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`Volume 11, Number 1 (1982)
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`Research Article
`
`Passage of Chemicals into Human and Animal Semen: Mechanisms and Significance
`Thaddeus Mann, Cecilia Lutwak Mann, Robert L. Dixon
`Critical Reviews in Toxicology Jan 1982, Vol. 11, No. 1: 1–14.
`| References | PDF (1070 KB) | PDF Plus (437 KB)
`
`Immunology of Hypersensitivity Pneumonitis
`Richard P. Stankus, Jane E. Morgan, John E. Salvaggio, Leon Golberg
`Critical Reviews in Toxicology Jan 1982, Vol. 11, No. 1: 15–32.
`| References | PDF (1314 KB) | PDF Plus (508 KB)
`
`A Critical Review of the Literature on Nitrobenzene Toxicity
`Robert O. Beauchamp, Richard D. Irons, Douglas E. Rickert, D. Bruce Couch, Thomas E.
`Hamm, J. P. Lyon
`Critical Reviews in Toxicology Jan 1982, Vol. 11, No. 1: 33–84.
`| References | PDF (3337 KB) | PDF Plus (1281 KB)
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`PASSAGE OF CHEMICALS INTO HUMAN A N D ANIMAL SEMEN
`MECHANlSMS A N D SIGNIFICANCE
`
`Volume 11, Issue 1
`
`1
`
`Authors:
`
`Thaddeus Mann
`Cecilia Lutwak-Mann
`University of Cambridge
`Cambridge, Great Britain; and
`National Institute of Child Health and
`Human Development
`Bethesda, Maryland
`
`Referee:
`
`Robert L. Dixon
`Laboratory of Reproductive a n d Developmental
`7-oxlcology
`National Institute of Environmental Health Sciences
`Research Triangle Park, North Carolina
`
`1. GENERAL CONSlDERATIONS ON T H E SECRETORY MECHANISMS
`IN THE MALE REPRODUCTIVE TRACT
`
`The male reproductive tract offers no barrier to many chemicals of exogenous origin.
`A number of such compounds cross into the fluids secreted by the testes and male
`accessory organs of reproduction, and ultimately pass into semen. This peculiar behavior
`of the male reproductive tract is largely inherent in the nature of the secretory
`mechanisms which operate in it. Furthermore, though the bulk of the material secreted
`by the epithelia which line the reproductive tract is composed of soluble substances, some
`of the secretory fluids also contain a variety of so-called debris or particulate matter in
`various shapes and 'sizes, sequestered from the secretory cells in the course of their
`activity.
`
`A. Apocrine and Merocrine Secretory Processes
`Two distinct mechanisms, namely an apocrine and a merocrine one, govern the
`secretory function of the male reproductive tract in mammals. The extent to which these
`two processes contribute quantitatively to the secretory activity in the male reproductive
`organs is still a matter of dispute but, in any case, it is subject to considerable interspecies
`variations as pointed out and extensively discussed in our monograph.' The apocrine
`mechanism is the one in which portions of the cytoplasm are discharged by the secretory
`cells together with the soluble secretory products. The merocrine mechanism on the other
`hand, is one in which the secretory cells remain intact in the course of their secretory
`activity. It is the apocrine mechanism which is responsible for the discharge of the
`seminal dkbris which, in most cases investigated, was found to consist of membrane
`fragments and portions of the apical cytoplasmic matrix. It is also the operation of the
`apocrine mechanism which probably provides at least partial explanation for the
`presence in the seminal plasma of so many enzymes, including those involved in
`glycolysis, which ordinarily one tends to associate with the intra- rather than
`extracellular milieu of the body. But there can be no doubt that the merocrine mechanism
`is also important for full secretory function of the epithelia which line the male
`reproductive tract as shown, for example, by the detailed study of the secretory
`mechanism operating in the ventral lobes of the rat prostate.*
`Another important fact to consider in assessing the results of any study on the passage
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`of chemicals into semen is that the extent to which the apocrine and merocrine
`mechanisms operate in the male reproductive tract is different in the testis, epididymis,
`vas deferens, ampulla, seminal vesicle, bulbourethral (Cowper’s) gland, urethral
`(Littrk’s) glands and other parts of the tract. In this respect, there is a particularly marked
`difference between the mechanism underlying the secretion of the clear, watery, and
`protein-poor fluid by the testis, an organ characterized by a dependence on the blood-
`testis barrier, and that operative in glands such as the prostate or the seminal vesicle,
`which are largely responsible for contributing particular matter or cellular detritus,
`usually referred to as the “debris”, to ejaculated semen. From this it follows that in order
`to assess properly and to interpret correctly the results of analysis of a chemical in seminal
`plasma (the composite mixture of all the secretions which constitute the liquid portion of
`ejaculated semen), the question must be asked whether this particular chemical has found
`its way into the ejaculate via testicular plasma (the fluid portion of testicular semen),
`epididymal plasma (fluid portion of epididymal semen), vas deferens and ampullary
`secretions, or the secretory fluids contributed to the whole ejaculate by the seminal
`vesicles, prostate, Cowper’s gland, and Littri’s glands, respectively.
`
`B. Exogenous and Endogenous Origin of Secreted Substances
`Yet another question to be answered is whether a given substance detected in semen is
`of exogenous or endogenous origin. A typical example of exogenous substances is
`provided by foreign substances, drugs for example, which having been ingested or
`injected, then have passed (either in their original form or as metabolites) into the tissues
`and body fluids, including the male reproductive glands and their secretions.
`Endogenous substances are natural products of the body; that is, metabolites which
`having originated in the body itself, but outside the male reproductive tract, subsequently
`crossed into the secretory fluids of that tract.
`Relatively little attention has been given so far to the ways in which chemicals can
`reach whole ejaculated seminal plasma, and the possibility of interactions between
`chemicals in the seminal plasma and the ejaculated spermatozoa. This, in spite of the
`existence of a large and fast growing literature on the subject of pharmacological effects
`exerted upon male reproductive function as a whole, by a variety of foreign chemicals,
`including substances as far apart as antispermatogenic (antifertility) agents, antiandro-
`gens, narcotics, pesticides, all sorts of chemotherapeutic and industrial compounds, food
`additives, and many other substances; the literature on this subject has been extensively
`and repeatedly reviewed.’”-’’
`
`11. ENTRY OF CHEMICALS INTO T H E TESTIS A N D
`TESTICULAR SEMEN
`
`A. Role of Blood, Lymph, and Scrota1 Skin
`There are several ways in which foreign chemicals are able to penetrate into the testis.
`Blood and lymph (after absorption from the gastrointestinal tract) are the most obvious
`vehicle. An alternative route is occasionally provided by the skin (after local application),
`as shown by the behavior of ‘Tris-BP’ (tris[2,3-dibromopropyl]phosphate), a major
`flame-retardant chemical used at one time extensively for impregnating childrens’
`clothing. This mutagen and carcinogen has been known(since 1977) to produce testicular
`atrophy and sterility in rabbits after cutaneous application and, more recently, 2,3-
`dibromopropanol, a metabolite of Tris-BP and a mutagen itself, has been found in urine
`samples of children who had been wearing Tris-BP-treated sleepwear.’* Potential
`adverse reproductive effects of Tris-BP and similar compounds are of special concern to
`men since the human scrotum is known to be more permeable to chemicals than other
`skin areas. This peculiarity is also shared by the skin of animals. Organophosphates for
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`instance, a group of compoynds widely used in agriculture as powerful insecticides, easily
`penetrate the skin of cattle. When applied to the hairy parts ofa bull’sskin, they produce
`only a minor and transient decline in motility of ejaculated spermatozoa, but application
`to the scrota1 skin lowers much more distinctly the quality of ejaculated bovine semen.”
`
`B. Inhalation as Route of Entry
`Inhalation of a toxic chemical constitutes yet another route along which that substance
`or its metabolites might enter the blood and ultimately reach the testis. Inhaled
`1,2-dibromo-3-chloropropane, a soil fumigant against nematodes, possesses marked
`antispermatogenic properties. I t causes severe degenerative changes in animal testes and
`atrophy of germinal epithelium in factory workers who had been chronically exposed to
`it.l4-I5 Screening tests performed on 7 1 workers showed that in 15 of the men employed in
`the production of dibromochloropropane there was severe oligospermia in semen;
`patchy hyalinization, but with some production of spermatozoa continuing, was the
`main histological finding in their testes. However, when the examination of semen was
`repeated 18 to 20 months after the last contact with the nematocide, significant
`improvement in the sperm count was noted in ejaculates, thus indicating that recovery of
`spermatogenesis is possible following withdrawal of dibromochloropropane.16
`
`C. Permeability of the Blood-Testis Barrier and Passage of Chemicals into Testicular
`Plasma
`Notwithstanding the function of the blood-testis barrier, a variety of chemical
`substances, including some antifertility drugs, pass into the testicular plasma - that is
`the fluid composed of the secretions originating in the seminiferous tubules, tubuli recti,
`rete testis (“rete-testis fluid”) and ductuli efferentes - which provides the suspending
`medium for the testicular spermatozoa (the latter still immotile and infertile)at the point
`of their entry into the caput epididymidis. The accessibility of testicular plasma to a
`selective range of compounds has been demonstrated amply thanks to the availability of
`microsurgical cannulation and catheterization techniques which permit the collection of
`substantial amounts of fluid from different regions of the exocrine system of the testis.
`For example, to obtain testicular semen from the ductuli efferentes of a ram, one uses a
`special catheter, about 30 cm long and 0.5 mm wide, which can be directly inserted into
`this portion of the exocrine system, thus enabling one to collect 1 to 2 mP testicular semen
`per hour, without seriously disturbing the ram’s feeding habits and other functions.
`Similar methods are available for various other animals such as the bull, rabbit, hamster,
`and rat. For the collection of fluid directly from the seminiferous tubules of a rat, a
`micropuncture technique is used resembling in principle the standard technique
`employed in the examination of kidney function. In addition to a method for collecting
`free-flowing fluid from a whole seminiferous tubule of the rat, one call use a
`microsurgical technique specially devised for obtaining fluid from different segmtnts of a
`single tubule. Using methods of this kind it has been possible to demonstrate that such
`diverse substances as ethanol, glycerol, a variety of steroids (testosterone in particular),
`a-chlorohydrin, iodoantipyrine, methanesulphonate, dimethylnitrosamine, barbiturates,
`and sulphonamides, cross the blood-testis barrier and reach the testicular plasma.”-*’
`The permeability of the blood-testis barrier is, however, by no means the sole factor on
`which the composition of testicular plasma is normally dependent. The events leading to
`the passage of inositol into the testicular plasma may serve as a n example. The ram rete-
`testis fluid normally contains inositol at a concentration level about 100 times higher than
`in blood plasma. Yet, upon i.v. infusion of radioactive inositol, little if any of the
`radioactivity can be demonstrated in the rete-testis fluid. However, upon administration
`of labeled glucose, radioactive inositol appears promptly in the testicular plasma, having
`been formed from glucose as a characteristic metabolite by the testis itself.24 The high
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`concentration of inositol in the rete-testis fluid probably reflects the rapid conversion of
`glucose to inositol.
`111. ENTRY OF CHEMICALS INTO T H E EPIDIDYMIS AND
`EPIDIDYMAL SEMEN
`
`A. Cannulation and Micropuncture of the Epididymis
`Cannulation and micropuncture are used commonly as methods for obtaining
`epididymal semen and demonstrating the passage of exogenous chemicals into that
`semen, collected either entire (that is at the point where the cauda epididymidis joins the
`vas deferens) or in separate fractions collected from distinct regions of the epididymis
`(that is the caput, corpus, and cauda). An example is the cannulation technique worked
`out for collection of epididymal semen from a rabbit.25 First, the testis, epididymis, and
`vas deferens of an anaesthetized buck are exposed through a scrota1 incision. Next, the
`vas deferens is cannulated close to the cauda epididymidis by means of a cannula partly
`filled with mineral oil, and electric current is then applied to stimulate contractions of the
`epididymis and thereby to propel the epididymal contents from the proximal region of
`the cauda into the cannula. The epididymal semen thus procured can then be separated
`into spermatozoa and epididymal plasma by centrifugation in a microspermatocrit
`capillary tube. Cannulation and micropuncture have also been used successfully for
`collection of epididymal semen from rats.
`B. Transfer of Proteins, Chlorohydrin, and Carnitine
`Rat epididymal plasma obtained by the above methods, has been used, among others,
`for differentiating between those protein constituents that are generated and secreted by
`the epididymis itself, and other proteins which are of exogenous nature and enter the
`epididymis from the blood.26 A further methodological refinement is achieved by placing
`ligatures on the tubuli recti of the testis, thereby stopping the entry of fluid from the testis
`into the epididymis.” In this manner it is possible to determine whether a given
`antifertility agent which acts predominantly on epididymal spermatozoa (for example,
`a-chlorohydrin) has arrived in the epididymis via the testicular semen, or by direct
`secretion into the epididymal tubules. As regards a-chlorohydrin, there is good evidence
`that this substance is capable of entering both testicular and epididymal
`Considerations similar to those which apply to a-chlorohydrin or indeed to
`antifertility agents in general, equally apply to certain natural body constituents which
`are formed outside the epididymis but enter this organ subsequently and areaccumulated
`by it. A good example of the latter type of compounds is carnitine, a major natural
`constitutent of epididymal semen in several mammalian species. The main site of
`carnitine accumulation is the cauda epididymidis, but some carnitine is also present in the
`luminal contents collected by micropuncture from the caput. In the rat, the concentration
`of carnitine in the epididymal plasma obtained from the cauda-semen is about 2000 times
`higher than in blood plasma, but most of it originates not in the epididymis as such, but
`has reached this organ from the outside, probably mainly via blood. Not only is the
`epididymis able to accumulate carnitine and secrete it into the tubular fluid in vivo, but
`when sections of the rat epididymal tubules are incubated in vitro in the presence of a
`medium containing 8 to 10 nmol [ ’H]carnitine/ mP, the intracellular concentration of
`carnitine quickly increases and ultimately can reach a level of 1400 t o 3200 nmol/g.*’
`
`1V. PASSAGE OF CHEMICALS INTO T H E SECRETIONS OF T H E
`PROSTATE AND T H E SEMINAL VESICLE
`
`A. Alcohol, Sulphonarnides, and Antibiotics
`One of the historically earliest indications of a foreign chemical passing into the
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`Volume 11, Issue 1
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`5
`
`prostatic secretion concerns ethyl alcohol, which was shown t o be excreted by the dog in
`its prostatic secretion (90 t o 594 mg/ 100 mQ) following alcohol admini~tration.~’Soon
`afterwards followed the demonstration that sulphonamides behave similarly; several of
`them were shown to pass readily into semen, not only in animals, but in man as ell.^'-^^
`Several other substances, including various antibiotics, accumulate in the prostatic
`secretion and it has been noted that weak organic bases such as erythromycin, for
`instance, tend to become more concentrated than weak acids, e.g., ampicillin or
`cephalosporin. It is conceivable that the prostatic secretion, being slightly acid, is able to
`trap preferentially ions of weak bases rather than weak a ~ i d s . ~ ’ As regards the rates at
`which the aforementioned and other exogenous substances pass through the prostate, a
`distinction must also be drawn between the so-called “resting” and “activated prostatic
`secretion”.
`
`B. Proteins, Zinc, and Ergothioneine
`Not only exogenous substances but a great many natural body constituents are
`secreted by the prostate. Of the various proteins present in the human prostatic fluid,
`several so closely resemble blood-serum proteins that they must be assumed to have
`reached that fluid from the blood.3R Zinc, of which the human seminal plasma contains,
`on the average, as much as 14 mg/100 m , is largely contributed by the prostatic
`secretion, and the same is true of the dog semenfwith a lower zinc content). The high level
`of zinc in human seminal plasma can be raised further by oral administration of zinc
`sulphate, provided that large doses of this salt are used, of the order of 240 mg daily and
`for extended periods of time.39 Such doses are, of course, huge when compared with the
`normal intake of zinc in the human diet which hardly ever exceeds 10 mg per day. When
`administered to a dog, Zn6’ promptly appears in the prostatic fluid, partly at least in the
`form of a polypeptide ~ o m p l e x ; ~ ’
`this is one more example of the ability of exogenous
`zinc to cross into the lumen of the male reproductive tract.
`Likewise, the secretion of the seminal vesicles can carry chemicals into the semen. A
`particularly interesting example is the passage of ergothioneine. This base, a betaine of
`thiolhistidine, occurs normally at a high concentration in the boar seminal vesicle
`secretion, but it can be shown by feeding a boar with syntheti~[~~S]ergothioneine, that at
`least some of the radioactive ergothioneine promptly reaches boar’s semen (collected by
`artificial ~ a g i n a ) . ~ ’
`V. DRUGS IN T H E SEMINAL PLASMA A N D THEIR INTERACTION
`WITH THE SPERMATOZOA
`
`Since whole ejaculates are much easier t o procure from a male (man or animal), than
`the individual male accessory fluids, it is not surprising that what has been learned so far
`about the quantitative aspects of the passage of chemicals into the male reproductive
`tract is derived largely from analyses performed on the whole semen rather than the
`accessory fluids. The use of whole semen in analytical studies of this kind carriesdefinite
`advantages, but has also certain disadvantages.
`
`A. Appraisal of Analytical Findings in Whole Ejaculated Semen and Seminal Plasma
`An important advantage inherent in the use of whole ejaculates from man or animal is
`that semen of this kind can be collected repeatedly and, if need be, over long periods of
`time, thus making it possible t o follow the time-course of the passage of a given chemical
`from the moment of its administration and appearance in semen to the time of its
`disappearance. By separating the whole ejaculate into spermatozoa and seminal plasma
`(usually by centrifugation but occasionally by other methods, e.g., Millipore filters), it is
`also possible to draw a distinction between intracellularly and extracellularly distributed
`chemicals, provided one does not lose sight of the possibility that a given chemical of
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`extraneous origin, which had found its way into the semen, was first excreted in the
`seminal plasma and has been incorporated only subsequently into the spermatozoa
`owing to sperm-seminal plasma interaction. Moreover, by using whole semen in studies
`on the passage of drugs, and examining the spermatozoa themselves, one should be able
`to discover whether a given chemical that had interacted with the spermatozoa produced
`an adverse effect in respect of the integrity and function of individual sperm organelles
`(plasmalemma, acrosome, mitochondria of the middle piece, axoneme) and either
`motility or fertilizing ability of the spermatozoa (the latter assessed by artificial
`insemination).
`The main disadvantage in the use of whole semen is that the mere presence in it of a
`chemical provides no clue as to the route of entry of that chemical into the male
`reproductive tract (that is, the site of secretion). This difficulty, however, can be partly
`overcome by analyses of so-called split ejaculates, to which more detailed reference will
`be made later in our article. Another disadvantage inherent in the use of whole ejaculated
`semen is the possibility that the ejaculate, while passing through the urethra, becomes
`contaminated with urine carrying the same chemical as the one detected in the semen.
`This difficulty can be overcome, a t least partly, by analyzing samples of both semen and
`urine obtained from the same individual. A study of this kind is described below; it
`concerns the aforementioned ability of 35S-labeled ergothioneine to pass into boar
`semen.4’
`[35S]Ergothioneine (0.4 g, giving 2 X lo7 counts per min) was dissolved in water (400
`ma) and an aliquot of this solution (30 mQ) added to the food of the boar each day on 13
`successive days. Urine samples were collected on the third and fifth day after termination
`of the feeding period, and semen was collected (by artificial vagina) on the fifth and ninth
`days. It could thus be shown that while both urine samples showed only negligible
`radioactivity, the two ejaculates (combined) which represented 111 offluid and yielded on
`purification 124 mg ergothioneine, contained this base in a highly radioactive form; the
`radioactivity was determined using 35S derived from semen in the form of the bromine-
`oxidizable sulphur fraction.
`
`C. Effect of Excreted Drugs on Spermatozoa
`As previously mentioned, ethyl alcohol administered to a dog is secreted in the
`prostatic fluid. Ethanol, ingested by man, also passes into the semen. In view of the
`considerable evidence, proving that alcoholism affects male libido, erection, ejaculation,
`copulatory behavior, and male fertility adversely, one might easily be led to conclude that
`alcohol which has actually passed into the semen has a direct deleterious effect on the
`ejaculated spermatozoa. But this does not appear to be the case, in spite of the fact that in
`chronically alcoholic men and animals there is a high incidence of structural
`
`abnormalities in testicular spermat~zoa.~’ In vitro, ejaculated spermatozoa appear to be
`highly resistant to treatment with ethanol. It was shown in 1913 that the motility of dog
`spermatozoa is not affected by adding 2 to 5% alcohol to them, and in the same year
`succeeded in obtaining normal puppies from a bitch artifically inseminated
`l v a n ~ v ~ ~ ’ ~ ~
`with dog semen to which 10% of alcohol was added prior to insemination. Similarly,
`elephant spermatozoa seem to be extraordinarily resistant to alcohol in vitro, in-so-far as
`can be judged from the observation that the addition of 20% ethanol to the sperm-Ringer
`diluent does not affect adversely the motility of elephant spermat~zoa.~’
`Salicylic acid derivatives which, like ethanol and various sulphonamides, pass into
`human and animal semen, also appear nontoxic to spermatozoa in vitro. but they d o
`exert an effect on the semen by markedly reducing its content of prostaglandins. This is
`understandable in view of the strongly inhibitory action which compounds such as
`aspirin and indomethacin have on the biosynthesis of prostaglandins in the seminal
`v e s i c ~ e s . ~ ~ - ~ ~
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`D. Rates of Drug Passage into Semen and the Semen/Blood-Plasma Concentration
`Ratio
`The rates at which drugs pass into human semen have been investigated in respect to
`several antibiotics including ampicillin, erythromycin, and cephalexin.s0,51 In some of
`these studies, semen analyses were run concurrently with blood analyses. It was found
`that 2 hr after oral administration of 160 mg of trimethoprim and 800 mg of
`sulphamethoxazole, the concentration of trimethoprim was equal to or higher in semen
`than in blood plasma, while the values for sulphamethoxazole were 20 to 74 pg/ mll in the
`seminal plasma and 58 t o 76 in blood plasma.s2
`Methadone, phenytoin, valproic acid, tranexamic acid, and selenite are all capable of
`passing into semen. Methadone, the potent analgesic pharmacologically resembling
`morphine, is excreted in rabbit and human semen; the semen/ blood concentration ratio
`of methadone was given as 1.8 in man,53 and 6 to 10 in the rabbit.54 Special significance
`attaches to the observation that when methadone is given to male rats before mating, the
`offspring of females mated to these males is adversely affected; namely, neonatal
`mortality is increased and the young show a distinctly reduced weight a t the time of birth
`Phenytoin (diphenylhydantoin) injected to a male rabbit as a single
`and ~ e a n i n g . ~ ~ . ’ ~
`dose of 4.64 mg, passes quickly into the blood and semen; the semen/ blood plasma
`concentration ratio in such a rabbit is about 0.2 and persists at this level over a period of
`at least 8 hr.” The same anticonvulsant drug, when orally administered to epileptic
`patients, is established in blood plasma at a concentration of 13.8 pg/mQ, but in the
`semen at 2.3 1 pg/ mll; this corresponds to a semen/ blood plasma concentration ratio of
`0.17, i.e., close to the value of 0.2 which was found in rabbits.” A similar study was
`carried out with valproic acid (dipropylacetic acid).54 In rabbits infused with valproic
`acid, the concentration of this drug was persistently lower in the semen (collected with
`artificial vagina) than in the blood, but the concentration-time curve in the semen was
`parallel (approximately) to that in blood plasma, indicating that the drug levels in semen
`are directly proportional to those in blood plasma. In the two human subjects used for
`this study who were given 500 mg valproic acid orally, the concentrations of the drug also
`remained at a lower level in semen than in the blood; in these two men the semen/ blood
`plasma concentration ratio ranged from 0.052 to 0.091 (mean = 0.072).
`The detection and determination of chemicals in semen gradually is becoming more
`reliable and simple, thanks to new sensitive analytical methods, so that compounds that
`may have escaped detection previously, even by gas chromatography-mass spectrometry,
`now can be screened routinely in human and animal semen. One such method is the
`application of negative-chemical-ionization mass spectral screening for detection of
`tris(dichloropropy1)phosphate (the flame retardant with mutagenic and antifertility
`properties). This screening technique also has been applied successfully to detect the
`presence of other chemicals such as hexachlorobenzene, D D T metabolites, and
`polychloronaphtalenes.5~58
`
`E. Adsorption of Excreted Thalidomide and Tetracycline on Spermatozoa
`The potential risk to the function of the spermatozoa in ejaculated semen, and
`ultimately to male fertility, need not be a serious one merely on the grounds that a given
`foreign chemical managed to pass into the seminal plasma. T o ascertain the existence of
`such a risk, supplementary evidence would be required to show that this substance is in
`fact capable of interacting with spermatozoa. Such evidence has been provided for
`several chemicals. Thalidomide and tetracycline are drugs known to be strongly
`adsorbed by spermatozoa. Experiments indicating that thalidomide administered to
`male rabbits adversely affects the pregnancy of females mated to these males, for the first
`time drew attention to the until then unrecognized eventuality of drug-induced
`pregnancy-wastage occurring by the paternal
`Subsequently, it was shown that
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`is administered to male rabbits, the presence of the radioactive
`when [ ''C]thalidomide
`label can be demonstrated in the semen(col1ected with the artificial vagina) within a short
`time after ingestion, and is still detectable there some 12 days later.6' The same study has
`shown that the radioactive label is present not only in the seminal plasma but also in the
`spermatozoa, from which it could not be dislodged even by extensive washing. Similarly,
`when semen from an untreated rabbit was incubated with [ ''C]thalidomide in vitro, this
`compound was rapidly and firmly bound to the spermatozoa.
`Tetracyclin behaves similarly.62 When administered to either man or animal, it
`distributes itself rapidly in tissues and body fluids, including human prostatic secretion
`and semen, and it is also adsorbed by spermatozoa both in vivo and in vitro.
`
`F. Other Examples of Coating of Spermatozoa by Constituents of Seminal Plasma
`Not only drugs, but substances normally present in the body and excreted in the
`seminal plasma are capable of interacting with, and firmly adhering to, the spermatozoa.
`Coating of spermatozoa by seminal plasma constituents has been demonstrated in many
`instances. The propensity to bind to the sperm surface is shared by substances as far apart
`as ions (zinc and calcium, for example), steroid hormones, retinyl acetate, and a variety
`of proteins including the antigens and antibodies of the seminal plas