Paper - Congenital urogenital anomalies in rats including unilateral renal agenesia (1936)
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Hain AM. Congenital urogenital anomalies in rats including unilateral renal agenesia. (1936) J Anat. 70: 566-576. PMID 17104614
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Congenital Urogenital Anomalies in Rats including Unilateral Renal Agenesia
By A. M. Hain (Carnegie Research Fellow), Institute of Animal Genetics, University of Edinburgh,
Edwin M. Robertson, Department of Midwifery, University of Edinburgh
- 1 The expenses of this investigation were largely defrayed by grants from the Medical Research Council and the Carnegie Trust for the Universities of Scotland.
Structural abnormalities which have been observed in certain rats of a stock bred primarily for experimental purposes appear to be worth recording, not only on account of their rarity, but also because of the existence of a close relationship between the affected individuals, and of the fact that similar anomalies have been encountered in man (Collins, 19382; Campbell, 1928; Kisendrath, 1924; and others).
The stock consists of pure albino rats (Wistar) and a cross between these and a “hooded” variety in both of which abnormalities are rarely found, although microphthalmia has occurred in the pure-bred stock and in the crosses. There is no known record of the existence of the abnormalities to be described either in mice or in rats. The stock has been injected with endocrine preparations over a period of years and more especially pregnant animals have been used; it has been impossible, however, to find any direct association between such treatment and the anomalies observed. The genealogical table reproduced suggests that the character is present as a recessive with various modifications of its expression, and its association with a microphthalmic ancestry diluted by outcrosses points to a possible connection with the factor for microphthalmia, such as has been cited by Collins (1982) in the list of anomalies associated with renal agenesia collated by him from the literature bearing on the human subject. From the descriptions which follow it would seem that, whereas unilateral renal agenesia in the rats observed was always accompanied by genital maldevelopment, the latter can occur in related indi- viduals without renal defects.
Description of the Abnormalities
It will be found that towards the end of this investigation the abnormalities are more fully recorded, as it was seen that the earlier observations were not sufficiently comprehensive. In the description which follows, the rats bear the initials given to them in the genealogical table.
Pedigree of rats having renal and genital anomalies
A circle denotes a female; a square denotes a male. Outcrosses (i.e. a different strain of rats) are represented by a circle within a circle and a square within a square. Solid squares and circles denote microphthalmics,
Rat A. Female with a cloaca (fig. 1). In this rat the anus and vagina did not exist as separate openings but, instead, the rectum opened into the dorsal portion of the vagina and within the vaginal lumen, so that a smearing wire, when inserted into the vagina penetrated either into the rectum or into the vagina proper. Smears taken for a period of 4 weeks showed that normal oestrous cycles existed; the rat died while pregnant at the age of 4 months when the right uterine horn was found to contain four foetuses and the left horn five, the development of which was equal to that of the 22nd day or term. Death was due to inability to litter.
Fig. 1. Female rat A.
Rat B. Female with abnormal vaginal opening (fig. 2). This rat appeared to have no vaginal orifice, but this was found immediately anterior to the anus from which it was separated by a thin septum. The opening was very small, and it was with difficulty that a fine suture needle was passed up the vagina into each uterine horn. The kidneys and ureters were normal.
Rat C. Female with no vaginal opening (fig. 3). This rat was killed when 5 months old and immediately after a course of injections of oestrone, during which 1-44 mg. or 7500 int. units were administered subcutaneously over a period of 4 days in an effort to establish an aperture. The normal position of the vaginal orifice was indicated by an area free of hair, and the occluding membrane appeared to be of a uniform thickness. The distance from the anus to the centre of this area measured 11:75 mm. At necropsy the right uterine horn was found to be greatly distended with fluid and was 8mm. wide x 45 mm. long. A sharp constriction at the cervix marked its entrance into a distended and closed canal 14 mm. in diameter and 42 mm. long, which proved to be the vagina. This did not connect with the natural site of the vaginal orifice but followed the course of the rectum along its entire extent although it did not open at the anus.’ The left uterine cornu was represented by a small spherical sac situated immediately below the ovary; it measured only 11 x8 mm. and was filled with fluid.
Fig. 2. Female rat B. A. anus, Fig. 3. Female rat C. U.P. urethral prominence.
It is likely from the data about to be presented demonstrating the asso- ciation between defects in development of the genital system and kidney anomalies, that rat C had a hypoplastic kidney on the defective side; however, this was the first animal in this series encountered with such an abnormality, and as no such association had at that time been observed, the existence of both kidneys was not ascertained.
Absence or hypoplasia of the left kidney
In the rats about to be described the absence or hypoplastic development of a kidney has always been found in association with genital abnormalities on the same side of the body, and it has always been the left side which has been affected.
1 A similar defect has been observed in a mouse, but both uterine cornua were normally developed. 570 A. M. Hain and Edwin M. Robertson
Rats D and F. Female rats in which neither kidney, ureter nor renal blood vessels were to be found on the left side (fig. 4). The adrenal gland and the ovary were present and the latter was normally situated, but no left uterine cornu existed. The right side of both rats was, in all respects, normal.
A female in the same litter as rat D was found to have no left cornu; this rat was unfortunately destroyed without complete examination.
Rat E. Female rat with hypoplastic left kidney (fig. 5). On the left side the place of the kidney was taken by a hard, yellowish body the size of a pea, which, on histological examination, proved to be a cystic, hypoplastic kidney. The renal artery and vein on this side were normal, but no ureter was found. Below the defective kidney were a normal ovary and a portion of uterus about 10 mm. long, having a blind lower end. The right side was normal. Litter- mates killed at the same time as rat E exhibited no abnormality. (See male rat N, i.e. father.)
Fig. 4. Female rats Fig. 5. Female rat E. Fig. 6. Female rat G. D and F.
Rat G. Female rat with hydronephrotic kidney and hydroureter on the left side (fig. 6). This female was killed when 42 days old; at that time she weighed only 15 gm. as compared with females in the same litter which weighed 90 and 92 gm. A litter-mate of her mother had a similar tiny female in her litter, but this was eaten on the day that rat G was killed. It is possible that a similar condition existed.
On the left side in place of the kidney there was a large translucent, hydro- nephrotic sac; the renal pelvis was greatly enlarged, also the ureter which was much kinked on itself. Under the dissecting microscope it was found that the left ureter was obstructed at its junction with the bladder and terminated at the site of its normal opening in a cystic dilatation projecting into the base of the bladder. The condition was apparently one of stenosis of the lower end of the ureter at its entry into the bladder, with subsequent distension of the occluding portion and also of the renal tract proximal to the barrier. Micro- scopic examination did not reveal any clue as to whether the cause lay in the ureter, the bladder wall or the bladder mucosa. On the embryological data, Congenital Urogenital Anomalies in Rats 571
however, it is evident that a secondary occlusion of the ureter must have occurred. As the lumen of the ureter is an outgrowth from the existing archinephric (i.e. mesonephric) duct, there must once have been a clear opening. If there had been no archinephric duct, there could have. been no mesonephros, but in the two male rats exhibiting a similar abnormality (rats L and M) the epididymis, itself derived from the mesonephros, is well marked.
The ovary and uterus on the defective side were normal, as also were the organs on the right side.
Rat H. Male rat with no left kidney (fig. 7). On the left side there was no trace of kidney or ureter. Midway between the normal renal site and the pelvic girdle lay a small testis only 10 mm. long; the epididymis was below this and not contiguous with the testis, and from it there arose three strands which appeared to bury themselves in the abdominal wall; the gubernaculum connecting with the scrotal sac was 55 mm. long. The seminal vesicle on the left side was underdeveloped, measuring only 7-5 x 6-5 mm. and weighing 100 mg. (cf. 28 x 11-5 mm. and 1-0 gm.—normal).
Fig. 7. Male rat H. Fig. 8. Male rat I.
The right kidney was greatly enlarged and weighed 2-7 gm. (ef. normal litter-mate’s kidney 1-6 gm.). The right testis and seminal vesicle were normal. There was much diffuse chromaffin tissue on both sides. A male in the same litter was a typical unilateral cryptorchid with no kidney abnormality.
Rat I. Male rat with no left kidney (fig. 8). On the defective side no renal vessel and no ureter were found. The testis occupied a position a little below the normal site of the kidney and away from the midline; it weighed only 0-2 gm., while that on the right side weighed 0-85 gm. There was a complete absence of ducts on the left side, and no seminal vesicle.
The right kidney was greatly enlarged, as in rat H, and weighed 2-2 gm. (cf. 1-6 gm., the average weight of a kidney of an animal of the same body weight). The seminal vesicle was peculiar in that it consisted of two lobes, the one arising out of the centre of the other.
Rat J. Male rat with an atrophic left kidney (litter-mate of rat I) (fig. 9). A small atrophic mass of tubules about 5 mm. long lay in a pad of fat, and the whole mass was connected to the abdominal vessel by a pedicle of blood vessels which was twisted on itself twice. That these tubules were renal tissue was verified by section, but as these must evidently have been a remnant of the mesonephros there was no ureter. The testis on the same side was ab- dominal, very small, and lay 80 mm. below the “kidney”; it had neither attachments nor vas. The gubernaculum was represented by a thin fibrous
Fig. 9. Male rat J. Fig. 10. Male rat K. Fig. 11. Male rat L.
cord which disappeared into the inguinal canal. The seminal vesicle was small and, like other underdeveloped vesicles in this series, was quite translucent. The prostate on this side was also very tiny and semi-transparent.
The right side was normal.
Rat K. Male rat with cystic hypoplastic left kidney (fig. 10). On the de- fective left side a small, soft and amorphous kidney lay about 25 mm. below the normal position. The testis on this side was tiny and had not descended (male 8 months old). There was no connection with the seminal vesicle which was underdeveloped as in rat J, and passing from the small globus major a thin, fibrous strand connected with the outer side of the kidney, i.e. the side remote from the hilum.
Rat L. Male rat with polycystic left kidney (figs. 11 and 12); killed when 7 weeks old, along with its litter-mate in which the right testis was interstitial in position but in which there was no renal abnormality. Congenital Urogenital Anomalies in Rats 573
Rat L exhibited considerable urinary incontinence. At necropsy the left kidney, which was in the normal position, was found to be almost three times the size of the right kidney and was a mere sac of renal tissue, distended with fluid; the wall was normal in colour; the left ureter was much dilated. By the use of probes and with the aid of the dissecting microscope, it was found that, as in the case of female rat G and male rat M (his litter-mate), an ob- struction apparently existed at the point at which the ureter was attached to the bladder at the left of the trigone, just above the neck (fig. 12). Cross- sections taken of the lower portion of the bladder and of the urethra demon- strated microscopically that the left ureter had no opening either into the bladder or directly into the urethra. The portion of bladder wall (?) ob- structing the ureteral lumen shared in the general distension of that tract, and this resulted in distortion of the neck of the bladder and consequent incontinence of urine. The testes, the vascular system of the seminal vesicles and vasa deferentia and of the bladder circuit were normal; the left lobe of the prostate was smaller than the right. The right side was normal.
Fig. 12. Male rat L. P.=prostate; V.D.=vas deferens; S.V.=seminal vesicle; U.=ureter.
Rat M. Born in a subsequent litter to the same parents as rat L. This male had shown signs of incontinence but to a less extent than its litter-mate, rat L. When killed at 5 weeks old, it was found to have a large, translucent, hydronephrotic kidney on the left side. Its appearance, and that of the ureter, which was also greatly distended and kinked, resembled in all respects the condition observed in female rat G already described (see fig. 6). The testes and other genital organs were normal.
Rat N. Kidneys normal but left testis was very much larger than the right and exceeded any other testis encountered both in weight and in size. The measurements were as follows:
Left testis: 28 mm. long, weighing 3-0 gm. Right testis: 20 mm. long, weighing 1-5 gm.
This male fathered female rat E already described.
Renal agenesia and hypoplasia as an inherited defect
The pedigree chart (p. 567) strongly suggests that the occurrence of the defect is not a random one. As the defect can rarely be detected externally in females, it is probable that instances of its occurrence in that sex have been overlooked; in males, however, all animals having a single descended testis or testicular underdevelopment have always been submitted to necropsy. Since the abnormality was observed to be a transmitted character, about 500 females closely related to rats in which a renal anomaly had been found have undergone palpation, laparotomy or post-mortem examination; brother- sister matings have been made in affected.groups and their litters have been carefully inspected. In spite of this, the particulars are, of necessity, incom- plete, and it is impossible to calculate with any degree of accuracy the inci- dence of the abnormalities; one can merely state that the defect is probably transmitted as a recessive and that several factors are involved. The ap- pearance within the chain, of females having genital deformities without an _ accompanying renal defect, suggests that such abnormalities may be a variant in expression of the same developmental anomaly rather than a chance occurrence, more especially as similar abnormalities are mentioned by Collins (1982) in his list of congenital anomalies described in the literature as asso- ciated in cases of renal agenesia, a list which totals some seventy-five forms.
The morphological development of the structures involved
The varying degrees of renal defect would seem to be attributable to the stage at which the arrest of embryological development occurred, e.g. the entire absence of a kidney must belong to an earlier date than the hypoplastic kidneys of rats E, J and K, which, in turn, belong to an earlier stage than those of rat L and also rats G and -M.
The regularity with which the left side only was affected is striking and suggests that an inequality exists in the rate of development of the two sides of the body. Gray (1980) has recorded that the right kidney of the common frog always develops more slowly than the left; this asymmetry is not ob- servable after metamorphosis. Cases of lateral asymmetry described in birds (Crew, 1981; Crew and Lamy, 1935) and in man (Potter and Urwick, 1935; Bowman, 19385) have almost entirely related to limb size and to colour. When gynandromorphism was present this was associated with gonadic abnormality. Crew (1981) is of the opinion that the various expressions of asymmetry can bear a single interpretation, viz. that “aberration in chromosome distribution is the cause of the regional expression of a recessive character” present in a heterozygote. He considers that the autosomal constitution is affected and explains the variations in manifestation as due to differences in time during development at which the loss of the particular autosome or its part occurred, the earlier the loss occurs the greater being the distribution of the recessive character.
In order that the earliest stages of the developmental idiosyncrasy might be observed, litter-mates of rats with renal agenesia were given to Dr Peter Gray (Zoology Department, Edinburgh University), when these were 8-12 days pregnant, for an embryological study of the abnormality, as it seemed possible that the defect would appear in closely related stock. The result of this investigation is not yet available.
The simultaneous occurrence of anomalies in both the genital and urinary systems in the affected animals is not surprising in view of the relation known to exist in the morphological development of the two systems. In those rats in which there is no trace of a urinary system (rats D, F and I) it is manifest that the defect dates to a stage prior to the development of the oviduct and archinephrie duct and involves the non-development of either a mesonephros or pronephros. This is compatible with the absence of epididymis and ducts in rat I. In those rats in which the ureter is absent but renal tissue exists along with partial development of a duct system and of the seminal vesicle (rats H, J and K), the developmental arrest must have taken place after the formation of the mesonephros but prior to the formation of the metanephric bud, since the ureter and pelvis of the kidney are not found.
In female rats C and E it would seem that the arrest in the devclopment of the oviduct occurred during the process of back growth of the inner end of the ostium abdominale tubae (Brambell, 1927). In describing the morpho- logical development of the gonads of the mouse Brambell writes: ‘The Miillerian duct develops, as stated by Felix and de Winiwarter in the human species, as a back growth of the inner end of the ostium abdominale tubae. The similarity in structure of the primordium of the ostium abdominale tubae to the nephrostomes and its similar position in the urogenital ridge slightly anterior to them, suggests that they may be homologous. On this view the ostium abdominale tubae would be a nephrostome which grew and extended posteriorly to form the Millerian duct.’’ Thus these abnormalities add striking support to the theory, not universally accepted to-day, that the mammalian oviduct develops in a postero-anterior direction.
Since the mesonephros is already well established and the tubules formed anteriorly by the 9th day post coitus (Brambell, 1927), it is manifest that development can be arrested at a very early stage. The existence of some adverse environmental influence upon the developing embryo would have suggested itself had all the members of a litter been abnormal, but in only two instances were defective genitalia encountered in more than one member of a litter.
The occurrence of a male with renal maldevelopment in each of two successive litters born to the same parents suggests that an inherent defect existed in the parent cell, and the ovum itself may have been defective.
Bowmay, M. (1935). Brit. med. J. 30 Nov. p. 1047.
BraMBELL, F. W. R. (1927). Proc. roy. Soc. B, vol. ct, p. 391. CaMPBELL, M. (1928). Ann. Surg. vol. LXxxvitl, p. 1039.
Corts, D. C. (1932). Ann. Surg. vol. xcv, p. 715.
Crew, F. A. E. (1931). J. Genet. vol. xxv, p. 359.
Crew, F. A. E. and Lamy, R. (1935). J. Genet. vol. xxx, p. 233. ErsenpratH, D. N. (1924). Ann. Surg. vol. LXxIx, p. 1924.
Gray, P. (1930). Quart. J. micr. Sci. vol. Lxxm1, p. 507.
Porter, C. T. and Urwiox, J. (1935). Brit. med. J. 14 Dec. p. 1179.
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