Two hundred and seventy samples from 24 subjects involved in 3 bedrest studies and from 3 subjects involved in Spacelab Mission Development Test 3 were assayed for erythropoietin (Ep), in an in vitro fetal mouse liver cell assay, and for ferritin using a commercially available immunoradiometric assay kit. No trends or significant changes in serum Ep were observed. Serum ferritin concentrations tended to increases slightly during the 'missions', reflecting a redirection of iron from the suppressed erythron into iron stores

Dunn, C. D. R.

Hen, J. P.

English

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,C - I t 
1. 
C. D. R. Dunn, Pn.D. 
J. P. Chen, Ph.D. 
. .- 
Final Report: HAS 9-15164 
Date : July 1980 
Contract T i t l e :  "Changes i n  erythropoietin levels 
during space f l i g h t  or  space f l igh t  
simulation" 
The Department of Medical Biology 
The University o f  Tennessee Memorial Research Center 
1924 Alcoa Highway 
Knoxvi 1 1 e , TN . 37920 
{SIASP-CB-163591) CBABlGSS IN EfiYTiiHOPOI E l i Y  N8U-33385 
U V E L S  DUaIUG SPACE P L I G H T  Oii SPACE FLIGHT 
S I l U L A T i O Y  Final T e c h n i c a l  Beport 
( Z e n m e s s e e  Unir,) 8 p HC A02/MF A01 Unclas 
CSCL 36P G3/52 34113 
The f i n a l  Technical Report on cont rac t  NBS 9-15164 attempts t o  sumnarize 
the major achievements o f  the work c a r r i e d  out  s ince October 1976. It i s  by 
way of review o f  t he  data - de ta i l ed  r e s u l t s  can be found i n  our qua r te r l y  
repor ts  and i n  the progress repor ts  submitted as p a r t  o f  our cont rac t  renewals. 
1. Space F l i q h t  Simulat ion Studies: Two hundred and seventy 
samples from 24 subjectk involved i n  3 bedrest studies and from 3 subjects 
. .. 
involved i n  Spacelab Mission Development Test I 1 1  were assayed f o r  erythro-  
p o i e t i n  (Ep), i n  an -- i n  v i t r o  f e t a l  mouse l i v e r  c e l l  assay, and f o r  f e r r i t i n  
using a commercially-avai l a b l e  immunoradiometric assay k i t .  Despite a small 
b u t  s i g n i f i c a n t  decrement i n  red  c e l l  mass i n  a l l  subjects no trends o r  
s i g n i f i c a n t  changes i n  serum Ep were observed. On the o ther  hand, serum 
f e r r i  t i n  concentrations tended t o  increase s l i g h t l y  dur ing the "missions" 
perhaps r e f l e c t i n g  a red i rec t i on  o f  i r o n  from the suppressed erythron i n t o  
i r o n  stores. 
2. Evaluat ion c f  I n f l i g h t  Blood Co l lec t ion  Tubes ( IBCT)  A considerable 
amount of e f f o r t  was d i rec ted  a t  determining the s u i t a b i l i t y  o f  the proposed 
IBCT t o  provide serum f o r  Ep and f e r r i t i n  assays. Given the l i m i t e d  nunber 
of f l i g h t  tubes avai lable, uncer ta inty  as t o  the exact temperature p r o f i l e  
t o  which the samples w i l l  be exposed dur ing f l i g h t  and the mechanical dys- 
funct ion o f  many o f  the tubes supplied t o  us, any conclusions must be ten ta t i ve .  
The data we have been able t o  c o l l e c t  do no t  suggest any problems w i l l  be 
encountered w i t h  the  proposed IBCT i n  so f a r  as prov id ing  mater ia l  f o r  Ep 
and f e r r i  ti n assays are concerned. 
3, Developmerit o f  a trtethod for Ile~iiog'lobi n p5G determi nat'i ons o ~ t  s tot-eti 
blood: S h i f t s  i n  the  hemoglobin oxygen d issoc ia t ion  curve ( character ized by 
-
the p50) have been theorized t o  be involved i n  the "anemia" o f  space f l i g h t .  
2 
An invest igat ion o f  hemoglobin p50 s h i f t s  during space f l i g h t  .is probleust ical  
because o f  the l a b j l i t y  of t h i s  component. We have deRonrtrated t ha t  the 
pW i n  blood stored a t  +b°C i n  heparinized micro-hematocrit tubes i s  stable 
for  a t  l eas t  7 days. Therefore, on the basis of our resu l ts  and provid ing 
the storage conditions can be sat is f ied (and the temperature and storage 
container are qu i te  c r i t i c a l  ) an evaluation of hemglobin p50 sh i f t s  during 
space f l i g h t  would Jkem feasible. 
4. Documentation: I n  observance o f  our contractural requirements the 
fo l lowing two documents were submitted t o  the Technical Honitor i n  Kay 1979; 
a. Hormonal Control o f  Erythropoiesis 
b. A Comparison o f  Erythropoiet in Assays w i t h  Par t icu lar  Enphasis 
on t he i r  S u i t a b i l i t y  f o r  Investicjations i n t o  the "Aneaia" o f  Spaceflight. 
5. Animal and Computer Studies i n t o  the "Anemia" o f  Space f l i g h t :  
a. Dehydrated Mice: We have shown tha t  mice deprived o f  water have 
i n  comon wi th ken i n  space hemoconcentration, secondary t o  a p l  asna volume 
reduction, and a negative energy balance. Vany studies, supported by 2 
mathematical model for the regulat ion of erythropoiesi s were undertaken t o  
elucidate the re l a t i ve  importance o f  these two parameters i n  p roduc in~  the 
resu l t ing anemia. These investigations suggested that ,  i n  dehydrated pice, 
the major cause of the a n e ~ i a  (expressed as an absoliite volume of red c e l l s )  
was the negative energy balance w i th  hemoconcentration playing a minor ro le .  
Perhaps the anemia represents an "adaptation" t o  a smaller body i gh t  as 
the red c e l l  mass, when expressed as ml/gm body weight, was es5 i a l l y  
normal. 
Despite the superf i cia1 simi 1 a r i  t i e s  o f  dehydrated mice and men 
i n  space, there i s  a considzrable "credi tab i  1 i t y  gap" between a four-? egged, 
3 
20 gm anisurl i n  l g  and a two-legged, 70 ke a n i m l  i n  0 g. To, a t  least  
par t ia l ly ,  avercone th is  gap experiments i n  ma1 1 primates were undertaken: 
b. Dehydrated mrslosets: Studies i n  dehydrated mirumsets were 
undertaken proy .: r dory t o  nor& on squirrel  monkeys. C q l e t e  water depri- 
vation of mamsets resulted i n  erythropoietic chaees qui te di f ferent frm 
those observed i n  sice under a s imi lar  experimntal protocol. The l iat i ted 
amount o f  data srrggeSted that i f  dehydration affected erythropoiesis a t  a l l  
i n  marunsets i t  was t o  stimulate, nor inh ib i t ,  red c e l l  production. Of 
revelance t o  spzce f l i gh t  was a s h i f t  i n  the hemoglobin p53 o f  earnmet 
blood dur i  fig dehydration. 
c. Squirrel monkeys : Under another NASA contract, Pr. M. hore-Ede 
a t  Harvard iYedica1 School has s h m  that squirrel  inonkeys exposed t o  lower 
body posi t ive pressure ( LBPP) exhib i t  endocrine and electrolyte changes 
simi lar t o  t h q e  seen i n  men during space f l i gh t .  Towards the end of our 
contract perioil, a small colony of squirrel  monkeys was established t o  
investigate the effects o f  LBPP on erythropoiesis. I n  th i s  facet o f  our 
work, the time was spent obtaining the necessary animals and equipment and 
training and catheterizing the monkeys. Erythroproieti c research ni 11 com- 
mence a f te r  the monkeys, necessary equipment and NASA funds have been 
relocated a t  the Baylor College o f  Medicine. 
6. Nodifications o f  Ep assays: Under th is  contract our routine i n  vivo 
and -- i n  v i t r o  assays were modified and/or simplified to  take in to  account 
recent methodological advances. Two studies, pa r t i a l l y  supported by NASA, 
d ~ m n r t r s t e d  a c o r r ~ l a t i o n  between EP t i t e r s  detected with an i n  vit.ro fe ta l  
-- 
mouse 1 iver  ce l l  assay and those detected i n  a standard, -- i n  vivo, ex-hypoxic 
mouse system. 
7. #level-t o f  new Ep assays: A l l  current assays f o r  Ep require 
rrhole aninxiis, animal t issue aftdfor sophisticated rad ia t ion counting devices. 
As suck thcy a n  probably not  su i tab le  f o r  use i n  a space fl ight environnent. 
Under tht aegis o f  t h i s  contract considerable progress was made towards the 
d e w l o p e n t  of an Ep assay for potent ia l  i n f l i g h t  use. This system depends 
on the a b i l i t y  o f  Ep - 'containing materials t o  prodace "rockets" when sub- 
. -- 
jetted t o  electrophoresis i n  rnagar ~ e l  containing wheat germ l e c t i n  (N'X). 
The potent ia l  use o f  such an assay was i den t i f i ed  but problems of spec i f ic i ty  
due t o  i q u r e  Ep and UGL prevented a d e f i n i t i v e  resolution. Simi lar  problems 
were encountered i n  the development o f  a, unique, two-si t e  immrnoradicmtric 
assay using UGL and Ep-specific, radio-iodinated antibodies. 
8. Publications: 
a. Dunn, C. 0. R., Preston, J., and Lange, R. 5. Serum erythropoiet in 
t i t e r s  during bedrest. I n  Final Report. Johnson Space Center - Methodist 
Hospital 28-Day Bedrest Simulation o f  Skylab. Volum 11. Johnson, P. C. 
and M i  t che l l  , C. (Eds. ). Lyndon B. Johnson Space Center, pp. D60-D-83, 1977. 
b. Dunn, C. D. R. The e f f ec t  o f  dehydration on erythropoiesis 
i n  mice: Relevance t o  the "anemia" o f  space f l i g h t .  Aviat. Space and Environ. 
Md. , 49: 990-993, 1978. 
c. Kimzey, S. L., Johnson, P. C., and Dunn, C. D. R. The influence 
of spaccflight on erythrokinetics i n  man: SMD 111, Experiment 68. I n  Final 
Report. Spacelab Mission Development Test I 1  I, Volume I Scien t i f i c  Experi- 
ments. Lyndon B. Johnson Space Center, JSC-13950, pp. 309-345, 1978. 
d .  Dunn, C. D. R., and Lange, R. D. L r J t i ~ t o i d  rsgulii'ioi+y f hc tu r s .  
Correlation o f  i n  vivo and i n  v i t r o  detectable t i t e r s .  Blood, 52:1238-1242, 
1978. 
c. Oum, C. 0. R., md Lange, R. 0. Etythmpoietic ef fects of 
spaceflight: Further studies in  a p t c r l t i a l  animal model. Acta Astn#rautica, 
6:-752, 1979, 
f. Cham, C. 0. R., and tk, W. The s t a b i l i t y  o f  erythroid s t i m l a t i n g  
a c t i v i t y  i n  norsal huuan senr .  Bioches. M,, 21:190-195, 1979. 
9. Rinn, C. D. R., Lange, R. O., and 3cl!ws, J. B. Evidence that  
. -- 
the fetal  mouse l i v e r  c e l l  assay detects Erythroid Regulatory Factors (ERF) 1 
not determined w i t h  a standard i n  vivo assay. Exp. ifetrrat., 7:519-523, 1979. 
h. Dunn, C. D. R. The effect o f  food and water res t r i c t i on  on 
erythropoiesis i n  mice: Relevance t o  the anemia o f  spree flight. Amr. J.  
Physi 01. , 238: R301 -R305, 1980. 
i .  Dunn, C. 0. R., and Lange, R. D. Erythropoietin: Assay and 
Characterization. In: "Topical Reviews i n  Henatolo3". Roath, S. (Ed. ). 
John Hright and Sons Ltd. , Br is to l  . I n  Press. 
j. Dunn, C. D. f, , and Smith, .L. N. The effect of dehydration on 
erythroid progenitor ce l l s  i n  mice. Exp. Hemtol . , 8:620-625, 1980. 
k. Dunn, C. D. R., and Lange, R. D. Erythropoietin t i t e r s  i n  
normal human serum. An appraisal o f  assay techniques. Exp. Hemat. , 8: 
231 -235, 1980. 
1. Leonard, 3. I., Kimzey, S. L., and Dunn, C. D. R. Dynamic 
regulation o f  erythropoiesis : A computer model o f  general appl icabi 1 i ty. 
Exp. Hemat. , I n  Press. 
m. Dunn, C. D. R., Smith, L. N., Leonard, 3. I., Andrews, R. B., 
and Lange, R. D. Anilia1 and cori;puteim ;;ves';igstjon; f c to  the mu,jne re;l;:rtsc 
t a  chronic hypoxia. Exp. Hemat., I n  Press. 
a. Omm, C. 0. R.,- a d  T m t ,  D. The e f f e c t  of parathyroid h m m e  
m mythropaiesis i n  smm-fme cultures o f  feta l  muse l i v e r  cel ls .  Subeitted. 
o. Dlan, C. D. R., Leamrd, 3. I . ,  and Kimzey, 5. 1. l n t e r a c t i w ~  
of aniaal and c o q u t e r  lodels i n  invest igat ions o f  the 'anemia' o f  space f l i g h t .  
In preparation. 
9. Presentations bt Keetings: 
. 0- 
a. Dunn, C. D. R., Preston, J. P., Lange, R. 0-. , and Kisuey, S. L. 
Serum erythropoiet in leve ls  during bedrest. Presented a t  the 48th Annual 
Sc ien t i f i c  W t i n g  o f  the Aerospace Medical Association. Las Vegas, 1977. 
b. ikinn, C. D. R. Erythropoiesis i n  mice w i th  absolute and r e l z t i r e  
increases i n  red c e l l  m s s  (WC~). Proceedings o f  the 7th Annual Wet ing  o f  
the Internat ional  Society f o r  Experimental Hmatology. Chicago. Exp. 
Hemat., 6 (Suppl. 3):57, 1978 (Abstract). 
c. Dunn, C. D. R., and Lange, R. D. The "anemia" o f  space f l i gh t .  
Some considerations from a potent ia l  animal model. Proceedings o f  the 21st 
Annual Meeting o f  the American Society o f  Heniatology. New Orleans, La. 
Blood, 52 (Suppl . 1 ) : 384, 1978 (Abstract ) . 
d. Dunn, C. D. R., and Lange, R. D. Erythropoiet i  c effects of space 
f l i g h t  studied i n  a potent ia l  animal model. Proceedings o f  the 50th Annual 
Sc ien t i f i c  Meeting o f  the Aerospace Nedical Association, Washington, D. C., 
pp. 14-15, 1979 (Prepr int) .  
e. Leonard, 3 .  I., Dunn, C. D. R., and Kimzey, S. L. Computer 
simulation o f  ery thropoie t ic  suppression i n  a potent ia l  animal model for  
space f l i g h t .  Procc.cLSrig: af t h ~ .  5O:i; ?,iiiiii~l S c i c n t i  f i c  I-lceting o f  tk.2 
Aerospace Medical Association, Washington, D.C., pp. 16-17, 1979   reprint). 
f. aaA, t. 0. R., a d  Lurgc, R. D. Thc t t y t h r o ~ o i e t i c  effects 
ef rg#c f l ight studied in  a potential mi=\ rrdel. Proceedings o f  the 
8 t h  kw#lal Weeti- o f  the International Society f o r  E x p e r i m t a l  Hematology, 
fbtteivlam, Exp. ilerat. 7 (Suppi. 6):37, 1979 (Abstract). 
g. Smith, L. PI., and i h n ,  C. 0. R. The e f fec t  o f  dehydration on 
erythmid progenitor cql ls.  The Proceedings o f  the Annual Sc ient i f ic  M t i n g  
o f  the Sotri;heas^rem.Sectior~ o f  the Society f o r  Experitmental Biology and 
Y?iicine, Oak Ridge, V~lume 4, Abstract 814-5 (1979). 
h. Wlnn, C. D. R., and Trent, C. kdu la t i on  o f  erythropoiesis 
by parathyroid hormone (PTH) i n  serum-free cultures o f  fe ta l  mouse l i v e r  
cel ls.  Proceedings o f  the 9th Annual fleeting o f  the International Socicty 
fo r  Experimntal Hematology, Dallas, Ext. Hemat., 8 (Suppl . 7):126, I980 
(Abstract). 


Changes in erythropoietin levels during space flight or space flight simulation

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