween femle offspring of the control nd sline-treted dms (Fig. 4Cii). The mximum concentrtions nd increment in lood glucose in femles were lso significntly higher in the dextreted group thn in the control group in contrst to the mles (Tle 2). There were no significnt correltions etween AUGC nd current ody weight, postwening FGR, ody ft content (DEXA or excised), heptic glycogen content, or ctivities of G6Pse nd PEPCK when dt from ll the dults were comined (PO0. 05, ll cses). In mles, AUGC ws positively correlted to DEXA ft content (P!0. 01, nz23 offspring from 11 dms), ut not to ny of the other vriles (PO0. 05, ll other cses). In femles, AUGC ws positively correlted to postwening FGR (P!0. 041, nz22 offspring from 12 dms) nd ws unrelted to ny of the other vriles (PO0. 05, ll other cses). Discussion The results demonstrte tht dex tretment nd the stress ssocited with sline injection of rts during lte pregnncy Journl of Endocrinology (2010) 204,

8 326 K L FRANKO nd others. Glucocorticoid progrmming wening, ut only dex tretment led to significntly higher postwening FGR. The two tretments lso hd different effects on heptic glucogenic cpcity, prticulrly in fetl nd erly postntl life. Furthermore, reltive to controls, dult glucose tolernce ws improved y prentl stress in the mles ut not in the femles, while it ws impired in the femle offspring ut not in the mle offspring of the dex-treted dms. Since mternl corticosterone concentrtions were elevted in the sline-injected dms reltive to the other two groups, the current findings suggest tht overexposure to oth nturl nd synthetic glucocorticoids hs progrmming effects in utero, ut tht their specific ctions differ in sex-linked mnner in the rts. Thus, nturl glucocorticoids my not entirely mimic the progrmming effects of synthetic glucocorticoids s shown previously in dult sheep overexposed to glucocorticoids in utero during erly gesttion (Moritz et l. 2005). Figure 4 Men (GS.E.M.) vlues of (i) lood glucose concentrtions with respect to time nd (ii) the re under the glucose curve for (A) ll dult offspring irrespective of sex, (B) mle offspring, nd (C) femle offspring of untreted control dms (Con, open circles nd open columns, nz7 mles nd nz7 femles from four dms) nd of dms treted with sline (Sl, tringles nd stippled columns, nz8 mles nd nz8 mles femles from four dms) or dexmethsone (Dex, closed circles nd striped columns, nz8 mles nd nz8 femles from four dms) from dy 15 to dy 20 of pregnncy. For (i), significnt effect of mternl tretment P!0. 01 (liner mixed model with mternl tretment, sex of the offspring, nd time s fctors, where pproprite). For (ii), columns with different letters re significntly different from ech other (P!0. 01), while columns shring common letters re not significntly different from ech other (PO0. 05, liner mixed model). hve differentil effects on the growth nd glucose metolism of their offspring. These effects depend, in prt, on the ge nd sex of the offspring nd re relted to ft deposition nd the plsm concentrtions of insulin, leptin, nd corticosterone in the dults. Compred with untreted controls, mternl dex tretment reduced offspring ody weight in utero nd t irth, wheres the stress ssocited with mternl sline injection did not. Both tretments reduced pup ody weight during suckling nd for 4 weeks fter Journl of Endocrinology (2010) 204, Growth nd ody composition Dex dministrtion reduced mternl weight gin during the period of tretment nd restricted prentl nd erly postntl growth of the pups in line with previous findings in rts treted with glucocorticoids during lte pregnncy y injection, ingestion, nd continuous infusion (Smith & Wddell 2000, Sugden et l. 2001, Swolin-Eide et l. 2002, Scheepens et l. 2003, O Regn et l. 2004, Woods 2006). The reduced mternl weight gin during oth dex nd sline tretments in the current study ws due, in prt, to the reduced weight of the fetuses nd plcents (not shown), nd my lso hve reflected the differences in concentrtion of corticosterone nd other stress hormones ssocited with injection, such s the ctecholmines. It ws not relted to decresed food intke. However, reduced growth of mternl tissues, such s the mmmry glnds, my hve compromised lcttion reltive to untreted dms, leding to lower pup weights during suckling. When the lcttionl constrint ws lifted t wening, there ws period of ctch-up growth in oth treted groups so tht ody weight ws not significntly different etween offspring of treted nd untreted dms from 8 weeks of postntl ge. Similr ctch-up growth fter wening hs een oserved in previous studies of mternl restrint stress nd dex tretment during rt pregnncy (O Regn et l. 2004, 2008, D mello & Lin 2006). Indeed, the degree of ctch-up growth ppers to depend on litter size nd is complete when litters re culled to eight pups, s in the present study, ut not with lrger pup numers (O Regn et l. 2004, 2008, Wyrwoll et l. 2006, 2008). Tken together, these oservtions suggest tht nutritionl constrint during suckling my contriute to the dult metolic outcomes ssocited with prentl stress nd dex exposure. The chnges in prentl nd erly postntl growth induced y mternl dex nd sline tretments were ccompnied y ltered ft distriution in the dult offspring. In the dextreted group, the mount of excised peritonel nd perirenl ft reltive to totl ody weight ws reduced, prticulrly in

9 Glucocorticoid progrmming. K L FRANKO nd others 327 the mles, consistent with the reduction in epididyml ft mss oserved previously in dult mles exposed to dex in utero (Sugden et l. 2001, Clesy et l. 2003). However, reltive to untreted controls, there ws no pprent effect of dex tretment on ft content of the dominl region mesured y DEXA scnning. The disprity etween the ft content mesured grvimetriclly nd tht mesured y DEXA scnning in the present study suggests tht ft distriution in the dult offspring is ltered y mternl dex tretment with decrese in peritonel nd perirenl ft nd n increse in sucutneous nd other dominl ft deposits reltive to untreted controls. In contrst, prentl stress induced y mternl sline injection reduced dult DEXA ft content compred with controls in prllel with comined peritonel nd perirenl ft weight, gin to greter extent in mles thn in femles. Offspring of the sline-treted dms, therefore, pper to hve more proportionte reduction in diposity thn tht oserved in the dex-treted group. However, there ws no influence of mternl tretment on plsm leptin concentrtions in the dult offspring, despite the differences in ft deposition nd the positive correltion oserved etween DEXA ft content nd plsm leptin levels when ll the dt were comined regrdless of mternl tretment or sex of the offspring. These findings re consistent with previous oservtions tht postntl hyperleptinemi does not develop in rts exposed prentlly to dex until t lest 3 months fter irth irrespective of the mternl route of steroid dministrtion (Sugden et l. 2001, Clesy et l. 2003, Wyrwoll et l. 2006). Differences in dult ody ft content nd distriution progrmmed in utero my, therefore, precede chnges in circulting leptin concentrtions in the rts. The explntion for the greter sensitivity of mles thn of femles to tretment-induced chnges in ft deposition remins uncler, ut it my e relted to the higher ft content of the mles overll. The percentge ft content of the dult mle nd femle rts mesured y DEXA scnning in the current study ws similr to those reported previously for 6-month-old Wistr rts using the sme methodology (Wyrwoll et l. 2006). When ll the current dt were comined, ft content mesured y DEXA scnning ws inversely relted to the plsm corticosterone concentrtions. Since corticosterone tends to moilize ft stores during stressful conditions (Bouchrd et l. 1993), mles my hve more ft thn femles etween 14 nd 15 weeks of ge ecuse they hve lower corticosterone concentrtions. Mles lso hd higher levels of insulin thn femles in the present study, which would tend to fvor ft deposition, lthough insulin concentrtions were not directly correlted to the DEXA ft content of the dult offspring in either sex lone or when the dt from oth sexes were comined. The higher concentrtions of insulin nd leptin nd lower concentrtions of corticosterone oserved in mles thn in femles etween 14 nd 15 weeks in the present study re consistent with previous findings of dult rts t older ges (Sugden et l. 2001, Wyrwoll et l. 2006, 2008). Heptic glucogenic cpcity Both mternl tretments ltered the heptic glucogenic cpcity of mle nd femle offspring reltive to untreted controls. The most pronounced effects of tretment were oserved in the fetuses, which suggest tht heptic glucogenic cpcity in utero is glucocorticoid sensitive in rts s occurs in other species ner term (Fowden et l. 1998). At irth, heptic glycogen content nd G6Pse ctivity were similr in the three groups of neontes, while heptic PEPCK ctivity ws lower in the neworn pups of the sline-treted dms thn in the other two groups of neontes. In the slinetreted group, dily exposure to rised corticosterone concentrtions vi mternl stress response to injection my hve delyed the ctivtion of the fetl HPA xis. In contrst, in the dex-treted group, withdrwl of the more potent synthetic steroid my hve lifted negtive feedck on the mternl nd fetl HPA xes nd llowed rpid reound in nturl corticosterone concentrtions (Fowden et l. 1998). At wening, the effects of mternl tretment with dex, ut not with sline, were still evident with rised PEPCK ctivity, ut y etween 14 nd 15 weeks, neither tretment hd significnt influence on the heptic glucogenic cpcity reltive to untreted controls. These oservtions suggest tht chnges in PEPCK ctivity progrmmed in utero re more evident t times of mjor chnges in nutrition t irth nd wening. However, heptic PEPCK ctivity ws higher in the dult offspring of the dex-treted dms thn in those of the sline-treted dms s reported previously for offspring of dex- nd vehicle-injected dms (Nyirend et l. 1998, 2006). This glucocorticoid progrmmed upregultion of dult heptic PEPCK ctivity is ssocited with incresed expression of heptocyte nucler fctor 4, known trnscription fctor for the Pck2 promoter (Nyirend et l. 2006). In the current study, the difference in heptic PEPCK ctivity etween offspring of the sline- nd dex-treted dms ws oserved in oth dult mles nd femles, wheres previously, this effect ws oserved only in mles (Nyirend et l. 1998, O Regn et l. 2004). This discrepncy etween studies my e due to differences in offspring ge or dose of dex dministered to their dms (Nyirend et l. 1998, 2006, O Regn et l. 2004). Overll, the current findings suggest tht the heptic glycogenolytic nd gluconeogenic pthwys hve differentil sensitivities to progrmming in utero, nd tht heptic PEPCK ctivity is prticulrly prone to control y the developmentl environment. Glucose metolism Neither mternl tretment ffected sl glucose concentrtions t ny ge studied. In previous studies, mternl restrint stress hs een shown to elevte fsting glucose concentrtions in dult mle offspring t 6 nd 24 months ut not t 3 4 months of postntl ge (Vllée et l. 1996, Lesge et l. 2004, D mello & Lin 2006). Similrly, mternl dex tretment is ssocited with fsting hyperglycemi in Journl of Endocrinology (2010) 204,

10 328 K L FRANKO nd others. Glucocorticoid progrmming 6-month-old mle offspring in some ut not in ll previous studies depending on the route of mternl dministrtion (Sugden et l. 2001, Drke et l. 2004, O Regn et l. 2004). In the current study, oth tretments influenced glucose tolernce of the dult offspring, lthough in different wys depending on sex of the offspring. In mles, mternl sline injection improved glucose tolernce, mesured s AUGC, while mternl dex tretment hd little pprent effect on this mesurement reltive to untreted controls. The differing AUGC with tretment ws lrgely due to differences in glucose clernce s the pek glucose concentrtion ws similr in the three mle groups. The cuse of these differences in clernce remins uncler, ut glucose tolernce ws est in the sline-treted group, which hd the highest plsm insulin concentrtion. There ws lso positive correltion etween mle AUGC nd DEXA ft content, which suggests tht dipose tissue-derived fctors reducing insulin sensitivity my lso hve contriuted to the reltive glucose intolernce of the ftter mle groups (Stocker et l. 2005). In contrst, femle glucose tolernce ws unffected y mternl sline injection, ut it ws impired y dex tretment reltive to untreted controls. The difference etween femle AUCG with tretment ws primrily due to incresed pek glucose concentrtions in the dex-treted group. Since femle ft content ws unffected y tretment, the glucose intolernce of femles tht were exposed to dex in utero my reflect poor first-phse insulin secretion or n incresed rte of glucose sorption from the peritonel cvity reltive to the other groups. In ddition, there my e sex-linked differences in the response of glucoregultory hormones, such s insulin, corticosterone, nd ctecholmines, to i.p. injection of glucose, which contriute to the oserved differences in dult glucose tolernce with mternl tretment. In the present study, glucose tolernce ws worse in the dex-treted group thn in the sline-treted group in oth sexes. The reson for this tretment difference ppered to depend on sex of the offspring with improved glucose clernce in the sline-treted group of mles ut impired glucose tolernce in the dex-treted group of femles reltive to the untreted controls. In ddition, heptic PEPCK ctivity ws highest in dult offspring of the dex-treted dms, irrespective of sex. Using n orl glucose tolernce test, similr impirment of glucose tolernce coupled with high heptic PEPCK ctivities hs een oserved in 6-month-old mle offspring ut not in femle offspring of rts given dex y the sme route for the sme period of gesttion s in the current study compred with vehicle-treted controls (O Regn et l. 2004). The resons for the differing responses of dult femles prentlly exposed to dex etween the current nd erlier studies re uncler, ut they my e relted to differences in dex dose, vehicle composition, route of glucose dministrtion, stge of estrous cycle, or offspring ge t study (Nyirend et l. 1998, O Regn et l. 2004). However, tken together, these studies suggest tht enhnced heptic glucose production my lso e Journl of Endocrinology (2010) 204, contriutory fctor to the glucose intolernce of dult rts prentlly exposed to dex (Seckl 2008). Anormlities in heptic glucose production ssocited with elevted PEPCK ctivity hve lso een oserved in mle offspring of rts tht were deprived of protein during pregnncy (Burns et l. 1997, Desi et l. 1997). Overll, the differences in intruterine progrmming oserved etween mternl dex nd sline tretments pper to e relted, in prt, to differences in ody weight in fetl nd erly postntl life nd to ltered ft content nd distriution in the dult offspring. These differences in progrmming hve implictions for evluting studies using control procedures tht rise endogenous glucocorticoid concentrtions. This my explin, in prt, the differences in glucocorticocoid progrmming oserved in previous studies using differing routes of steroid dministrtion nd, hence, control procedures (Sugden et l. 2001, Clesy et l. 2003, Wyrwoll et l. 2006). However, since glucocorticoids lter prentl development of mny tissues involved in postntl glucoregultion (Fowden et l. 1998), these hormones my e common fctor linking poor fetl growth during suoptiml conditions to developmentl progrmming of postntl glucose metolism, prticulrly s mny of the nturl nd experimentl conditions leding to IUGR increse glucocorticoid exposure in utero. Declrtion of interest The uthors declre tht there is no conflict of interest tht would prejudice the imprtility of the reserch reported. Funding This reserch ws funded y the Gtes Cmridge Trust. Acknowledgements The uthors would like to thnk Prof. Gordon Smith for his help with the sttisticl nlyses, the stff of the niml house for their dily cre of the nimls, nd the Gtes Cmridge Trust for funding the PhD studies of KLF. References Brznges A, Pizz PV, Le Mol M & Mccri S 1996 Mternl glucocorticoid secretion medites long-term effects of prentl stress. 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Dietologi Poore KR & Fowden AL 2004 The effects of irth weight nd postntl growth ptterns on ft depth nd plsm leptin concentrtions in juvenile nd dult pigs. Journl of Physiology Scheepens A, vn de Wrenurg M, vn den Hore D & Blnco CE 2003 A single course of prentl etmethsone in the rt lters postntl rin cell prolifertion ut not poptosis. Journl of Physiology Seckl JR 2008 Glucocorticoids, developmentl progrmming nd the risk of effective dysfunction. Progress in Brin Reserch Smith JT & Wddell BJ 2000 Incresed fetl glucocorticoid exposure delys puerty onset in postntl life. Endocrinology Stocker CJ, Arch JRS & Cwthorne MA 2005 Fetl origins of insulin resistnce nd oesity. Proceedings of the Nutrition Society Sugden MC, Lngdown ML, Munns MJ & Holness MJ 2001 Mternl glucocorticoid tretment modultes plcentl leptin nd leptin receptor expression nd mterno-fetl leptin physiology during lte pregnncy, nd elicits hypertension ssocited with hyperleptinemi in the erly-growth-retrded dult offspring. Europen Journl of Endocrinology Swolin-Eide D, Dhlgren J, Nilsson C, Alertsson Wiklnd K, HolmängA& Ohlsson C 2002 Affected skeletl growth ut norml one minerliztion in rt offspring fter prentl dexmethsone exposure. Journl of Endocrinology Vllée M, Myo W, Mccri S, Le Mol M & Simon H 1996 Long term effects of prentl stress nd hndling on metolic prmeters: reltionship to corticosterone secretion response. Brin Reserch Wrd IL & Weisz J 1984 Differentil effects of mternl stress on circulting levels of corticosterone, progrsterone nd testoterone in mle nd femle rt fetuses nd their mothers. Endocrinology Woods L 2006 Mternl glucocorticoids nd prentl progrmming of hypertension. Americn Journl of Physiology. Regultory, Integrtive nd Comprtive Physiology 291 R1069 R1075. Wyrwoll CS, Mrk PJ, Mori TA, Puddey IB & Wddell BJ 2006 Prevention of progrmmed hyperleptinemi nd hypertension y postntl dietry u-3 ftty cids. Endocrinology Wyrwoll CS, Mrk PJ, Mori TA & Wddell BJ 2008 Developmentl progrmming of dult hyperinsulemi, incresed proinflmmtory cytokine production, nd ltered skeletl muscle expression of SLC2A4 (GLUT4) nd uncoupling protein 3. Journl of Endocrinology Received in finl form 2 Decemer 2009 Accepted 16 Decemer 2009 Mde ville online s n Accepted Preprint 16 Decemer Journl of Endocrinology (2010) 204,

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