Mar 10, 1989 - which can then be con- verted back to alkylacyl-GPC ... A2 will generally lead to an increased ...... J, Burtin C, Gubler. MC,. Benveniste. J, 1984.
BIOLOGY
OF REPRODUCTION
A Paracrine
40, 907-913
Factor
(1989)
MINIRE VIEW Platelet-Activating Factor: in Preimplantation Stages MICHAEL
Department The
University San
J. K.
of
Obstetrics
of
Texas
Antonio,
HARPER and
Health
Texas
of Reproduction?1
Gynecology Science
Center
78284-7836
ABSTRACT Platelet-activating factor (PAF) exerts its actions through activation of specific membrane binding sites found in a variety of tissues, including hypothalamus and endometriwn. PAF has been identified in several reproductive tissues (i.e. etnbryo, ovary, uterus, and spermatozoon). In the uterus, PAF levels are hormonally controlled, being elevated by progesterone and prostaglandin E2 (PGE2). Antagonists of PAF interfere with sperm function, ovulation, and implantation. The available evidence suggests that PAF may be an important physiological regulator in reproduction.
INTRODUCTION
The main features of this molecule include a C 16:0 or a C18:O alkyl side-chain in position 1, an acetyl group in position 2, and a phosphorylcholine side-chain in position 3, all of which seem to be important for biological activity (Tenc#{233}et al., 1981; Tokumura et al., 1985; Braquet and Godfroid, 1986; Godfroid and Braquet, 1986; Ludwig and Pinckard, 1987). Most studies on PAF (tissue levels, binding sites and actions), have concentrated on these C16:0/C18:0 choline-containing compounds. However, there is great molecular heterogeneity among PAF species (Pinckard et at., 1984; Ludwig and Pinckard, 1987; Pinckard et a!., 1988), and PAF variants may be derived from many parent phospholipids. The biological activity of such compounds remains to be determined, and no systematic study has been done on their presence or actions in the reproductive system. In the discussion that follows, the term PAF refers to the C16:0 or C18:0 AGEPC variants.
Platelet-activating factor (PAF) is the name assigned to a family of acetylated glycerophospholipids, primarily because of their ability to release histamine from platelets (Benvemste et al., 1972). PAF is present in many tissues (Renooij and Snyder, 1981; Nishihira et al., 1984; Pirotzky et aL, 1984; O’Neill, 1985c, 1987; Schlondorff et al., 1986; Yasuda et al., 1986; Tokumura et al., 1987; Angle et aL, 1988a,b; Kumar et al. 1988a,b; Whatley et al., 1988; Sugatani et aL, 1989), produced by inflammatory cells (Pinckard et al., 1982, 1988) and released in IgE-mediated anaphylaxis (Pinckard et aL, 1979). One molecular species, acetyl-glyceryl-ether-phosphorylcholine (AGEPC: 1 -O-alkyl-2-acetyl-sn-glycero3-phosphoryicholine), of PAF has been characterized and synthesized (Demopoulos et a!., 1979) (Fig. 1).
Synthesis
and
Metabolism
PAF synthesis in the platelet occurs via the remodeling pathway (see Braquet et at., 1987, and Pinckard et at., 1988, for references). Phospholipase A2 acts upon alkylacyl-glyceryl-phosphoryicholine (alkylacyl-GPC) to release a long-chain unsaturated fatty acid (usually arachidonic acid) and 2-alkyl-2-lyso-GPC (lyso-PAF). Lyso-PAF is both the key substrate for and key metabolite of PAF. A calcium-dependent, membrane-bound
Accepted Received
April 7, 1989. March 10, 1989. tThese studies were supported in part by NIH grants HD 14048; HD 25224 (MJ.K.H., P.1.); HD 10202 (Carl J. Pauerstein, P.!.; Radloimmunoassay and Hormone Receptor Cores); HD 21649 (Larry L. Espey, P.1.); HL 22555 (R. Neal Pmckard, P.1.); Lalor Foundation Fellowship (George B. Kudolo); the Special Programme of Research, Development and Research Training in Human Reproduction. World Health Organization no. 87007 (Donald J. Hanahan and MJ.K.H., co-P.Is.), and CONRAD no.012 (M.J.K.H., P.!.).
907
HARPER
908
o
H
PAF and the Hypothalamo-Pituitary
H2C-O--(CH2)--CH 15-17 CH3
CH3-C-O-CH
Ill
H2C-O-P-O--CH2--CH2-N--CH3
0I
#{234}O FIG. choline,
enzyme,
1. Chemical one molecular
structure species
(H3
of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylof platelet-activating factor.
acetyl-CoA acetyltransferase, acetylates lysoto form PAF. Acetylhydrolase, a calcium-independent enzyme located intracellularly in the cytosolic fraction and extracellularly in plasma, rapidly deacetylates PAF back to lyso-PAF, which can then be converted back to alkylacyl-GPC by an acylt.ransferase, a membrane-bound enzyme inhibited by calcium. Thus, in the platelet, the metabolic cycle for PAF has two major points of physiological interest. First, activation of phospholipase A2 will generally lead to an increased production of both PAF and eicosanoids, depending on the relative abundance and activity of the cyclooxygenase and lipoxygenase enzymes. Second, the major substrate for PAF synthesis is also the major metabolite. This scheme utilized by platelets for synthesis and metabolism of PAF may not be employed by other cells and tissues. For example, rat tissues synthesize PAF via the de novo pathway from alkylacetylglycerol by a dithiothreitol (DTT)-insensitive cholinephosphotransferase (Renooij and Snyder, 1981; Femandez-Gallardo et at., 1988). Preliminary experiments suggest that, in rabbit uterus, the DTT-insensitive cholinephosphotransferase pathway may also be the prefened route for synthesis of PAF. In any event, it appears that the pathway for PAF degradation is similar in most tissues, i.e. via acetylhydrolase to lyso-PAF. This seems to be the case for the uterus, where PAF is rapidly converted to lyso-PAF, and the lyso-PAF to alkylacyl-GPC with crude membrane preparations (Kudolo and Harper, 1989).
PAF
Axis
Junier et at. (1988) showed that PAF at a concentration of 104M in tissue culture inhibited luteinizing hormone-releasing hormone (LHRH) and somatostatin release from median eminence, while release of GRF was unaffected. PAF also inhibited the stimulatory effect of calcium ionophore on release of these hypothalamic neuropeptides, but apparently had no direct action on the pituitary since luteinizing hormone (LH) and growth hormone (GH) release were unaffected. Camoratto and Grandison (1989) showed that PAF, over a range of 1-100 nM, dose-dependently increased prolactin secretion from dispersed rat anterior pituitary cells within 1 mm of exposure. This stimulation lasted for 2 h and could be inhibited by PAF antagonists. Lyso-PAF did not stimulate prolactin secretion. It is of interest that Junier et at. (1988) found specific binding sites for PAF in membrane preparations from hypothalamus, but not in those from pituitary. Two types of binding sites with affinities (Kd) of 2.1 and 62 nM and capacities of 25 and 146 fmollmg protein for the high and low affinity sites, respectively, were observed. They suggested that the discrepancy between the concentrations of PAF required for receptor occupancy and maximal inhibition of neuropeptide release could be due to nonlinear coupling between the binding and the physiological response.
Ovulation
may be involved, in some as yet not understood in the process of ovulation. Instillation of a PAF antagonist into the ovarian bursa of immature gonadotropin-primed rats reduced the number of ovulations, in association with a reduction of the human chorionic gonadotropin (hCG)-induced ovarian collagenolysis and vascular permeability. This action could be reversed by simultaneous administration of PAP, but PAF did not induce ovulation in unprimed, sodium pentobarbital-blocked rats (Abisogun et at., 1989). In addition, ovarian PAF concentrations in superovulated rats declined after the hCG injection (Espey et at., 1989). However, doses of indomethacin that significantly reduced the ovulation rate did not prevent the decline in ovarian PAP (Espey et at., 1989). In contrast, PAP injected into the ovarian bursa partially abrogated the inhibitory action of indomethacin and nordihydroguaiaretic acid on ovulation (Abisogun et al., 1989). PAP manner,
PAF AND Thus, along latory Zygotes
taken together, with eicosanoids, process.
and
these data somehow
REPRODUCTION
indicate that PAP is, involved in the ovu-
Spermatozoa
O’Neill described a significant thrombocytopenia in mice from the morning of Day I of pregnancy and continuing through Day 6 (O’Neill, l985a). By use of various surgical manipulations and study of pseudopregnant mice, he demonstrated thrombocytopenia was dependent on the presence of fertilized eggs (zygotes). Evidence was provided that the responsible factor was PAP-like material released from the zygotes (O’Neill, 1985b). Lipid extraction of medium derived from cultures of 8- to 16-cell mouse zygotes, followed by thinlayer chromatography (mc), confirmed that the zygote-derived PAP-like material had chemical and biochemical properties similar to synthetic PAP. PAP was never found in cultures of (unfertilized) ova. Culture of zygotes for more than 24 h led to a diminution of the amount of PAP in the medium (O’Neill, 1985c). Later studies indicated that it was not just 8- to 16-cell zygotes that produced PAP, since 12-h cultures of mouse blastocysts were also positive for PAP (O’Neill, 1987). Experiments by other investigators (Angle et at., 1988a) confirmed the observations of O’Neill and showed that maximal PAP was secreted by mouse morulae. In these studies, a peak activity of 79 fmol PAP/zygote was recorded between 25 and 36 h of culture. O’Neill et at. (1985a) also observed thrombocytopenia in women in an in vitro fertilization program who became pregnant. Thrombocytopenia was evident from Day 1 through Day 6 of pregnancy, and was never observed in women who failed to become pregnant. In addition, medium from 24-h cultures of 4-cell human zygotes tested positive for PAP in the splenectomized mouse assay (O’Neill et at., 1985a). Biochemical and pharmacological characterization of medium used to culture human zygotes to the 2- to 4-cell stage indicated that the active substance was homologous to synthetic PAP (Collier et at., 1988). Present evidence suggests that human zygotes produce more PAP/zygote than do those of mice (O’Neill, 1985c; O’Neill et at., 1985a; Collier et at., 1988). PAP production by human zygotes has been used as a parameter for assessing their potential viability, and it has been shown that zygotes that resulted in pregnancy produced significantly higher 1ev-
909
els of PAP in culture prior to transfer (O’Neill et at., 1987). Experiments to detect the presence of PAP-like material released from marmoset zygotes have been less definitive. In some cases, thrombocytopenia could be observed during the preimplantation stage of pregnancy, but was also seen in some nonpregnant animals (O’Neill, 1987). In rabbits, PAP was not observed in Day 5 or Day 6 blastocysts, nor in medium used to culture blastocysts from Day 5 of pregnancy for 24 h (Angle et at., I 988b). However, the lack of albumin in the medium may have caused these negative results, since serum albumin is known to be involved in cellular secretion of PAP (Ludwig et at., 1985). The physiological role for PAP production by and secretion from zygotes remains to be defined. It is not essential for the survival of the preimplantation embryo, since zygotes cultured from the 2-cell to blastocyst stage with PAP antagonists, which inhibit implantation in vivo, developed normally in vitro (O’Neill, 1987). However, addition of PAP to the culture medium promoted utilization of glucose and lactate, and increased incorporation of leucine by mouse zygotes. Such zygotes exposed to PAP for 72 h had a significantly increased potential for implantation and subsequent embryonic development (O’Neill, 1989). We have preliminary evidence that specific binding sites for PAP exist on Day 6 rabbit blastocysts (Harper et at., 1989), and in membrane preparations from rabbit endometrium (Kudolo and Harper, 1988, 1989) and oviduct (Kudolo and Harper, unpublished data). Thus, PAP could exert a biological action, via such binding sites, to cause, for example, secretion of early pregnancy factor (EPF; an immunosuppressive glycoprotein that is one of the earliest signals of pregnancy, Morton et at., 1974) or to initiate changes associated with implantation. PAP administration to estrous mice causes the appearance of EPF in the serum (Orozco Ct at., 1986), and it is known that EPF is released from in vitro perfusions of rabbit ovary and oviduct within 3 h after fertilization (Sueoka et at., 1988a). In estrous rabbits, i.v. injection of PAP caused the appearance of EPF in serum only in the presence of both the ovaries and oviducts (Sueoka et at., 1988b). In vitro perfusion studies confirmed that perfusates from both the ovary and oviduct must be present for EPF release (Sueoka et a!., 1988b). PAP released from fertilized ova might conceivably be the factor responsible for the differential transport of zygotes and ova through the oviduct in horses (Van
HARPER
910
Niekerk and Gerneke, 1966; Van Niekerk, 1976; Betteridge et al., 1976), bats (Rasweiler, 1979), and rats (Villal#{243}net al., 1982). PAP has been found in ejaculated spermatozoa of both rabbits and humans (Kumar et at., 1988a; Minhas et at., 1988). PAP antagonists exert spermicidal activity both in vitro and after vaginal instillation (Harper et al., 1989). This activity may not be due to antagonism of PAP action, but rather to the intrinsic detergentlike activity of such compounds. Although the physiological significance of PAP for sperm function is uncertain, Ricker et at. (1989) reported that the motility of “sluggish” human sperm was increased 57% by exposure to 3.69 x 10-7M PAP for 5 mm. Even spermatozoa with a normal initial velocity showed a modest increase after exposure to PAP. These data suggest that PAP plays a role in sperm motility. Uterine
PAF
Levels
PAP has been detected in uterine tissue of rats (Yasuda et at., 1986), rabbits (Yasuda et at., 1986; Angle et a!., 1988b), and humans (Alecozay et a!., 1989a). The levels observed in estrous rat uterus (21 ng/uterusu8l pmol/g wet weight) were much higher than those in estrous rabbit uterus (less than 2 pmollg) (Yasuda et at., 1986; Angle et a!., 1988b). Most of the PAP in the estrous rat uterus was found to be C16:0 AGEPC, with much smaller quantities of the C18:1 AGEPC (Yasuda et a!., 1988). Larger quantities of 1-acyl-2-acetyl GPC (acyl type PAP) were also found, the ratio of C16:0 acyl type to CI6:0 alkyl type PAP (AGEPC) being about 4.5:1 (Yasuda et al., 1988). However, the biological activity of the acyl type PAP is more than 500-fold less than that of AGEPC (Blank et at., 1982). Thus, the levels of AGEPC are likely to be of greater physiological significance. In the rabbit uterus, levels of PAP were low at estrus, and started to increase from Day 3 of pregnancy or pseudopregnancy. Peak levels of approximately 35 pmol/g were seen on Day 4 of pseudopregnancy and Day 5 of pregnancy (Angle et at., 1988b). In the pseudopregnant animals, PAP remained elevated through Day 7, whereas in pregnant ones levels had returned to estrous values on Day 7. The decline in uterine PAP was greatest at the implantation sites, and less marked in the interimplantation areas, which strongly implicates the blastocyst as a causal factor for this difference. Examination of PAP levels in endometrium and myometrium revealed that the majority of
PAP
was
in the
endometrium, and that endometrial levels varied with the reproductive state. During this stage of pregnancy in rabbits, only progesterone levels increase; thus it seemed probable that endometrial PAP was hormonally regulated by progesterone. Myometrial PAP did not vary with hormonal status (Angle et at., 1988b). Whether the increase in endometrial PAP is due to increased synthesis, decreased metabolism, or both is not known. The rapid decline at the implantation Site could be caused by release of cell-associated PAP, or to inhibition of PAP synthesis, due to presence of the blastocyst.
Endometrial
Cell
Cultures
Study of cultures of separated epithelial glandular and stromal cells from human uteri collected during the luteal phase has shown that PAP is produced by the stromal, and not by the glandular, cells. The PAP remains cell-associated, and its concentration is elevated by addition of progesterone, but not of estradiol (Alecozay et al., 1989a). Smith and Kelly (1988) demonstrated that addition of PAP to glandular cell cultures increased the release of PGE2, but not PGF2a. We have confirmed this observation, and shown that the response is amplified by estradiol, but not progesterone (Alecozay et at., 1989b). We also found that PGE2 further increases PAP concentrations in stromal cell cultures in the presence of progesterone, but not of estradiol. When stromal and glandular cells were cocultured, PAP was similarly elevated in the presence of progesterone, presumably due to glandular cell release of PCE2 (Alecozay et at., 1 989b). These results obtained from human endometrial cell cultures imply a paracrine interaction between PAP and PGE2 in the regulation of endometrial cell function. It seems clear that PAP is synthesized in the stromat, and not in the glandular, cells, and that this synthesis can be stimulated by progesterone and PGE2. These results also confirm the observations made in rabbits, where at! the PAP was found in the endometrium and was apparently increased at the time of rising progesterone levels. Uterine Binding
PAF-Specific Sites
Kudolo and Harper (1988) reported preliminary evidence of specific binding sites for PAP in rabbit uterine
PAF
AND
REPRODUCTION
membranes. These studies indicated that binding sites with similar high affinities could be found in the uteri of estrous, Day 2 pregnant and Day 6 pseudopregnant animals. More extensive studies have now been conducted using purified endometrial membrane preparations from Day 6 pregnant animals (Kudolo and Harper, 1989). By saturation analysis, the Kj was estimated as 0.8 nM and the Bm as 377 fmol/mg protein. The calculated Kd from kinetic analysis was 3.3 nM. With crude membrane preparations, a second low affinity class of binding sites was observed. Binding to the high affinity sites was saturable and thermally labile, and could be displaced by PAP and lyso-PAP and by structurally related PAP antagonists. PAP antagonists that were not structurat analogs of PAP did not compete in this system, which implies some different specificity of the uterine binding sites compared to those in other tissues (Junier et at., 1988; van Delft et at., 1988). In other systems, lyso-PAP is considered to be biologically inactive, which raises the question of the specificity of the endometrial PAP binding sites, at which lyso-PAP competes for binding. It may be that lyso-PAP acts to down-regulate the expression of these sites except in the face of a high local concentration of PAP, which may, for example, occur only at a specific time such as during the 24 h prior to implantation. In this connection, it is noteworthy that endogenous inhibitors of PAP (choline containing lysoglyceroiphospholipids and sphingophospholipids) have been found in rat uterus (Nakayama et at., 1987) and liver (Miwa et a!., 1987). It is generally considered that PAP exerts its biological actions by binding to specific receptors (see Braquet et at., 1987, and Pinckard et at., 1988, for references), and thus, given the stimulation of PGE2 release by PAP from endometrial glandular epitheliat cells, it may be supposed that such cells possess PAP binding sites. At present, the location of the PAP membrane binding sites in specific cells of the endometrium has not been determined. The signal transduction mechanism following PAP binding may be similar to that of other membrane receptors that have a direct linkage with adenylate cyclase through an inhibitory guanyl nucleotidebinding regulatory protein (Hwang et at., 1986). Implantation Spinks is
essential
and O’Neill for
(1987,
implantation
1988) in
concluded the
mouse,
that PAP because
administration
911 of PAP
antagonists
over
the
first
4 days
of pregnancy reduced the number of implantations seen on Day 8. Similarly, administration of a PAP antagonist (SRI 63-441) on Days 1-4 significantly reduced the number of uterine Pontamine Sky Blue bands on Day 4; these are an index of increased vascular permeability, which normally occurs at the implantation sites. The inhibitory action of SRI 63-441 on pregnancy could be prevented by the simultaneous administration of PAP. However, in another study (Milligan and Finn, 1988), PAP antagonists were administered hourly (i.p.) to ovariectomized mice with delayed implantation starting 1 h before and continuing for 24 h after an injection of estradiol sufficient to induce implantation. Neither implantation nor vascular permeability changes were inhibited. Similarly, PAP antagonists failed to block the vascular permeability induced by a decidual stimulus. Intraluminal instillation of PAP itself did not induce decidualization in sensitized mice, perhaps since PAP may have been rapidly metabolized. The major differences in these protocols is apparently the much longer treatment schedule of Spinks and O’Neill (1987, 1988). In rats, the situation is more clear cut. Instillation of the PAP antagonist, BN52021, into the uterine horns of rats on Day 4 of pregnancy almost completely inhibited implantation (Acker et at., 1988). This treatment was much less effective on other days of pregnancy. When PAP was instilled into one uterine horn of pseudopregnant rats on Day 5, a dose-dependent decidual reaction occurred, and this reaction was inhibited by concomitant instillation of BN52021 or indomethacin (Acker et at., 1989). BN52021 did not inhibit a decidual reaction induced by PGE2 instillation or insertion of a cotton thread (Acker et at., 1989). These studies provide at least prima facie evidence for a role of PAP in implantation and decidualization, possibly via PG release. PAP is known to be a highly potent inducer of vascular permeability (Humphrey et at., 1982, 1984; Angle et at., 1986). PAP is produced by endotheliat cells in a variety of vascular beds, but remains cell-associated (Zimmerman et a!., 1985; Whatley et at., 1988). The endothelial cell levels of PAP, and release of prostacyclin from the same cells, are increased by mediators, such as bradykinin, angiotensin II, and histamine, depending on the species and vascular source (Whatley et al., 1988). An increase in vascular permeability in the stroma at the site of impending blastocyst implantation occurring over the 24-h period prior to attachment is an obligate accompani-
912
HARPER
ment of normal implantation and decidualization. PAF is found in stromal cells, where its concentration is elevated by progesterone and also by PGE2 (produced by the glandular epithelium and also by blastocysts in some species). This increase is followed by a rapid decline at the site of the blastocyst. This suggests the possibility that stromat cell PAP is released, and combines with endothelial cell PAP, to cause endothelial cell and vascular basal membrane damage, thus resulting in vascular leakage and increased permeability. All this evidence supports a role for PAF, associated with eicosanoids, in the implantation process. Conclusion
Present evidence suggests that PAP plays a significant paracrine role in the hypothalamus and in stromalepithelial cell interactions in the uterus. The evidence for embryonic PAP, as a determinant of normal pregnancy, is suggestive, as is the possible role of embryonic and/or stromal cell PAP in the implantation process. The role of PAP in ovulation, oviduct function and sperm function, and fertilization is still uncertain. ACKNOWLEDGMENTS Thanks are due to the various collaborators the work referenced herein, in alphabetical Alecozay. Marlane J. Angle. Larry L. Espey, Jones. George B. Kudolo. Raj Kumar. Linda and Donna S. Woodard.
have assisted in portions of they are Drs. Abraham A. Donald J. Hanahan. Marjorie A. M. McManus, R. Neal Pinckard, who
order,
REFERENCES Abisogun AO. Braquet P. Tsafriri A. 1989. The involvement of platelet-activating factor in ovulation. Science 243:381-83 Acker 0. Braquet P. Mencia-Huerta JM. 1989. Role of platelet-activating factor (PAF) in the initiation of the decidual reaction in the rat. J Reprod Fertil 85:623-29 Acker 0, Hecquet F. Etienne A, Braquet P. Mencia-Huerta JM. 1988. Role of platelet-activating factor (PAF) in the ovoimplantation in the rat: effect of the specific PAF-acether antagonist, BN52021. Prostaglandins 35: 233-41 Alecozay AA, Cassl#{233}nBG. Riehl RM. DeLeon FD. Nouchi T, Hanahan DJ. 1989a. Platelet-activating luteal phase cndometrium. Biol Reprod (in press)
Harper factor
MJK, (PAF)
Silva M, in human
AA, Schenken RS, Hanahan Di. Nouchi 1. Silva M, Harper MJK, 1989b. Paracrine interactions between platelet-activating factor and prostaglandin E2 (POE2) in human luteal phase endometrial cell cultures. The Endocrine Society 71st Ann Meeting, Program and Abstracts (in press) Angle J, Byrd W. Johnston JM, l988a. Embryonic production of platelet-activating factor in culture. Ferul Steril 44th Ann Meeting Program Suppl:
Alecozay
Angle
S96 (Abstr. Mi, Jones
P-158) MA, McManus
LM,
Pinckard
RN,
Harper
MJK,
1988b.
Plate-
let-activating factor in the rabbit uterus during early pregnancy. J Reprod Fertil 83:711-22 Angle Mi, McManus LM. Pinckard RN, 1986. Age-dependent differential dc-
velopment of leukotactic matory mediators. Lab Benveniste mine
J. Henson
PM.
and vasoactive Invest 55:616-21 Cochranc
responsiveness
CG,
1972.
to acute
Leukocyte-dependent
release from rabbit platelets: the role of IgE, basophils activating factor. J Exp Med 136:1356-77
inflam-
histaand a platelet-
Betteridge KJ, Flood PF. Mitchell D, 1976. Possible role of the embryo in the control of oviductal transport in mares. In: Harper MJK. Pauerstein CJ, Adams CE. Coutinho EM, Croxatto HB, Palon DM (eds.). Ovum Transport and Fertility Regulation. Copenhagen:Scriptor, pp. 381-89 Blank ML. Cress EA. Lee T-C, Malone B, Surles JR. Piantadosi C. Hajdu J, Snyder F. 1982. Structural features acetyl-sn-glycero-3-phosphocholine) let serotonin releases. Rca Commun Braquet P. Godfroid JJ, 1986. PAF-acether Braquet
of platelet
activating factor (1-alkyl-2for hypotensive and plateChem Pathol Pharmacol 38:3-20 specific binding sites: 2. Design of
specific antagonists. Trends Phannacol P. Touqw L, Shen TY. Vargaftig activating factor research. Pharmacol
required
Sci 7:397-403 BB, 1987. Perspectives Rev 39:97-145
in platelet-
Camoratto AM. Grandison L. 1989. Platelet-activating factor stimulates prolactin release from dispersed rat anterior pituitary cells in vitro. Endocrinology 124:1502-06 Collier M. O’Neill C, Ammit AJ, Saunders DM. 1988. Biochemical and phaxmacological characterization of human embryo-derived platelet-activating factor. Human Reprod 3:993-98 Demopoulos CA. Pinckard RN. Hanahan DJ. 1979. Platelet-activating factor. Evidence for 1-O-alkyl-2-acctyl-sn-glyceryl-3-phosphoiylcholine as the active component a new class of lipid chemical mediators). J Biol Chem Espey
254:9355-58 LL, Tanaka
N, Woodard
DS,
Dombroski
RA,
Harper
MIX.
Okamura
H,
1989. Decrease of ovarian platelet-activating factor during ovulation in the gonadotropin-primed immature rat. Biol Reprod (in press) Femandez-Gallardo 5, Gijon MA, Garcia Mdcl C, CanoE, Sanchez Crespo M, 1988. Biosynthesis of platelet-activating factor in glandular gastric mucoas. Evidence for the involvement of the de novo’ pathway and modulation by fatty acids. Biochem J 254:707-14 Godfroid JJ, Braquet P. 1986. PAF-Acether specific binding sites. 1. Quantitative SAR study of PAF-Acether isosteres. Trends Pharmacol Sci 7: 368-73 Harper MJK, Kudolo GB, Alecozay AA, Jones MA. 1989. Platelet-activating factor (PAF) and blastocyst-endometrial interactions. In: Yoshinaga K, Mon I (eds.), Development of Preimplantation Embryos and their Environment. New York: Alan R. Liss, Inc. Progr Clin Biol Res 294:305-15 Harper MJK. Woodard D5, Norris CJ, 1989. Spermicidal effect of antagonists of platelet-activating factor. Fertil Steril 51:890-95 Humphrey DM, McManus LM, Hanahan DJ, Pinckard RN, 1984. Morphologic basis of increased vascular permeability induced by acetyl glyceiyl ether phosphorylcholine. Lab invest 50:16-25 Humphrey DM, McManus LM, Satouchi K, Hanahan Di, Pinckard RN, 1982. Vasoactive properties of acetyl glyceryl ether phosphoiylcholine and analogues. Lab Invest 46:422-27 Hwang S-B, Lam M-H. Pong S-S. 1986. Ionic and GTP regulation of binding of platelet-activating factor to receptors and platelet-activating factor-induced activation of GTPase in rabbit platelet membranes. J Biol Chem 261:532-37 Junier PM, Tiberghien C, Rougeot C, Fafeur V. Dray F. 1988. Inhibitory effect of platelet-activating factor (PAF) on luteinizing hormone-releasing hormone and somatostatin release from rat median eminence in vitro correlated with the characterization of specific PAF receptor sites in rat hypothalamus. Endocrinology 123:72-80 Kudolo GB. Harper MJK. 1988. Binding parameters of rabbit uterine PAFreceptors:pilot study. Biol Reprod 38 (Suppl. 1): 153 (Abst. 314) Kudolo GB, Harper MJK, 1989. Characterization of platelet-activating factor binding sites on uterine membranes from pregnant rabbits. Biol Reprod (in press) Kumar R, Harper MJK. Hanahan Di. 1988a. Occurrence of platelet-activating factor in rabbit spermatozoa. Arch Biochem Biophys 260:497-502 Kumar R, Harvey SAK, Kester M, Hanahan Di, Olson MS, 1988b. Production and effects of platelet-activating factor in the rat brain. Biochim Biophys Acta 963:375-83 Ludwig JC, Hoppens CL, McManus LM, Mott GE, Pinckard RN, 1985. Modulation of platelet-activating factor (PAF) synthesis and release from human polymorphonuclear leukocytes (PMN): role of extracellular albu-
PAF
AND
REPRODUCTION
miii. Arch Biochem Biophys 241:337-47 Ludwig IC, Pinckard RN, 1987. Diversity in the chemical phil-derived platelet-activating factors. In: Winslow New
Horizons
in Platelet-Activating
Factor
structures of neutroCM. Lee ML (eds.). Research. New York: John
& Sons Ltd., pp. 59-71 Milligan SR. Finn CA, 1988. Failure to demonstrate platelet activating factor involvement in implantation in mice. J Reprod Fertil Abstract Ser No 2:29 (Abstr. 53) Minhas BS, Kumar R, Dodson MG, Palmer TV, Harrill JL Robertson IL, 1988. The presence of platelet-activating factor (PAF)-like activity in human spermatozoa and its implications concerning male infertility. Fertil Steril 44th Ann Meeting Program Suppl:522-23 (Absir. 065) Miwa M, Hill C, Kumar R, Sugatani J, Olson MS. Hanahan Di, 1987. Occurrence of an endogenous inhibitor of platelet-activating factor in rat liver. J Biol Chem 262:527-30 Morton H, Hegh V. Clunie GJA, 1974. lmmunosuppression detected in pregnant mice by rosette inhibition test. Nature (Lund) 249:459-60 Nakayama R, Yasuda K, Saito K. 1987. Existence of endogenous inhibitors of platelet-activating factor (PAF) with PAF in rat uterus. I Biol Chem 262: 13174-79 Nishihira J. Ishibashi I, Imai Y, Muramatsu 1. 1984. Mass spectrometric evi-
Rasweiler IV ii. 1979. Differential transport of embryos by the oviducts of the long-tongued bat. Glossophaga Fettil Renooij
W,
55:329-34 Snyder
F,
1981.
Biosynthesis
of
and
degenerating ova soricina. J Reprod
1-alkyl-2-acetyl-sn-glycerol-3-
Wiley
(platelet-activating factor and a hypotensive lipid) by cholinephosphotransferase in various rat tissues. Biochim Biophys Acts 663:545-56 Ricker DD, Minhas BS, Kumar R, Randall OW, Dodson MG. Harrill JL, Robertson JL, 1989. The effects of platelet activating factor on the motility of human spermatozoa. Theriogenology 31:247 (Absir.) Schlondorif D, Goldwasser P, Neuwirth R, Satnano JA, Clay KL, 1986. Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells. Am J Physiol 250:F1 123-27 Smith SK. Kelly RW, 1988. Effect of platelet-activating factor on the release of PGF-2a and PGE-2 by separated cells of human endometrium. .1 Reprod Fertil 82:271-76 Spinks NR, O’Neill C, 1987. Embryo-derived platelet-activating factor is essential for establishment of pregnancy in the mouse. Lancet 1:106-07 Spinks NR, O’Neill C, 1988. Antagonists of embryo-derived platelet-activating factor prevent implantation in the mouse. J Reprod Fertil 84:89-98 Sueoka K. Dharmarajan AM. Michael E, Atlas SJ, Wallach EE. 1988a. Detec-
dence
tion of early pregnancy factor (EPF) using the rabbit ovary and oviduct perfused in vitro. J Reprod Fertil 84:325-31 Sueoka K. Dhannarajan AM, Miyazaki T, Atlas SJ, Wallach EE, l988b. Platelet activating factor-induced early pregnancy factor activity from the perfused rabbit ovary and oviduct. Am J Obstet Gynecol 159:1580-84 Sugatani J, Fujimura K, Miwa M, Mizuno T, Sameshima Y, Saito K, 1989. Occurrence of platelet-activating factor (PAP) in normal rat stomach and alteration of PAP level by water immersion stress. FASEB J Monogr 3: 65-70 Tenc#{233} M, CodffierE, Heymans F, Polonsky I, Godfroid JJ, Benveniste J. 1981. Structural analogs of platelet-activating factor (PAF-Acether). Biochimie 63:723-27 Tokumura A, Homma H, Hanahan Di, 1985. Structural analogs of alkylacetylglycerophosphocholine. Inhibitory behavior on platelet activation. J Biol Chesn 260:12710-14 Tokumura A, Kamiyasu K, Takauchi K, Tsukatani H, 1987. Evidence for existence of various homologues and analogues of platelet activating factor in a lipid extract of bovine brain. Biochem Biophys Res Common 145: 4 15-25 van DeIft JL. van Haeringen NJ, Verbeij NLJ, Domingo MT. Chabrier PE, Braquet P, 1988. Specific receptor sites for PAF in iris and ciliary body of the rabbit eye. Current Eye Res 7:1063-68 Van Niekerk CH, 1976. Retention of unfertilized ova in the oviducts of mares. in: Harper MJK, Pauerstein Ci, Adams CE, Coutinho EM, Croxatto HB, Paton DM (eds.). Ovum Transport and Fertility Regulation. Copenhagen: Scriptor, pp.375-80 Van Niekerk CH, Gemeke WH, 1966. Persistence and parthenogenetic cleavage of tubal ova in the mare. Onderstepoort I Vet Res 33:195-232 Villaldn M, Ortiz ME, Aguayo C. Mufioz I. Croxatto HB, 1982. Differential transport of fertilized and unfertilized ova in the rat. Biol Reprod 26: 337-41 Whatley RE, Zimmerman GA, Mcintyre TM, Prescott SM, 1988. Endothelium from diverse vascular sources synthesizes platelet-activating factor. Arteriosclerosis 8:321-31 Yasuda K, Satouchi K, Nakayama R, Saito K, 1988. Acyl type platelet-activating factor in normal rat uterus determined by gas chromatography mass spectrometry. Biomed Environ Mass Spectrum 16:137-41 Yasuda K, Satouchi K. Saito K. 1986. Platelet-activating factor in normal rat uterus. Biochem Biophys Res Common 138:1231-36 Zimmerman GA, Mcintyre TM. Prescott SM, 1985. Production of plateletactivating factor by human vascular endothelial cells: evidence for a requirement for specific agonists and modulation by prostacyclin. Circulation 72:718-27
for the presence of platelet-activating factor (l-O-alkyl-2-acetylsn-glycero-3-phosphocholine) in human amniotic fluid during labor. Lipids 19:907-10 O’Neill C, 1985a. Thrombocytopenia is an initial maternal response to fertilization in mice. J Reprod Fertil 73:559-66 O’Neill
C, 1985b. Examination of the causes of early pregnancy-associated thrombocytopenia in mice. J Reprod Fertil 73:567-77 O’Neill C, 1985c. Partial characterization of the embryo-derived platelet-activating factor in mice. I Reprod Fertil 75:375-80 O’Neill C. 1987. Embryo-derived platelet-activating factor: a preimplantation embryo mediator of maternal recognition of pregnancy. Domestic Anim Endocrinology 4:69-85 O’Neill C. 1989. PAF: an essential embryonic autocoid and an initial mediator of maternal recognition of pregnancy. Society for Gynecologic Invest. Scientific Program and Abstracts, 36th Aim Meeting:38-39 C. Gidley-Baird AA, Pike IL, Porter RN. Sinosich Mi, Saunders DM, 1985. Maternal blood platelet physiology and luteal -phase endocrinology as a means of monitoring pre- and postimplantation embryo viability following in vitro fertilization. J In Vitro Fertil Embryo Transf 2:87-93 O’Neill C, Gidley-Baird AA, Pike IL, Saunders DM, 1987. Use of a bioassay for embryo-derived platelet-activating factor as a means of assessing quality and pregnancy potential of human embryos. Ferul Steril 47: 969-75 Orozco C, Perkins T. Clarke FM, 1986. Platelet-activating factor induces the expression of early pregnancy factor activity in female mice. J Reprod Fertil 78:549-55 Pinckard RN, Farr RS, Hanahan Di, 1979. Physicochcmical and functional identity of platelet-activating factor (PAF) released in vivo during IgE anaphylaxis with PAP released in vitro from IgE sensitized rabbit basophils. I Immunol 123:1847-57 Pinckard RN, Jackson EM. Hoppens C, Weintraub ST. Ludwig IC, McManus LM, Mott GE. 1984. Molecular heterogeneity of platelet activating factor produced by stimulated human polymorphonuclear leukocytes. Biochem Biophys Rca Commun 122:325-32 Pinckard RN, Ludwig JC, McManus LM, 1988. Platelet-activating factors. In: Gallin JI, Goldstein IM, Snyderman R (eds.), Inflammation: Basic Principles and Clinical Correlates. New York: Raven Press. Ltd.. pp. 139-67 Pinckard RN, McManus LM, Hanahan DJ, 1982. Chemistry and biology of acetyl glyceryl ether phosphoiylcholine (Platelet-activating factor). Adv Inflammation Res 4:147-80 Pirotzky E, Bidault J, Burtin C, Gubler MC, Benveniste J, 1984. Release of platelet-activating factor, slow-reacting substance, and vasoactive species from isolated rat kidneys. Kidney ut 25:404-10 O’Neill
913
phosphocholine
