International Review of Cytology: A Survey of Cell Biology, Volume 112

INTERNATIONAL

REVIEW OF CYTOLOGY VOLUME112

ADVISORY EDITORS H. W. BEAMS HOWARD A. BERN DEAN BOK GARY G. BORISY PIET BORST BHARAT B. CHATTOO STANLEY COHEN RENE COUTEAUX MARIE A. DIBERARDINO BERNDT EHRNGER CHARLES J. FLICKINGER NICHOLAS GILLHAM M. NELLY GOLARZ D E BOURNE YUKlO HIRAMOTO Y UKINORI HIROTA MARK HOGARTH K. KUROSUMI ARNOLD MITTELMAN KEITH E. MOSTOV

AUDREY MUGGLETON-HARRIS DONALD G. MURPHY ANDREAS ODSCHE MURIEL J . ORD VLADIMIR R. PANTIC W. J . PEACOCK DARRYL C. REANNEY LIONEL I. REBHUN JEAN-PAUL REVEL L. EVANS ROTH JOAN SMITH-SONNEBORN WILFRED STEIN RALPH M. STEINMAN HEWSON SWIFT K . TANAKA DENNIS L. TAYLOR TADASHI UTAKOJI ALEXANDER YUDIN

INTERNATIONAL

Review of Cytology A

S U R V E Y OF C E L L

BIOLOGY

Editor-in-Chief

G. H. BOURNE

St. George's University School of Medicine St. George's, Grenada West Indies

Editors

K. W. JEON Department of Zoology University of Tennessee Knoxville, Tennessee

M. FRIEDLANDER Jules Stein Eye Institute UCLA School of Medicine Los Angeles, California

VOLUME112

ACADEMIC PRESS, INC. Harcourt Brace Jovanovich, Publishers

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0 1988 BY ACADEMICPRESS. INC.

ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING. OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

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NUMBER:52-5203

Contents Prolactins of Pregnancy and Their Cellular Source LINDA OGREN 1. Introduction 11. Placental Lactogens Ill. Decidual Prolactin

AND

FRANKTALAMANTES I 4

......................................................... ............................................

41

50 51 52

..................... References ..........................................................................................

Membrane Oligosaccharides: Structure and Function during Differentiation PAULL. MANN

I. Introduction ... .................................................................. The Aging Cell Surface ......... .................... Developmental Phenomena .................................................................... Immune Regulation .... ...................................... Neoplastic Regulation ................................................................ odulation and IMR-90 Cellular Senescence Cell-Surface Oligosacc References ................................................................

11. 111. IV. V. VI.

67 71 78

92

Endosperm Development in Maize RICHARD v . KOWLES A N D RONALD L. PHILLIPS

I. Introduction ........................ Early Development ............................................................................... Microscopic Characterization of Endosperm Cells Cellular and Nuclear Activity ................................................................. Evidence for Endoreduplicati Differences in Nuclear DNA .................................. Biological Significance of DN Further Directions ................................................................................ References ................................ ...............

11. 111. IV. V. VI. VII. VIII.

V

97 97 101 I04 1 I4 I22 125 131 I33

vi

CONTENTS

Ameboid Movement and Related Phenomena W. STOCKEM A N D W. KLOFQCKA

........................................ ........................................................................................ Phenomena ............................................................ Organization of the Microfilament System ................................................ stem ................................. Function of the Microfil Concluding Remarks ... .............................................................. Summary ..................................................................... References ................ ....................................................

I. Introduction 111.

IV. V. VI. VII.

137 139 140 149 156 175 177 I79

The Role of Hepatocytes and Sinusoidal Cells in the Pathogenesis of Viral Hepatitis PATRICIA S. LATHAM

............................................................... ................

11. Role of Liver Architecture in the Pathogenesis of Viral Hepatitis 111. Role of Liver-Derived Cells in The Pathogenesis of Viral Hepatitis

185

185

............... 196

IV. Role of Interferon and the Immune Response in the Viral Pathogenesis of Hepatitis ......................................................... V. Genetic and Age-Dependent Determinants of Susceptibility ............................................................... in Viral Hepatitis ....... VI. Conclusion ....................................................... ........ References ................. ................................................................

213 216 219 220

“Leaky” Cells of Glandular Epithelia S. S. ROTHMAN A N D T. MELESE I. Introduction ............................................................. 11. Paracellular versus Transcellular Movement ...................

Ill. IV. V. VI.

The Experimental System ..................................................... Other Evidence of Transcellular Transport and Permeabilit Nature of the Paracellular Path .......................................... Concluding Remarks ... ................................................................... References ....................................................................

INDEX .........................................................................................................

243

245

INTERNATIONAL REVIEW OF CYTOLOGY, VOL. I12

Prolactins of Pregnancy and Their Cellular Source LINDAOGRENAND FRANK TALAMANTES Department of Biology, University of California, Santa Cruz, Santa Cruz, California 95064

I. Introduction

The placentas of numerous species produce hormones that are structurally and functionally similar to the pituitary hormones prolactin (PRL) and growth hormone (GH), which are 20-25K molecular weight proteins that regulate various processes including mammary gland differentiation, steroidogenesis, somatic growth, and intermediary metabolism. The most extensively studied placental PRL-like hormones are the placental lactogens (PLs). Historically, hormones called PLs were identified in the fetal component of placentas from various species on the basis of their ability to mimic the actions of pituitary PRL in various bioassays and radioreceptor assays. Subsequently, substances with PRL-like activity were purified from placentas and characterized biochemically. Although each of these hormones is called a PL because it possesses activity in assays for PRL-like activity, the PLs differ from one another in size and primary function, and some species produce more than one hormone that is a PL. Table I summarizes the nomenclature used to describe PLs in various species. In addition to PLs, the fetal component of the rat, mouse, and bovine placenta has recently been reported to produce other molecules that have amino acid sequence homology to pituitary PRL; their functions are currently unknown. In the mouse these substances include proliferin and proliferin-relatedprotein. In the rat they include PRL-like protein A. This PRL-like protein of the bovine placenta has not been named, but its cDNA has been designated PRL-related cDNA I. The maternal component of the placenta, the decidua, also produces PRL-like substances in some species. The primate decidua secretes a molecule that appears to be structurally identical to pituitary PRL. The rat decidua produces a substance designated decidual luteotropin, which has PRL-like biological activity but is not identical to rat pituitary PRL. In this review we will discuss the biochemistry, the mechanism and regulation of secretion, and the functions of these hormones. The literature from several areas of research has been summarized in tabular I Copyright 0 1988 by Academic Press, Inc. All rights of reproduction in any form reserved.

TABLE I NOMENCLATURE A N D SOMEBIOCHEMICAL PROPERTIES OF PLs" Percentage sequence homology* Hormone (synonyms)

Molecular weight

Number of amino acids

PRL

GH

Number of cysteines

p1

Human

hPL (hCS, chorionic PRL)

22,279'

191

67

%

4

4.6-6.2

Rhesus monkey

rhPL (rhCS)

-20,000-22,5Wd

?

7

?

4

?

Baboon

baboon PL

-20,000-25,000'

?

?

?

?

?

Mouse

mPL-I complex (midpregnancy) lactogen) mPL-I1 (mPL)

5

?

31

4

6.6-7.0

?

?

4.5

Species

References

rd .-

Rat

29,000-42,000d

1 94

21,812'

191

51

Li er al. (1973); Belleville er al. (1975); Chattejee er al. (1977); Cooke er a / . (1981) Shome and Friesen (1971); Vinik el al. (1973) Josimovich er a / . (1973) Colosi ef a / . (1987a,b)

Colosi er al. (1982); Jackson er a / . ( 1986) Robertson e r a / . (1982)

34

Hamster

W

4

6.0-6.4

9

> >

6

? 8.3-8.8 6.8-9.0

-25.000d

,

Sheep

haPL-I haPL-I1 (haPL) OPL (OCS)

-20,000-23.000d

?

?

Bovine

bPL (bCS)

-30,000-34,000d

?

?

?

?

4.8-6.3

Goat

CPL

-20,000-25,00Od

?

?

?

?

?

-35,000‘

?

1

Robertson and Friesen (1975): Robertson ef 01. (1982); Duckworth er a / . (1986a) Southard cf u / . (1987) Southard ef a / . (1986) Hurley ef a / . (1975, 1977a.b): Marta1 and Djiane (1975); Chan el a / . (1976. 1986): Reddy and Watkins (1978a) Murthy cf al. (1982); Eakle er a / . (1982); Arima and Bremel (1983); Byatt er nl. (1986) BeCka ef al. (1977)

Abbreviations: PL, placental lactogen; PRL, prolactin; GH, growth hormone: PI,isoelectric point; CS. chorionic somatomammotropin. Percentage homology figures include conservative amino acid replacements. ‘ Molecular weight obtained from amino acid sequence. Apparent molecular weight determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. ‘ Apparent molecular weight determined by gel exclusion chromatography. I T h e term rPL (without the designation “I” or “11”) has been used in two different contexts to refer to PLs from the rat. The term was originally used to designate rPL-I1 (Robertson and Friesen, 1975). More recently, it has been used by several authors to designate placental substances that are detected by assays for PRL-like activity and presumably reflects a combination of rPL-I and rPL-I1 (see Section 11,C.l). a

4

LINDA OGREN AND FRANK TALAMANTES

form to conserve space. Reference citations for literature appearing in the tables are included in the tables rather than in the text. 11. Placental Lactogens

Placental lactogens have been identified in the placentas of a large number of primates, rodents, and artiodactyls (for a complete list see Talamantes, 1975a,b; Kelly et al., 1976; Forsyth, 1986). A PL does not appear to be produced by the pig, cat, dog, horse, zebra, bat, armadillo, ferret, several shrews, and several rhinoceroses (Forsyth, 1986). The existence of a PL in the rabbit is controversial. Purification of the hormone has been reported (Bolander and Fellows, 1976), but its presence in placental tissue has not been confirmed by bioassay or radioreceptor assay (Talamantes, 1975a,b; Kelly et al., 1976). A. BIOCHEMICAL CHARACTERIZATION PLs have been purified from the placentas of the human (e.g., Josimovich and MacLaren, 1962; Cohen et al., 1964; Friesen, 1965a,b; Hunt et a1.,1981), rhesus monkey (Shome and Friesen, 1971; Vinik et al., 1973), mouse (mPL-I: Colosi et al., 1987a; mPL-11: Colosi et al., 1982), rat (rPL-11: Robertson and Friesen, 1975), hamster (haPL-11: Southard et al., 1986), sheep (e.g., Hurley et al., 1975, 1977a; Marta1 and Djiane, 1975; Chan et al., 1976), and bovine (Murthy et al., 1982; Eakle et al., 1982; Arima and Bremel, 1983). Placental lactogens from the baboon (Josimovich et al., 1973) and goat (BeEka et al., 1977) have been partially characterized. Some properties of these hormones are listed in Table I. Structurally, PLs can be divided into two general groups: (1) PLs that have structures that are highly similar to those of the PRL and GH from the same species, and (2) PLs that have structures that appear to differ somewhat from those of GH and PRL. Placental lactogens in the first group are single-chain polypeptides having molecular weights ranging from about 20,000 to 25,000. This group of proteins is characterized by the presence of either two or three intrachain disulfide bonds that are in positions analogous to those of GH and PRL. Both GH and PRL contain a small disulfide loop in the carboxy terminal region of the molecule and a large loop enclosing about 110 amino acid residues. In addition, PRL contains a third small disulfide loop at the amino terminus. Structural similarity to PRL and GH has been best demonstrated for hPL, mPL-11, and rPL-11, which are the only PLs whose complete amino acid sequences are known. As shown in Table I, each of

PROLACTINS OF PREGNANCY

5

these hormones shows significant sequence homology to both PRL and GH from the same species (hPL: Bewley et al., 1972; Cooke et al., 1981; mPL-11: Jackson et al., 1986; rPL-11: Duckworth et al., 1986a). The other PLs of this group are haPL-11, oPL, rhPL, baboon PL, and probably cPL. With the exception of cPL, each of these PLs has been shown to be related immunologically to the homologous PRL and/or GH and to other PLs of this group; the immunological properties of cPL have not been reported (haPL-11: Southard and Talamantes, 1987; oPL: Hurley et al., 1975; rhPL: Shome and Friesen, 1971; Vinik et al., 1973; baboon PL: Josimovich et al., 1973). The amino acid compositions of oPL (Hurley et al., 1977a,b; Chan et al., 1986) and rhPL (Shome and Friesen, 1971) are similar to those of other members of the PRL-GH family. Although the PLs in this group are structurally related to both PRL and GH, some of the PLs are more PRL- than GH-like structurally, while others are more GH- than PRL-like. Analysis of the primary structures of hPL, rPL-11, and mPL-I1 has revealed that the rodent PL-11s share more sequence homology with the homologous PRL than with the homologous GH, while the converse is true for hPL (Table I). Since data on the biological activities and amino acid sequences of PLs are still limited to very few species, it is not known how accurately the degree of sequence homology between a PL and the PRL and GH from the same species predicts the primary functions of the PL. In the case of mPL-11, the relationship between greater sequence homology to mPRL and biological activity appears to be a good one, since all of the known functions of mPL-I1 are PRL-like and the hormone does not bind to mGH receptors in several tissues (Haro and Talamantes, 1985, and unpublished observations). In the case of hPL, however, the high degree of amino acid sequence homology with hGH suggests that the GH activity of hPL should be very high, when in fact, it is relatively low in several different bioassays (Sherwood et al., 1980), demonstrating that seemingly minor differences in amino acid sequence between a PL and GH or PRL can result in significant differences in the activity of the molecules. [The specific differences in primary structure between hGH and hPL that may account for the differences in their bioactivity have been discussed by Nicoll et al. (1986).] Since amino acid sequence data are not available for the other PLs. the number of cysteine residues obtained from amino acid composition analysis has been used by some investigators as a criterion for comparing PLs with the homologous GH and PRL. Based on their cysteine content, hPL, rhPL, mPL-11, and rPL-I1 are similar to GHs, whereas oPL is similar to PRL (Table I). The conclusion suggested by these data on mPL-I1 and rPL-I1 differs from that based on the analysis of the hormones’ amino acid sequences, which raises questions about the

6

LINDA OGREN AND FRANK TALAMANTES

suitability of this method for assessing the structural relatedness of PLs, GHs, and PRLs. The other structural group of PLs includes bPL, mPL-I, haPL-I, and rPL-I. Bovine PL is a single-chain polypeptide having a molecular weight of 30,000 to 34,000 (Eakle et al., 1982; Murthy et al., 1982; Arima and Bremel, 1983). Although complete amino acid sequence data for bPL have not been reported, preliminary studies indicate that it shares about 45% amino acid sequence homology with bPRL (Schuler and Hurley , 1985).The large difference in molecular weight between bPL and bPRL or bGH is due to the presence of additional amino acids in the polypeptide chain of bPL (Schuler and Hurley, 1985). Despite its larger size, bPL appears to share at least some structural features with oPL since it crossreacts with antiserum to oPL (Murthy et al., 1982). Mouse PL-I consists of two complexes of proteins that have been classified by molecular weight and their behavior during purification; they have been designated mPL-I (29-32K) and mPL-I (36.5-42K) (Colosi et al., 1987a). Mouse PL-I (29-32K) comprises three proteins with apparent molecular weights of 29,000, 30,500, and 32,000; the two larger molecular weight components are glycosylated. Mouse PL-I (36.5-42K) is composed of 5 glycoproteins. The protein moiety of mPL-I is a single-chain, 194-amino acid polypeptide (Colosi et al., 1987b). It differs structurally from mPRL, mGH, and mPL-I1 in that it does not contain the large disulfide loop that is characteristic of the family (Colosi et al., 1987a). Very little is known about the structures of rPL-1 and haPL-I. Neither hormone crossreacts with antiserum to the PL-I1 from the same species (rPL-I: Robertson et al., 1982; haPL-I: Southard et al., 1987). The fact that the molecular weights of rPL-I and haPL-I are similar to that of mPL-I and the gestational maternal serum profile of rPL-I is similar to that of mPL-I (Section II,C,2) suggests that these hormones may be analogous to mPL-I. Variant forms of PL that differ with respect to molecular weight, amino acid composition, and net surface charge have been described for PLs from both structural groups. The most extensively examined of these variants are the high molecular weight forms of hPL and haPL-11. These PLs differ from the other PLs that have been characterized in that they exist to a significant extent in the placenta and circulation as high molecular weight forms. The large molecular weight forms of hPL consist of dimers and higher oligomers of the monomeric hormone. About 25% of dimeric hPL is composed of noncovalently-associated monomers, and the remainder consists of two molecules of monomeric hPL that are joined in antiparallel configuration by a disulfide bond between Cys-182 of one monomer and Cys-189 of the other (Schneider et al., 1977, 1979). Higher

PROLACTINS OF PREGNANCY

7

oligomers are non-covalently-associated aggregates of monomer (Schneider et al., 1975a; Cox et al., 1979). The large molecular weight forms of hPL are biologically active (Schneider et al., 1977) and account for about 55 and 10% of the total hPL in the placenta during the first and third trimesters, respectively (Schneider et al., 1975a,b; Calvert et al., 1985). They are also present in serum throughout pregnancy, but account for less than 10% of the total hPL activity (Schneider et al., 1975a; Calvert et al., 1985). haPL-I1 exists in both the placenta and circulation almost entirely as high-molecular-weight forms that are maintained by both disulfide linkages and noncovalent interactions (Southard et al., 1986, 1987). The high-molecular-weight forms of haPL-I1 in the blood differ from those in the placenta. In maternal plasma, haPL-I1 is present primarily as 600K, 210K, and monomeric forms, whereas placental haPL-I1 is very heterogeneous, with molecular weight forms ranging from monomer to >1500K (Southard er al., 1987; J. Southard and F. Talamantes, unpublished observations). It is not known whether these forms are composed of several molecules of monomeric haPL-I1 or whether they consist of molecules of haPL-I1 linked to other proteins. The high-molecular-weight forms of haPL-I1 are probably biologically active since they show activity in radioreceptor assays for PRL-like activity (Southard et al., 1986). The reason hPL and haPL-I1 exist to a significant extent as high molecular weight forms, whereas other PLs do not, is not known. It is possible that in the native proteins, the disulfide linkages of hPL and haPL-I1 are oriented in a configuration that increases their likelihood of forming interchain disulfide bonds with other molecules. Variants of oPL (Chan et al., 1986) and rhPL (Shome and Friesen, 1971) having slightly different amino acid compositions, and charge isoforms of hPL (Belleville et al., 1975; Chattejee et al., 1977), mPL-I1 (Southard et al., 1986), haPL-I1 (Southard et al., 1986),rPL-I1 (Robertson et al., 1982), oPL (Marta1 and Djiane, 1975; Chan et al., 1976; Hurley et al., 1977a; Reddy and Watkins, 1978a; Southard et al., 1986), and bPL (Arima and Bremel, 1983; Byatt et al., 1986) have also been reported. The structural basis for differences in the net surface charge of the PLs is not understood. The existence of forms of rhPL and oPL that differ with respect to amino acid composition could be due to genetic variation, but this question has not been examined experimentally. Structure-function relationships of PLs have not been examined extensively. Studies carried out on hPL suggest that biological and immunological activity are conferred by the amino terminus, and the carboxy terminus is involved in maintaining the conformation of the molecule (Burstein et al., 1978; Russell et al., 1979). The disulfide bonds

8

LINDA OGREN AND FRANK TALAMANTES

of hPL confer stability to the secondary and tertiary structures of the molecule (Aloj et al., 1972). B. SECRETION 1. Site of Production Information about the cell types in the placenta that contain PLs is available for the human, mouse, rat, sheep, and bovine. In all cases, PL-containing cells originate in the fetal component of the placenta. In the human placenta, mRNA for hPL has been localized to the syncytial layer by in situ hybridization (McWilliams and Boime, 1980; Boime et al., 1982; Hoshina et al., 1982a, 1985), indicating that the hormone is synthesized in the syncytium. In situ hybridization studies on mRNAs for other PLs have not been carried out. Information about the cell types that produce PLs in ruminants and rodents has been obtained largely by immunohistochemical staining methods, whereby cells containing the hormone are detected by staining with an antiserum to the hormone. With these methods it is not possible to determine whether a cell stains for the hormone because the hormone is synthesized there or because the cell is a target of the hormone. In the sheep and bovine, oPL and bPL have been localized largely to the binucleate cells of the chorion (Marta1 et al., 1977; Reddy and Watkins, 1978b; Watkins and Reddy, 1980; Wooding, 1981; Verstegen et al., 1985; Duello et al., 1986), and within the binucleate cells of the sheep placenta, oPL has been localized to secretion granules (Wooding, 1981; Lee et al., 1986; Rice and Thorburn, 1986a). The presence of oPL in secretion granules suggests that these hormones are synthesized within the binucleate cells. In the mouse, mPL-I1 has been localized to the giant cells of the chorioallantoic and choriovitelline placentas and to basophilic cytotrophoblasts (Hall and Talamantes, 1984). Less information is available about the cells in the mouse and rat placenta that contain mPL-I, rPL-I, and rPL-11. Data obtained from culturing mouse (Soares et al., 1983)and rat (Soares et al., 1985)placental explants indicate that each of these hormones is secreted by both the chorioallantoic and choriovitelline placentas, probably by giant cells, 2. Synthesis and Mechanism of Secretion Most of the work that has been carried out on the synthesis and mechanism of secretion of PLs has focused on hPL. Two genes, HCS-A and HCS-B, code for hPL, and both are expressed under normal conditions. Their products differ in one amino acid, which is in the signal sequence (Barrera-SaldaAa et al., 1983). HCS-A and HCS-B are linked

PROLACTINS OF PREGNANCY

9

to three other genes of the GH-PL gene family and are located at band q22-24 of chromosome 17 (Harper et al., 1982). The structure of these genes has been reviewed by Barsch et al. (1983) and Parks ( 1984). hPL is synthesized as a prehormone containing a 25-amino acid signal peptide (Sherwood et al., 1979) which is cleaved by microsomal membrane peptidases (Boime et al., 1975, 1980; Cox et al., 1976; Szczesna and Boime, 1976; Strauss et al., 1980). Studies examining the kinetics of hPL synthesis and release in vitro have suggested that the mature hormone exists in two different pools in the tissue: a stable storage pool and a readily releasable pool, with newly synthesized hormone being preferentially channeled into the latter (Suwa and Friesen, 1969; Golander et al., 1978a). The physical basis of this compartmentalization is not understood. A recent study suggests that hPL may be packaged into small secretory granules (Fujimoto et al., 1986), but whether the hormone in these granules represents the storage pool suggested by kinetic experiments is not known. The kinetics of PL secretion have also been examined in mice (Basch and Talamantes, 1986). As is the case with hPL, newly synthesized mPL-I1 is rapidly released. In contrast to the secretion kinetics of hPL, however, there does not appear to be a significant storage pool of mPL-I1 in the mouse placenta. The mechanism by which PLs are released from the cell is not well understood. Evidence obtained from humans and sheep suggests that the processes regulating basal and secretagogue-stimulated PL release differ. Basal hPL and oPL release are not calcium dependent (Choy and Watkins, 1976; Handwerger et al., 1981a; Rice and Thorburn, 1986b),and hPL release is in fact stimulated by the absence of extracellular calcium and by agents that inhibit the influx of calcium or interfere with formation of a calcium-calmodulin complex (Choy and Watkins, 1976; Handwerger et al., 1981a; Handwerger and Siegel, 1983; Zeitler et al., 1983; Hochberg et al., 1984). In contrast, secretagogue-stimulated release of both hormones requires the presence of extracellular calcium (Zeitler et al., 1986; Rice and Thorburn, 1986b). The manner in which PLs are delivered to the maternal blood differs between species. In the human placenta, hPL is released from the syncytial layer of the trophoblast directly into the maternal blood in the intervillous space. In contrast, delivery of PL to the maternal blood in the sheep and bovine appears to depend on the continued movement of PL-containing binucleate cells from the fetal to the maternal component of the placenta (Steven et al., 1978; Wooding, 1981; Duello et al., 1986). PL is synthesized and packaged into secretion granules in the binucleate cells of the chorion. These cells then migrate across the fetal-maternal

10

LINDA OGREN AND FRANK TALAMANTES

junction and fuse to form a syncytium which is closely associated with the maternal circulation. C. GESTATIONAL PROFILES A N D METABOLISM 1, Assays for Measuring PL Concentrations

PL concentrations in various biological fluids were originally estimated with various bioassays and radioreceptor assays for PRL-like, and in some cases, GH-like activity. Although many of these assays have been valuable in identifying tissues containing PLs, their usefulness in determining the absolute concentrations of PLs in tissues is limited by the fact that these assays detect other hormones in addition to PLs. Consequently, as pure preparations of PLs have become available, highly specific radioimmunoassays (RIAs) for the hormones have been developed. At the present time RIAs are available for hPL, rhPL, mPL-I, mPL-11, rPL-11, haPL-11, oPL, and bPL (see references in Section II,C,2). Concentrations of rPL-I and cPL have only been estimated by bioassay and radioreceptor assay. In some cases, the specificity of bioassays and radioreceptor assays for PLs from the rat and goat have been improved by ( I ) neutralizing the activities of PRL-like hormones that are not of interest by treating samples with specific antisera (e.g., Tonkowicz et al., 1983), ( 2 ) using RIAs to measure the concentrations of PRL-like hormones that are not of interest and then “subtracting” these values from the total PRL-like activity measured by radioreceptor assay or bioassay (e.g., Hayden et al., 1980), or (3) in the case of samples containing rPL-I and rPL-11, by separating the two hormones chromatographically prior to assay (Soares et al., 1985). However, in many other instances the total PRL-like activity of samples has been reported, which has created confusion, particularly in the rat PL literature. In these experiments, no attempt was made to distinguish between rPL-I and rPL-I1 and investigators have referred to the species being measured as “rPL.” In the present discussion, references to the “rPL” literature have been omitted when similar experiments utilizing specific RIAs have been reported. When the “rPL” literature has been cited, we have designated the activity “total PRL-like activity” or “total placental lactogenic activity” to indicate that all PRL-like activity in the placenta or blood was measured. 2 . Gestational Projles of PLs The gestational profiles of PLs in the maternal blood of several species are shown in Figs. 1-3. These profiles differ between species with respect to ( I ) their overall pattern, (2) the absolute concentration of PL that is

PROLACTINS OF PREGNANCY

Mid-gestation

Term (-38 weeks)

FIG. I . Gestational profiles of PI, in the maternal circulation of the human (top) and rhesus monkey (bottom). Hormone concentrations were measured by RIA. Kedrawn from Berle (1974) (hPL), Walsh ('1 rrl. (1977:)) (rhPL). and Novy i ~ fctl. (1981) (rhPL).

present, (3) the stage of gestation when the hormone first appears in the circulation, and (4) the relative concentrations of hormone in the maternal and fetal circulations. The gestational profiles of PLs in the maternal circulation fall into two general patterns. The first includes the serum profiles of rat and mouse PL-I, which are characterized by a very large peak during or slightly after midpregnancy , with hormone concentrations falling to very low to undetectable values several days later (Fig. 2). In contrast to this general pattern, the gestational profiles of the other PLs are characterized by the continued presence of the hormones in the blood from the time they first appear until parturition. In some species of this group, the PL concentration of the maternal blood increases gradually throughout pregnancy and

12

LINDA OGREN AND FRANK TALAMANTES

P I

b c

5.0

c

C

a, -

._ 9

3

a, 0

7

2.5

a .c

.

E

m

I

Y

J

Mid-gestation

a L

Term (-16 days) 800

8.0

I

? A

E 400 &

-

<m 4.0

-

C

-

I

Y

-

L a

i a

E

E

Mid-gestation

?

Term (-19 days) 900

3.0

A

h

m

I

c

a, m

._ 3

450

1.5 1

P

a:

-

. -

a;

a 0 -

l l

E

m

5

-

-J

a;

Mid-gestation

Term (-22 days)

FIG. 2. Gestational profiles of PL-I and PL-11 in the maternal circulation of the hamster (top). mouse (middle), and rat (bottom). The concentrations of haPL-11, mPL-I, mPL-11, and rPL-II were measured by RIA. The concentrations of haPL-I and rPL-I were estimated by radioreceptor assay as PRL-like activity not due to PRL or PL-11. Redrawn from Southard el d.(1987) (haPL-I, haPL-II), Colosi er a / . (1986) (mPL-I), Robertson and Friesen (1981) (rPL-11)- and Robertson el ul. (1982) (rPL-I). Data for mPL-I1 from D. Bravo and F. Talamantes, unpublished.

PROLACTINS OF PREGNANCY

13

in others it levels off or drops toward the end of pregnancy. The rodent PL-11s appear in the maternal blood somewhat later in pregnancy than do the other PLs; the serum profile of haPL-I1 is particularly striking in this respect. The PL-I1 profile shown for the mouse in Fig. 2 is that of the Swiss Webster strain. Balb/c mice show a similar profile, whereas the PL-I1 profile of C3H mice levels off during the final week of gestation (Soares and Talamantes, 1982, 1983, 1985). The species differences in the maximum PL concentrations of the maternal blood are quite marked, with values ranging from a few nanograms per milliliter of serum in the bovine to micrograms per milliliter of serum in the primates, sheep, mouse, and hamster. It is interesting to note that major differences in maximum PL concentrations exist even between species from the same order; for example, compare PL (PL-11) concentrations between the sheep and bovine (Fig. 3) or between the hamster and mouse or rat (Fig. 2). Of the species that have been examined thus far, it appears that the ruminants differ from both the primates and rodents in the distribution of PL between the maternal and fetal circulations. In the sheep, the oPL concentration of the fetal blood exceeds that of the maternal blood for the first half of pregnancy (Chan et al., 1978a; Gluckman et al., 1979), and in the bovine, the fetal serum PL concentration is about 5 to 10 times higher than the PL concentration of the maternal blood throughout gestation (Beckers et al., 1982; Duello et al., 1986). In contrast, the PL (PL-11) concentration of the fetal blood is less than 1% that of the maternal blood at term in the human (Kaplan and Grumbach, 1965) and rhesus monkey (Novy et al., 1981) and less than 10% that of the maternal blood during the last third of pregnancy in the mouse (D. Bravo and F. Talamantes, unpublished observations). It is not known whether the differences in gestational PL profiles between species are associated with differences in the primary functions of these hormones. This question cannot be answered until more information is obtained about the biological activities of the PLs in homologous systems (see Section 11,E).The species differences in the distribution of PL between the fetal and maternal compartments are particularly interesting because they suggest that the role of PL in the fetus may be relatively more important in those species in which fetal PL concentrations are high than in species in which the fetal blood contains a very low concentration of the hormone. 3. Placental Lactogens in Amniotic and Allantoic Fluid Human PL (Grumbach et al., 1968; Berle, 1974; Nielsen and Schioler, 1981) and mPL-I1 (D. Bravo and F. Talamantes, unpublished observa-

14

LINDA OGREN AND FRANK TALAMANTES

Bovine

C 1 a I]

0.5 '

Mid-gestationO

'

Term Z (-40 weeks)

Sheep e

E

-4

1.5 -

1

a

I

//

300

-c

I

-

0,

1

%

I

I

Mid-gestation

I

I

Term (-21 weeks)

F I G . 3. Gestational profiles of PLs in the maternal circulation of the bovine (top), sheep (middle), and goat (bottom). The concentrations of bPL and oPL were measured by RIA. The concentration of cPL was estimated by radioreceptor assay as PRL-like activity not due to PRL. Redrawn from Beckers et a / . (1982) (bPL), Handwerger PI ul. (1977) (oPL). and Hayden et ul. (1980) (cPL).

tions) have also been detected in the amniotic fluid, their concentrations in this compartment being significantly higher than those of fetal serum. Ovine PL (Chan et al., 1978a; Handwerger et al., 1977) and bPL (Beckers et al., 1982) are present in both amniotic and allantoic fluid. The role of PLs in these compartments is unknown. The source of amniotic fluid hPL and oPL appears to be direct secretion into the amnion, since very little hormone is transferred from either the maternal or fetal circulation into the amniotic fluid (Kaplan et al., 1968; Reddy and Watkins, 1983).

15

PROLACTINS OF PREGNANCY TABLE I1 HALF-TIME OF DISAPPEARANCE OF PLS FROM Rapid phase (minutes)

(,