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From www.bloodjournal.org by guest on August 9, 2017. For personal use only. Hepatic Erythropoietin Production Lead-poisoned By J. C. Extrar.nal production erythropoietin creased above normal after renal NEMIA count ing. and in VARIOUS 1. J. Mahlmann poisoned rats production OF inhibition and and either immediately nephrectomy. Extra- erythropoietin A Rat is in- in lead-injected to hypoxia or 1 day after exposed Schooley in the rats the is actinomycin D sensitive, site of production of the hormone in normal or anephric rats is the liver. major extrarenal or activation lecid-poisoneci lead- degrees of severity occurs following This anemia is usually hypochromic increased red cell hemolysis. These with an changes of several synthesis, the transport in erythroid enzymes involved in heme an ofiron, as well as changes in the erythrocyte differentiation and maturation has also been ing also inclusion results bodies in renal are found The importance of erythropoiesis well established, tubular in the dysfunction, tubular lining functioning renal and cells tissue lead interference for the an with membrane.1 noted.2 Lead characteristic of rats.3 by the production or activation of the as is the finding that extrarenal poison- increased reticulocyte are attributed to A defect poison- intranuclear regulation hormone erythropoietin of normal erythropoietin production is occurs.4 Evidence will be presented that in the lead-poisoned rat (1) extrarenal erythropoietin production is increased, and (2) the liver is necessary for extrarenal erythropoietin production to occur. AND MATERIALS All experiments nephrectomy using the Rats 5 hr. before another was exposed to a allowed to rats was collected the serum was and were were Blood bled g. Bilateral performed (Metofane, 22,000 of rats 320-360 (80#{176},,)was weighing hepatectomy methoxyflurane altitude operated ft. clot, using simulated rats Partial hepatectomized of similarly to 22,000 Sprague-Dawley previously.5 Anderson6 of anephric group male ft (P02 exposed (1.5 from removed. 67 to ml/ the Pitman-Moore) torr) w) from hr. In 52 torr) immediately aorta serum 5 ft (P02 100 g body abdominal The for 28,000 under two ether three rats pooled. Lead acetate mg/kg 0.5 and Higgins a 5-hr exposure anesthesia, was of a group and using as described were experiment, for performed performed procedure anesthesia. one were was METHODS body g/g dissolved wt body lyophilized, wt. and From body serum samples All was the Lawrence dextrose mM/kg restored Erythropoietin Calif in 5,, (0.105 to volume assayed using Berkeley (25 mg/mI) were with saline before the 7-day post Laboratory. injected D was dialyzed against intravenously injected several at a dose intravenously changes of 40 at a dose of of distilled water, mouse.5 One milliliter bioassay. CO Donner female LAF1 Laboratory. /JAX University of Califrnia. Berkeley, 94720. Submitted May /5, /973; revised A ugust 10. /973; Work done under the auspices of the United States Supported J. C. by the Schooley, Laboratory. Lawrence University Radiation © 1974 Blood, was wt). Actinomycin by Grune United States Ph.D.: Senior Atomic of (‘alifornia. Laboratory, & Stratton, Vol. 43, No. 3 (Morch), Energy Research Berkeley. Donner accepted A tonzic August Energy 27. /973. Co,nmi.s.sion. Commission. Physiologist. Calif Laboratory, Lawrence L. J. University Radiation Mahlmann, of (‘alifornia. BA.: Laboratory. Research Berkeley. Donner Associate. (‘a/if Inc. 1974 425 From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 426 SCHOOLEY of test 22 serum was 26 g. The iron incorporated body weight. reference are subcutaneously. expressed in 72 hr that the the increase oferythropoietin in per blood using radioiron was cent made in six-eight error of was the Reference in the MAHLMANN mice the to 72-hr be 59Fe assay radio7 of the uptakes Preparation plethoric weighing injected assumed from International incorporation injected which were the assayed standard ± volume, of erythropoietin prepared in the sample mean calculated of units curve Each as the into Estimations to a standard assumed result injected results AND by (IRP). mice was It is a direct sera. RESULTS The effect of lead, operations, on exposure, production nephrectomy nephrectomy in Fig. hormone by times greater rats than 3 compared to (group exposure Hepatectomy liver to controls the is 4.5 nephrectomy does in the as a result before of’erythropoietin or hepatectomy as a result 1. It is clear that of the or both a 5-hr total of the of rats not normal rat injected with 5 HRS the does exposure HYPOXIA. 4), increase hypoxic not 22.000 to hypoxia injected with whereas, serum alter (group lead AT exposed in rats 1 day injection the lead (group of hormone a 5). produced 1), but hypoxic after before without level to the removal exposure of sig- FEET DAYS GROUP of amount before when lead is to 2). The immediately lead I day erythropoietin 6 compared hypoxic production as a result of a hypoxic exposure, is not altered before the 5-hr hypoxic exposure (group I compared of hypoxic 1 day production is compared of erythropoietin, injected 1 day the injected the 72-HR I.R.P. 59Fe UPTAKE 1 SAMPLE 11 2[ UNITS! ml SERUM 27 ±0.83 1.9 25 ±1.5 1.9 ±0.82 0.22 15 ±1.7 1.0 0.42 ±0.08 ND 28 ±1.2 1.9 17 ±2.7 1.0 0.36 ±0.04 ND 0.68 ±0.17 ND A Pb 3 __________________ 7.3 A NEPHRECTOMY I El A Pb A NEPHRECTOMY 1 5 A SAMPLE Apb V J::.:.:.:.: 61 A HEPATECTOMY El 8 A Pb A HEPATECTOMY 1 El I A Pb Siandard error A HEPATECTOMY & NEPHRECTOMY A HEPATECTOMY & $EPHRECTOMY of ihe mean Fig. 1. A comparison of the production of serum erythropoietin before a hypoxic exposure. Six-eight mice per group, no detectable injected controls. in rats receiving (ND) difference lead from 1 day saline- From www.bloodjournal.org by guest on August 9, 2017. For personal use only. HEPATIC ERYTHROPOIETIN 427 PRODUCTION HYPOXIA. 5 HRS AT 22.000 FEET DAYS 72.HR GROUP’ 59Fe L:;;: A B NEPHRECTOMY A NEPHRECTOMY A C NEPHRECTOMY A NEPHRECTOMY A I A Pb HEPATECTOMY ±O.06 ND i::::I 8.2 ±0.67 0.25 ji#{149}:.1 1.4 ±0.18 0.86 ±0.10 ND 0.77 ±0.08 ND AcE A 1 E 0.05 < A EI A Pb ml SERUM 0.68 A [ 0 UPTAKE UNITS! A I A Pb I.R.P. A Apb SAMPLE Standard Fig. before injected error of the mean 2. A comparison of the production a hypoxic exposure. Six-eight mice of serum erythropoietin per group, no detectable lead from 2 days saline- controls. nificantly decreases A combination the amount of hormone of hepatectomy duction of poietin hypoxic levels are not elevated exposure is increased erythropoietin in produced and nephrectomy normal and The effect serum of lead phrectomy, as is compared tomy, measurable hypoxic exposure nephrectomy, duction significant by partial before the without hormone a hypoxic in a similar time hypoxic pro- erythro- rats when the are bled before of the by the (groups exposure does not (group E). 2. One occurs anephric schedule the after the to this prior to B). The is almost pro- completely of actinomycin D). The injection increase of ne- nephrec- exposed 1 day (group rats injection C and production 1 day after day not found in rats if lead is injected hormone lead-injected on exposure in Fig. are however, hepatectomy or hypoxic exposure to 7). the Serum rats nephrectomy as shown production in the to a 5-hr to controls, prevents 72-hr 59Fe uptakes are, respectively, to an uptake of 0.8% ± 0. 1 in unin- prior of levels of erythropoietin for 5 hr (group A); of erythropoietin prevented mediately I day a result 6 compared rats. in anephric hepatectomized 28,000 ft or when the to injection erythropoietin, (group completely lead-injected exposure to an altitude of 22,000 ft. The 0.86 ± 0.09 and 0.98#{176}c± 0. 1 compared jected plethoric mice. alone in rats receiving ( ND) difference serum D imof lead level of the of erythro- DISCUSSION The importance poietin since poietin operation, in the the of rodent initial is kidney in the been demonstrated observations produced but the has 1 day of in anephric later the poietin production.5’8’9 The tinguishable immunologically same production Jacobson rats and exposed hypoxic erythropoietin from the or by activation a number of co-workers to exposure produced hormone in hypoxia does investigators,4 l957. Erythro- immediately not result after in erythro- in anephric rats produced in normal is indisrats.5”#{176} From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 428 SCHOOLEY The production of extrarenal erythropoietin appears tained hypoxic stimulus than renal erythropoietin of renal erythropoietin via a hypoxic stimulus synthesis,” and is decreased by lead injection.’2 The present experiments clearly in response to erythropoietin acetate greater production in lead-poisoned indicate that erythropoietin It might ized rats the is the in the be objected normal that respond deprived animals do tionally stressed the to site production lead data of Fried.’3 hepatectom- oxygen The erythropoietin, demand fact even exposure, or that also of extrarenal this in that these when addi- by increasing failure is related to a decreased oxygen demand. production in lead-poisoned animals in biogenesis compensate or of The findings partially tissue. suggests than of injection D. a decreased 22,000-ft ft, strongly involved liver of prior or activation active of to itself, rather erythropoietin in the the to production to 28,000 processes in is related prior production by actinomycin of production metabolically with of the liver extrarenal that renal hypoxia much altitude normal changes to sus- of the hormone is much in extrarenal erythropoietin rat, corroborating the recent the failure of nephrectomized, so respond inhibited site a more renal by production involved MAHLMANN The production of de novo protein although is depressed are major by bleeding simulated above of not to the absence The increased suggests rats liver to animals the that, on this time schedule, extrarenal in injected animals. The processes require production.” is the result indicate hypoxia to AND of for the the activation hormone kidney of the are increased dysfunction. hormone Similar may occur in disease. REFERENCES 1. Goldberg biosynthesis. A: Lead poisoning Br J Haematol 23:521, 2. Morse BS, Abnormal acute lead in mice. RA, of the Environ 4. Krantz SB, Chicago of Pr, poietin tion, 6. and 39:3 1, 1972 pathology 7. CM, of the Jacobson LO, Plzak L: Nature (Lond) 8. Wang Role of the Fried anephric Arch of produc- erythropoiesis. E, Fried 1957 W: Renal extrarenal female 79:181, W, TP, Rossanigo F: F, Ricerca dell 34:24. sulla eritropoietina su animali ad exposia. binefrectoRiv T, Krantz Studies on Med 1971 Kilbridge Lange RD: erythropoietin. I 1. Schooley for the J Lab de JC. novo Clin Med rats. Blood Landa SA, erythropoietin 1931 impaired erythropoiesis W, poisoned 13. 1972 rats. Fried Clin W: erythropoietin Mahlmann synthesis Decreased renal and GF. Lipparine sottoposti Fried hypoxic Experimental in Goldwasser and Med 5, extra73:244, 1969 rat. 12:186, male Clin extrarenale Spaz 10. time Pathol Sasso G, e 12. RM: kidney C, McDonald Erythro- erythropoietin 179:633, F, Li: in J Lab preliminari mizzati renal Anderson liver. indagini Erythropoietin nephrectomy, exposure, Higgins produizione p 27 in Peschle Mastroberardino the Chicago, ages. 1972 JF, Arch production various Aeronaut LO: between Blood and body. of 9. 1972 Moore dosage Mahlmann production hypoxic DG: 13, Erythropoiesis. 1970, JC, I. Relationship rats 1970 Jacobson Regulation 5. Schooley 39:7 inclusion 20:705, erythropoietin following DL, Lead intranuclear Health the Univ MR: haem Guiliani Blood Leonard B, Krigman role GJ, maturation toxicity 3. Goyer Rhyne and Germano erythroid and 1972 The Li: of 40:662, IC. (ESF) in 21:559, liver in 1972 Schooley Res Evidence erythropoietin Arroyo synthesis acutely and lead- 1973 as a source production. FL: Blood of extra40:671, From www.bloodjournal.org by guest on August 9, 2017. For personal use only. 1974 43: 425-428 Hepatic Erythropoietin Production in the Lead-poisoned Rat J. C. Schooley and L. J. Mahlmann Updated information and services can be found at: http://www.bloodjournal.org/content/43/3/425.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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