Paper - Congenital urogenital anomalies in rats including unilateral renal agenesia: further data in support of their inheritance (1937)
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Hain AM. Congenital urogenital anomalies in rats including unilateral renal agenesia: further data in support of their inheritance. (1937) J Anat. 72: 83-100. PMID 17104683
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Congenital urogenital anomalies in rats including unilateral renal agenesia: Further data in support of their inheritance
By A. M. Hain (Carnegie Research Fellow), The Institute of Animal Genetics, Edinburgh University,
and Edwin M. Robertson Midwifery Department, Edinburgh University
- The expenses of this investigation were largely defrayed by grants (to A.M.H.) from the Medical Research Council and the Carnegie Trust for the Universities of Scotland.
Introduction
In the previous descriptive report of renal and genital abnormalities in rats (Hain & Robertson, 1936) it was suggested that the occurrence of such anomalies within a related group indicated that the defect might not occur at random, but be transmitted as an inherited tendency. As the number of defectives observed was too small to justify a conclusion, it was decided to test this hypothesis; brother-sister matings have therefore been made within the affected group throughout successive generations, and at the same time an adequate number of rats outside the group has been retained as a control. All rats born in the colony, whether related to the affected or not, have been systematically palpated bilaterally for any abnormal renal development and their external genitalia have been examined, and all stillborn young have been dissected. In this way a further series of rats possessing renal and/or genital anomalies has been obtained, and, in every instance, these have been found to be closely related to the defective rats previously described, whereas the remainder of the stock is free from the defect. The regularity with which urogenital anomalies occurred in the descendants of VII. 19 (i.e. female D— Fig. 4 in the previous paper) is well shown in the pedigree chart between pp. 100 and 101; this female possessed only one kidney and was responsible for twenty rats with various renal defects, of which three exhibited her own form of abnormality.
Description of the Abnormalities
The new series consists of forty-five rats and these will be referred to by the numbers within the circles (females) and within the squares (males) on the pedigree chart between pp. 100 and 101. The Roman numeral denotes the generation to which they belong, four earlier generations appearing on the previous chart; renal defects are indicated by the kidney sign, and microphthalmia by solid circles and squares. The abnormalities were of four main types, and with hardly an exception were confined to the left side of the body: (a) renal agenesia, (b) renal hypoplasia, (c) hydronephrosis, (d) genital anomaly without an associated renal defect.
The schematic drawings used in the earlier report are again employed for the conditions (a) to (c) but illustrate (b) in the female only, i.e. Fig. 8. A drawing reproduces the condition typical of renal agenesia in the male rat and forms the basis for the anatomical data given for this sex (Fig. 2). Any departures from the illustrations are described in the text. The right side of the body of all the rats was normal, unless expressly stated to be otherwise.
A. Renal agenesia.
Seven examples of this defect were observed: females XII. 26, XIII. 5 and 6, and males XI. 15 and 20, XII. 13 and XIII. 8, of which XIII. 6 was stillborn or died soon after birth.
Fig. 1. Renal agenesia in Fig. 2. Renal agenesia in Fig. 3. Renal hypoplasia female rat. male rat. in female rat.
The typical condition is that shown in Figs. 1 (female) and 2 (male) and consists of absence of the left kidney, renal vessel and ureter. In the females there was no uterine horn on the same side but the ovary was present; in two instances in this series, however—XII. 26 and XIII. 6—the ovary also was lacking. A certain amount of hypertrophy had occurred in the right kidney of female XII. 26 which was killed when 5 months old; this kidney weighed 1-0 g., ef. 0-75 g. which is the normal for a female of the same body weight (Donaldson, 1915). In males with renal agenesia the testis was under-developed, placed high in the abdomen and lacked epididymis, globus major and vas deferens. The four males belonging to this group exhibited the condition shown in Fig. 2, but the seminal vesicle and prostate on the left side were diminutive. In XI. 15 and XII. 18 the prostate appeared to be of normal dimensions and in XII. 13 there was no seminal vesicle on the left side.
B. Renal hypoplasia.
The condition in the female rat is illustrated in Fig. 8. Generally the hypoplastic left kidney was only one-third or one-fourth of the size of the kidney on the right side and showed cystic degeneration. As there was considerable variation both in the associated genital defects and in the extent to which ureteral development existed, the rats belonging to this section have been arranged in two groups: (i) those in which a ureter existed either in whole or in part, and (ii) those in which there was no ureter.
(i) Partly developed ureter. Four females and one male exhibited this form: females XI. 22 and 24, XII. 17, XIII. 11 and male XIV. 6. The kidney of female XII.17 retained the foetal lobulation; it would seem that renal secretion had not been established in this rat as the maldeveloped ureter was not distended. This was thick-walled and connected with the cervico-vaginal junction and not with the bladder; the uterus on the same side ended in a fibrous band attached to the cervix and showed cystic dilatation.
In female XI. 24 the hypoplastic, cystic condition of the left kidney was associated with a ureter only 5mm. long. Apparently some secretion had taken place as the ureter was a distended sac; the renal vessel was very small, however, although a normal ureteral vessel was present. Below the ovary on the same side was a portion of uterine horn only 2-3 mm. long, ending blindly.
Renal hypoplasia and cystic degeneration in females XI. 22 and XIII. 11 were accompanied by a hydroureter which was connected with the bladder but had no entrance into it. It is possible that XIII. 11 would, at a later date, have developed the condition depicted in Fig. 5 but she was killed when only 15 days old. The ovaries and uterus were normal in both animals. Comparison with a litter-mate of XI. 22 showed that there was no hypertrophy of the right kidney.
Male XIV. 6—one of four renal defectives in the same litter—had a hypoplastic kidney on the left side showing cystic degeneration of the cortex. There was partial hydronephrosis and both the pelvis and ureter were distended with fluid. The blind ureter, which was only 6 mm. long, was connected at its lower, distended end by means of the vas deferens with the globus major of the testis which was placed high in the abdominal cavity. A condition somewhat similar but less marked was illustrated in Fig. 10 of the previous report and is shown in Fig. 4a. Fig. 4b depicts a modified form encountered in four other males in this series: XI. 5, 14 and 26 and XII. 12. The seminal vesicle on the defective side in XIV. 6 was very small, but the prostate was enlarged.
(ii) Without ureter. Five males and two females belong to this group— males X. 25, XI. 14, XII. 4, 11 and 12, and females XII. 20 and 21. The developmental defect was most marked in XII. 11 which had neither testis nor vas deferens on the left side. The kidney measured only 5x2 mm. (cf. 12x 8 mm. on the right side) and passing to it was a long fatty pedicle in which the renal vessel was twisted on itself five times. The prostate was normal on both sides but the left seminal vesicle was smaller than that on the right. In spite of a more marked degree of hypoplasia in the kidney of this measured only 3 x 2 mm., cf. 12 x 8 mm. on the right side—the testis was present, although no vas deferens existed; the left seminal vesicle was very small but the prostate showed normal development. As was to be expected, the renal vessel was much smaller than that to the healthy kidney.
Rat X. 25, which was killed when 10 months old, presented a similar picture to XII. 4, but although the prostate was normally developed there was no seminal vesicle on the defective side. The left kidney was represented by a yellowish body 7-5 x 5 mm. and weighing 0-2 g., whereas the right kidney was 24 mm. long and weighed 2:5 g. Hypertrophy had occurred as the healthy kidney of a rat of the same body weight (326 g.) is 1-4 g. (Donaldson, 1915).
Fig. 4. Male rat with perverted vas. a, as in XIV. 6; Fig. 5. Hydronephrosis in 6, as in XI. 5, 14 and 26 and XII. 12. female rat.
The condition shown in Fig. 46 existed in male XI. 14; the kidney proper, which was highly cystic, measured 8 x 5 mm. (cf. 11-5 x 8-5 mm. on the right side and the same kidney in a litter-mate). The pelvis was greatly distended with fluid and translucent and was connected to the epididymis and globus major by means of the vas deferens which, however, was not patent at this point. The left testis was normal in size, but the left seminal vesicle and prostate were tiny; the absence of a vas at this site was confirmed and it was observed that that on the right side was normal. The renal blood supply was deficient; a small blood vessel passed over the external surface of the kidney to the vas deferens, followed along its course and passed thence to the testis.
Male rat XII. 12 presented similar features—the hypoplastic kidney on the left side measured only 7 x 2 mm., cf. right kidney 12 x7 mm. and that of its litter-mate—11-5 x7 mm.; in both of the latter the kidney weighed 0-2 g., agreeing with Donaldson’s figures. Both the ureter and the seminal vesicle on the same side were wanting although the prostate was normal. The vas deferens connected the globus major with the lower pole of the kidney and from this site a vascular band passed to the hilum of the testis. The renal vessel was normal. ;
The two female rats with marked hypoplasia of the left kidney and no ureter were litter-mates, viz. XII. 20 and 21, and had a sister with hydronephrosis. In one female only a trace of renal tissue (cystic) existed, measuring 2-5 x2 mm., and in this rat no uterine horn was present. Its litter-mate had a cystic kidney 4-5 x 2-5 mm. and on the same side the blind uterine horn was only 2 mm. long. The ovaries and oviducts were normal in both rats.
C. Hydronephrosis. In rats exhibiting this condition the place of the kidney was taken, as a rule, by a large, translucent hydronephrotic sac with, occasionally, a trace of kidney substance showing cystic degeneration in the wall of the sac. The renal pelvis was greatly enlarged and also the ureter which was much kinked on itself and had no opening into the bladder. The condition is illustrated in Fig. 5, and the way in which the ureter was obstructed at its lower end is demonstrated in the detailed drawing on p. 573, J. Anat. 70, 1936. In some rats, however, the kidney, though a hollow organ, was much smaller than that on the right, in marked contrast with the huge spherical sac of fluid present in others. Rats with hydronephrotic kidneys have been divided into two groups: (i) those in which the ureter was joined to the bladder though without exit, and (ii) those in which there was an entire absence of ureter or in which a hydroureter existed but ended as a blind duct some distance from the bladder.
(i) Ureter connected with the bladder. Eight females and three males exhibited the renal condition as this is typified in Fig. 5—females X. 15 and 16, XI. 21, 25 and 29, XII. 15, 19 and 22 and males XI. 23, XII. 14 and 18. In two of the males—XI. 23 and XII. 18—the seminal vesicle on the defective side was larger than that on the right, whereas the prostate was smaller. In all other respects the gonads and accessories were normal in both sexes.
Examples of the small, hydronephrotic kidney also described are provided by female XIII. 7 and male XIV. 14. The condition was associated in the female rat with cystic degeneration in the upper pole. This rat had neither ovary nor uterus and in this respect resembled its sister, in which, however, there was no trace of kidney substance on the defective side. The association of partial renal development with an absence of the gonad and secondaries on the same side has already been described in the case of male XII. 11 (p. 85) and will be observed again later (female XIV. 9, Fig. 6). In XIV. 14 the ureter was represented by a strand of tissue communicating with the bladder but not patent. The testis lay high in the abdominal cavity, with epididymis and globus ‘major but no vas deferens. The seminal vesicle and prostate were diminutive; the renal vessel was present.
As a general rule, the right kidney showed little, if any, enlargement as the result of the lack of function on the defective side, and although in a large number of cases the weight or measurement of the right kidney was compared with the organ on the same side in a normal litter-mate, in only two rats in this section was any measurable difference observed; this amounted to a 20 per cent increase in the right kidney of female XII. 19 and a 25 per cent increase in that of female XI. 25. Both rats were only a month old when killed and it is possible that a more marked hypertrophy would have occurred in time (vide X. 25 and XII. 26). Our findings are in general agreement with those of Bagg (1926). He states that ‘“‘certain animals (mice) have been found with a solitary kidney that showed no appreciable enlargement. However, compensatory hypertrophy is usually associated with solitary kidney in animals examined in the adult state.””» When mice with extreme hypoplasia of one kidney were killed soon after birth Bagg found no hypertrophy in the functioning organ. Doctors Rytand and Addis of Standford University Hospital, San Francisco, have taken glomerular counts of the normal kidney in several of our rats in which unilateral agenesia or hydronephrosis was present, and these showed no increase in number as compared with the same kidney in a littermate.
(11) No connexion with the bladder. Considerable variation existed in the expression of the abnormality in this section, which comprises six females and two males—females X. 14 and 21, XII. 16, XIV. 7, 8 and 9, and males XI. 5 and 26. In female XII. 16 (sister of XII. 17) both the cortex and the pelvis were translucent and full of fluid and a hydroureter ended as a blind duct near the bladder but had no connexion with it, although the ureteral vessel extended to the base of the bladder.
Commencing hydronephrosis with a hydroureter was present in X. 21, a stillborn female. The ureter, which was dilated in the upper two-thirds, had a sudden constriction at the junction of the middle and lower third and, from this point to the base of the bladder, was represented by what appeared to be a solid band of tissue. The ovaries and uterus were normal in both rats.
The three female litter-mates of male XIV. 6 (p. 85) belong to this section. Two of them had the small hydronephrotic kidney previously described (7x5 mm., cf. 12x 8 mm.) and in each rat no trace of a ureter existed. The abnormality was associated in the one female with the entire absence of the uterine horn on the same side, and in the other with partial development of this horn, which was only 3 mm. long. In both rats the ovaries and oviduct and also the ureterine vessel were normal.
In the third female—XIV. 9—a hydroureter passed from the distended renal sac but did not communicate with the bladder. By the use of probes and with the aid of the dissecting microscope it was found that the hydroureter ended blindly at the skin of the vaginal introitus (Fig. 6). The abnormality was somewhat similar to that encountered in XII. 17 (p. 85), but in the female here illustrated neither ovary nor uterine horn existed on the left side. This female affords the third example in this series of an absence of the gonad and its accessories in association with partial development of the kidney on the same side of the body (see female XIII. 7 and male XII. 11, pp. 87 and 85).
The abnormalities present in the remaining female in this section—X. 14, which was killed when 4 months old—are illustrated in Fig. 7. The pelvis of the left kidney was greatly enlarged, translucent and full of water. Passing from this was a hydroureter which was coiled on itself and ended blindly and abruptly at about three-quarters of its length, without any connexion with the bladder. The left ovary and uterus were normal and also the right ovary, but the right uterine horn was represented by a cord, which on section proved to be solid. This was in marked distinction from the condition observed in defective rats hitherto, in all of which genital defects have occurred only on the side on which a renal abnormality existed. In addition, this rat had no vaginal opening and the vagina ended in a closed sac, distended with fluid. An opening beside the anus was caused by the bursting of an abscess, the channel of which contained much granular material.
Fig. 6. Female rat XIV. 9. Fig. 7. Female rat X. 14.
The two male rats with small hydronephrotic kidneys—XI. 5 (the left kidney measured 4x3 mm., cf. 12x 8 mm. in a litter-mate) and XI. 26— resembled XIV. 6 in that there was in both a suggestion of a duct joining the kidney to the testis (Fig. 4b). In XI. 5 and 26, however, no ureter existed, although the main ureteral vessel was present. The small testis which was placed high in the abdominal cavity had both epididymis and globus major,
1 Since going to press more rats with urogenital defects have been observed and in one female
with hydronephrosis on the left side the right uterine horn was found to be a solid cord, whereas the left horn was normal.
but the vas deferens was represented only by the cephalic end which was 3 mm. long. There was neither prostate nor seminal vesicle on the defective side in either rat.
D. Genital anomalies without associated renal abnormalities. These were of three kinds:
(i) Interstitial testis. In males with this condition the testis lay between the layers of the abdominal wall, and was not descended. The epididymis was generally under-developed, and the testis was soft and smaller than that on the other side. Generally the left side was defective (IX. 24 and X. 20) but in one instance (X. 19) the abnormality occurred on the right side.
(ii) No vaginal opening. This abnormality was encountered in X. 14 (Fig. 7) and in rat C, i.e. VI. 19 (Fig. 3 in the previous paper on this subject), but in both rats was associated with other defects. In rat XII. 25 no other defect was present. The vagina, which had no outlet, followed the course of the rectum as far as the anus and was distended with fluid, the vaginal sac measuring 20 x 10 mm.
(iii) No testis on the left side (adult male X. 34). The kidneys and ureters on both sides were normal, and the seminal vesicles and prostatic glands were well-developed. On the left side, however, the vas deferens ended in a blind duct about 20 mm. long and the testicular vessel was absent. This male fathered a female with a hydronephrotic kidney, viz. XI. 29.
The Various Forms of Renal and Associated Genital Defects in Relation to their Morphological Development
As in the earlier series, renal defects were confined to the left side of the body, and, with two exceptions, the associated genital anomalies were similarly restricted. Owing to the much larger number of defectives available in the new series and the wider range of abnormalities encountered, as well as the various modifications and the typical forms by which these were expressed, a fuller examination of their nature has been attempted with a view to throwing some light on the process by which the defect may have developed.
The attendant anomalies in unilateral renal agenesia are readily understood: the absence of renal vessel, ureter and uterus or vas. The development of the Millerian and Wolffian ducts is so intimately related to that of the kidney anlagen that the factor inhibiting the development of the latter would suppress the former also. This was discussed in the earlier descriptive report. It is not surprising, therefore, that in those rats in which renal development was not totally suppressed—in cases of hypoplasia and hydronephrosis—the degree of maldevelopment of the ureter ran almost parallel with that of the uterus in the female and of the vas in the male. Thus, for example, one finds a fibrous ureter associated with an equally non-functioning strand for uterus; a ureter 5 mm. long accompanies a uterine horn of similar dimensions, and where there is no ureter—which occurred in certain examples of hypoplasia and hydronephrosis in addition to the accepted cases of renal agenesia—there is likewise an entire absence of any uterine development on the same side, and occasionally, even, of the ovary also.
Owing to the greater complexity of the secondary sex apparatus in the male, greater variety existed in the abnormalities encountered in this sex; counterparts of conditions found in the female were observed. In one, the ureter is represented by a solid strand and there is no vas deferens; in another, marked renal hypoplasia and an entire lack of ureteral development are associated with an absence of the vas, and (in rat XII. 11) also of the testis. Development of the prostate and seminal vesicles varied in rats exhibiting the same degree and form of renal defect (in such rats it was observed, moreover, that the prostate apparently develops independently of the seminal vesicle). Although renal deficiencies were accompanied also by defects in the vas deferens, actually only three out of seven males in which there was an entire absence of ureter showed no trace of a vas. The remaining four, together with a fifth rat in which the ureter was partially developed but ended in a blind duct, were peculiar in that, in each case, the vas connected the globus major with the kidney (or, in the last named rat—XIV. 6—with the blind end of the distended ureter); also, in two of the rats, the course of the connecting vas was traversed by a blood vessel linking kidney and testis. It is intended to examine, in some detail, the possible morphological development of this peculiarity, not only in view of its interest, but because of the light that it is hoped may be thrown on the origin of other urogenital anomalies herein described. The authors are indebted to Dr Peter Gray of the Zoology Department, Edinburgh University, for the suggested explanation and for the schematic drawings appended.
Fig. 8 illustrates renal development in the theoretical normal. From the pronephros there passes the archinephric duct which, in the course of its development, makes contact with the urogenital sinus. Round about it the mesonephros develops, and a connexion between the latter and the testis is established and persists, since the upper end of the mesonephros becomes the epididymis. From the archinephric duct near its lower end, i.e. at the caudal end of the mesonephros, there springs the bulbous epithelial bud which, by outgrowth, develops into the ureter and pelvis of the kidney. This bud is covered by a cap of nephrogenic tissue derived from the lower extremity of the mesonephric blastema which goes to form the kidney substances.
This revision of facts gives a clearer understanding of. Figs. 9 and 10 which illustrate what has possibly happened in the males with a perverted vas. In Fig. 9 a less extreme condition is typified than in Fig. 10 and may be taken to represent rat XIV. 6 in which a portion of ureter existed. In both illustrations the archinephric duct is shown as failing to complete its connexion with the anlage of the bladder, and, in consequence, both the mesonephros and the ureter are shortened. In Fig. 9b the condition as found in the adult is shown; the archinephric duct (vas deferens), instead of extending to the bladder, is joined to the lower end of the shortened ureter; the kidney, which arose from the incompletely developed mesonephros, is, in turn, hypoplastic or hydronephrotic. The more extreme condition exhibited by four males is typified in Fig. 10a and b from which it appears that the so-called vas in these rats is really a fusion of the vas and ureter, though not patent at the renal end and not connecting with the hilum of the kidney.
It would seem that the adverse factor which suppressed renal development in rats with agenesia operated at a slightly later date in those animals in which hypoplasia was associated with an absence both of ureteral development and of vas; also, that the five rats with “ perverted vas” possibly occupy a position intermediate between the latter and those females in which a hydronephrotic kidney was associated with a hydroureter having a stricture at its entrance into the bladder. With a single exception (female XIII. 7) the uterus and ovary on the defective side in such rats showed normal development.
Fig. 8. Schematic diagram showing renal development in the theoretical normal. P. pronephros; £, epididymis; 7’. testis; A.N.D. archinephric duct; M. mesonephros; K. kidney; U. ureter; U.G.S. urogenital sinus; V. vas deferens. .
Fig. 9. Schematic diagram showing possible course of renal retardation as this occurred in Male XIV. 6 (i.e. Fig. 4a). a, developmentally; 6, in the living rat. Lettering as for Fig. 8.
Fig. 10. Schematic diagram showing retarded development of mesonephros and ureter which may have given rise to condition in Fig. 4b. a, developmentally; 5, in the living rat. Lettering as for Fig. 8.
The occurrence of genital anomalies independently of renal defects, together with the absence of a gonad in rats in which the kidney was either lacking or only partially formed, may be explained only on the assumption that, owing to the development of the gonad at a site on the urogenital ridge adjacent to and in contact with the early nephric rudiments, the factor which caused abnormal development of the latter might, either in addition, or alternatively, cause malformation of the former. The irregularity sometimes encountered in the attendant anomalies may, perhaps, be accounted for in this way.
Two female rats exhibited special features requiring comment: XIV. 9 and X. 14, In the former (Fig. 6) a condition found in early embryonic development persisted, viz. the ureter maintained the position which it had in the cloaca before it acquired a separate opening, and, by occupying a more cephalic position, communicated with the bladder. The lack of an outlet was responsible for the hydronephrosis present in this female. The complicated picture presented by female X. 14 (Fig. 7) suggests that in this rat there occurred a developmental arrest of a more general and diffuse character than that elsewhere encountered. The fact that rats within the related “renal”? group which gave promise of large litters frequently produced only two or three youngsters, having absorbed the others or eaten them at birth, suggests that the latter may not have been viable owing to the number and complicated character of the defects exhibited. Beaver (1933) cites such a case in man, and Bagg (1926, 1929) found many such in mice.
The occurrence of eye defects, particularly microphthalmia, in the same stock has already received comment (Hain & Robertson, 1936). The association between the eye and the kidney is obscure; according to Bagg (1924), who experienced a similar association in a strain of mice descended from X-rayed animals, “an experimental disturbance during the very early embryonic period is likely to result in various eye defects, whereas an identical disturbance acting somewhat later will result in defective brain or branchial systems, and still later in malformation of the viscera”. In this connexion the two litters produced by XIII. 1 and 2 are of peculiar interest: the first contained five rats with eye defects, the second had four with renal defects. This association between eye and kidney abnormalities is referred to again later.
It is possible to account for the abnormalities described only on the basis of developmental arrest; the nature of the factor causing the arrest in development is not clear. Under-nutrition of the embryos is exceedingly unlikely as such abnormalities would then be of frequent occurrence in the litters carried by suckling females, which has been demonstrated not to be the case (Hain, 19845).
That faulty diet. and lack of exercise can have serious effects on the development and function of the kidney is well known. Spontaneous nephritis in rats fed on a diet deficient in vitamin A is recorded by Jackson (1924) and recalls the term “‘renal rickets” in man. The rats employed in this study have been fed on a standard diet for the past 6 years, and this is so well balanced in vitamin content that it is unlikely that any dietary defect is responsible for the abnormalities. Flaked maize, cod-liver oil, liver and yeast powder, milk, green vegetables and a little salt are given daily, and, in all material points, the quality of the stock bears comparison with the original Wistar rats from which it sprang (Hain, 1934a).
In a histological study of the embryos of a large number of mice of Bagg’s X-rayed anomalous strain, Brown (1931) investigated the retardation processes at different stages of embryological development. She attributes the condition to an aberrant vascular system in the embryo resulting in deficient nutrition, whereby, when the stress of twisting of the posterior region of the early embryonic body occurred, the deficient excretory and drainage mechanisms failed to unite. Abnormally large iliac and umbilical veins were found in embryos of fourteenth-day development and undue pressure from these, together, perhaps, with pressure from the foetal membranes in twisting, played an important part in effecting those strictures which arrested the development both of the ureter and of the metanephros. Definite retardation points were observed in the ureter anlagen and the nature and extent of renal deficiency were related to the stage at which ureteral growth was arrested. She offers no satisfactory explanation for the association of eye and kidney defects repeatedly found in the same mice.
Urogenital Anomalies as Inherited Defects
The pedigree chart reproduced between pp. 100 and 101 shows the descent of sixty rats with urogenital abnormalities, of which fifteen rats appeared on the previous chart but were necessarily included here both for purposes of relationship and to illustrate the incidence of the defect in the different generations. Only those rats are shown on the chart which were directly involved in the inheritance of urogenital anomalies; an exception has been made, however, where it was possible to show also the relationship to rats with microphthalmia and other eye defects. It will be noted that the pedigree table consists of six groups of rats, all of which are descended from a single litter in the first generation shown on the original chart. In Table I the six groups are referred to by the chart number of the female heading each group in generation V, and the incidence of both urogenital anomalies and eye defects is shown not only in each generation but also in each group. The number of rats comprising the nine generations reviewed, viz. 5007, does not represent the total number. of living offspring produced, as, owing to the exigencies of space, and the needs of other scientific workers, rats were disposed of, which, had they been retained for breeding purposes, might have swelled the ranks of the defectives. In addition, considerable numbers of rats related to defectives were used in experiments involving abortion or dead litters (this accounted for the fading out of groups II and VI) or necessitating the deaths of the rats employed; and finally, prior to the ninth generation the presence of renal defects was ascertained in the female only by laparotomy or post-mortem examinations and it was obviously impossible to examine the whole stock in this way. From the ninth generation onwards it was found possible, by means of palpation, to detect any renal defect before the fourteenth day of life; as a result, in this series, the majority of the rats described were killed when only 3-5 weeks old. Although the above facts detract from the value of the report as a genetic study, it is unlikely that they affect materially the percentage of incidence of the defect. Table I. Showing the occurrence of urogenital anomalies and eye defects in ten generations of rats and descent from six females in the first generation
No. of 99 that gave birth Total Total to total No. of living descendants of No. with urogenital defects: descendants of No. with eye defects: descendants of withuro- with in each A A A
Genera-_- ~ c — c — | Total genital eye generation V.3 V.4 V.8 V.10 V.13 V.15 V.3 v.4 v.8 v.10
vI 6 2 7 12 6 19 — _ _— _ — 19 1g 19 — 18 299 — 19 13 1 6 6 1g hydro.* VII 37 150 77 65 £65 =~ 381 _ 233 — 1g 19 — 233 233 1g 19 — 1g 299 13 425 6 5 27 hydro.* hydro.* VIII 149 67 140 108 100 48 _ — 13 — 299 — — 3d6 _ 1g 83s 299 19 612 3 10 46 IX 90 59 52 207 122 — _ _ — 1g 19 — _— T3S 699 — 8443 399 23g 19 — . 580 2 22 50 xX 134 #50 110 334 193 — _ — 33s 43d 499 19 — 233 19 = _ 1g 399 — 821 12 7 63 XI 110 126 148 519 250 — —_ _— 13 533 599 — — 53S 299 — — _— —_ 1153 11 1 112 XII «486 «686 122 380 304 — — _— 1g 533 TOP 299 — — _— — 23h 12 455 499 | 978 15 11 114 XI «668 «26: «100)—Sssd1St «131 — — — 13 499 — — — — — — _— _ 340 5 _ 35 XIV 6 — 6 — 4 — 1g 399 — 13 —_ _ — 53h 699 _— — oo — 15 5
Totals 145 587 762 1640 1175 98 1g 392 233 83S 492 1WOSS 2092 399 25919 | WSS 1G6PP 1912 5S 5OQ NSS 999 443 699 | 5007 60 19 466 334 hydro.* 134 hydro.*
Totals 4 2 12 36 3 3 39 2 lu 18 10
hydro. =hydrocephalic. t Others too young to mate.
If the chart and Tables I and II be examined it will be seen that, of 466 rats that gave birth to live litters, thirty-nine produced a total of sixty urogenital defectives. It is striking that 60 per cent (or thirty-six) of these occurred in Group IV, and were descended from female V. 10, and that 334 per cent of the total (i.e. twenty rats) are traced back to a single rat—VII. 19. In proportion to the number of rats born, rat V. 8 gave almost as high an incidence, . but whereas in this case the defect was spread over seven generations of rats, in VII. 19’s the abnormality was confined—with a single exception and excluding VII. 19 herself—to two generations.
The percentage of urogenital defectives within the whole related stock indicates a high incidence, viz. 1-2 per cent or approximately 1 in 83; renal agenesia, however, is apparently as rare as in man for only seven examples have been encountered, i.e. 1 in 715 rats. The data collected from the literature by Collins (1932) showed that renal agenesia was observed in man in 1 in 920 necropsies; his own figures placed the incidence higher, viz. 1 in 705, and Campbell (1928) has recently observed 1 in 400 (personal communication). If the incidence of urogenital anomalies within a restricted group such as that of female VII. 19 be contrasted with that in related animals as a whole, the increase will be found to be sufficiently significant to warrant the defect being considered inherited. Among 480 descendants of rat VII. 19, comprising generations XI and XII, there occurred twenty rats with urogenital anomalies, i.e. over 4 per cent were defective. The high familial incidence is plainly obvious on the chart; Table II demonstrates the inherited character of the abnormalities in other ways, most notable of which is the occurrence of animals with renal and/or genital defects in successive litters born to the same parents, and the frequency with which the mating of normal litter-mates of such defectives again produced abnormals. The pedigree chart shows several instances. It will be observed that the percentage of urogenital defectives rises from 1-2 per cent in the related stock to almost 21 per cent in affected litters or 9 per cent in all the offspring born to parents of affected animals.
Lest it be suggested that an unhealthy condition either of the ovum or of the uterus was responsible for the maldevelopment of the embryo in its early stages, figures have been given in Table II showing the number of normal litter-mates both within affected litters and born in previous or subsequent litters—for frequently two and three normal litters were born to parents of affected offspring. Apart from the consideration of litter size, the general physical fitness both of the defective rats themselves and of their parents renders the hypothesis unlikely, although it does not preclude the possible existence of some adverse influence affecting the ovum at an early stage of segmentation and thus providing a physiological as well as a genetic basis for the anomaly, such as was put forward by one of us (Hain, 1936) in the case of microphthalmia in a recent study of the inheritance of eye defects in the same stock. This is discussed more fully below.
In the six groups of rats covered by this study, eye defects were hardly more Pedigree Chart of rats having renal and genital anomalies
GROUP I GROUP II GROUP III GROUP IV GROUP V GROUP VI
"fe oF 2 8
P 1 a |
Vil
m € pep ge pede £4 sees Ix
o eQ-@GH Le oe oO
©} @ Bo %&
s 69 £> » € £F £H ¢ [fs
XII # ® 2 T an 2 2 b> &» do» | x > @ O ? :@9 O wh» Oo
sv yh 6 6 6 6 6 & & 6 Le
202 @2 ©? ©2
VII. 1 same as VII. 17; ©=female outcross; (G)=male outcross (i.e. from a different strain of rats); . VII. 10 same as VIII. 8; @W=nicrophthalmics; @=genital abnormality only; VII. 11 in direct descent from V. 11 x 12; 9 =kidney defects,
(V. 4, 5, 6 and 7 cousins; . O =female; O=male; VII. 14 same as VIII. 13. Congenital Urogenital Anomalies in Rats 97
Table II. Showing the proportion of defectives to normals born to the
same female No. defective No. normal Total Generation Mothers of — in same normal to of rats defective rats 3d 99 litter same 9 VI V.15 _— 1 8 18 VII VI. 6 2 — 9 ' 19 1 _ 5 VI. 16 {2 i of 24 VI. 22 2 — 6 17 VIII VII. 7 1 —_ 10 33 VIL. 17 —_— 1 11 33 VII. 21 — 1 3 7 IX VIII. 15 —_ 1 5 5 VIII. 22 1 _— 5 5 x IX. 33 —_ 1 6 47 IX. 32 1 _— 5 5 IX. 28 1 _ 7 7 IX. 25 _— 1 8 10 IX. 23 1 _ ll 18 IX. 22 1 —_ 6 24 —_— 1 5 IX.17 {= i bo 31 IX. 15 _— 1 4 15 IX. 13 { : = of 21 XI X. 27 1 1 8 29 X. 28 —_ 1 10 16 X. 30 1 1 5 23 X. 32 1 1 10 25 1 — 4 X. 22 { l = of 24 X. 33 _ 1 4 ll X. 6 1 — 5 15 XII XI. 4 1 — 9 18 XI. 12 {4 = 3 ul XI. 13 2 1 4 16 XI. 16 _— 2 5 13 XI. 18 1 _ 10 10 XI. 19 —_ 1 2 2 XI. 27 — 3 5 15 XI. 32 — 1 10 10
XI. 34 —_ 1 7 24 XIII XII. 5 _— 1 6 12 XII. 8 1 2 ll 24 XII. 9 —_— 1 4 10 XIV XIII. 1 1 3 6 13 XIII. 10 1 — 2 2 Totals 39 92 29 31 287 662 Ve 60 Percentages of urogenital defectives: (a) To normals in same litter (287) wee ose 20:9% orc. 1 in 5. (6) To normals to same 2 parent (662) .. aes 9:0% ore. 1 in 11. (c) To all related stock (5007)... eee eee 1-2% orc. 1 in 83.
prevalent than defects of the urogenital system, which, owing to the difficulty of detection, were apt to be missed. Collins (1982) included microphthalmia in his list of anomalies found associated with renal agenesia in the literature bearing on the human subject. However, a comparison of the numbers with urogenital and eye defects totalled for each group in Table I does not show any association between the frequency of the two abnormalities in any group. Of special interest are those occasions on which rats having eye defects and others with urogenital defects were born either in the same or in successive litters to the same parents, e.g. VII. 19-24, VIII. 7-10, X. 11-13 born to blind parents, XIV. 1-9 and XII. 23, 24 blind where one might reasonably have expected urogenital abnormalities. The most interesting case is that of rat XIII. 1, which, after having a litter containing five rats with microphthalmia, produced four with urogenital defects.
The occurrence of eye and kidney defects in the same stock of rodents necessitates a discussion of the results obtained by Bagg in rats (1922) and more notably in mice. Developmental arrests which were noted in the surviving young of pregnant rats irradiated on the nineteenth day of gestation, consisted especially of brain defects and also of cataract and gross eye abnormalities. Blood vascular disturbances were noted also in the young of rats irradiated several days before mating. The experiments were repeated in a modified form on mice (Bagg & Little, 1924; Bagg, 1926, 1929) and demonstrated that abnormalities can be induced in the descendants of irradiated mice, without any immediate physiological effects being manifested in the irradiated animals themselves or in their litters. The first eye defect occurred in the third generation removed from the treated animals, and kidney abnormalities developed four generations later (Bagg, 1926). Eye and kidney defects were frequently observed in the same individuals, and the mortality was high owing to the frequency with which both kidneys were missing. Clubfeet and skull asymmetry also appeared with relative frequency and were associated with the defects described. In the opinion of Bagg and also of Bagg & Little the tendency to abnormality in structure was associated with blood extravasations in the developing young of strains showing a high percentage of defectiveness. These caused lesions which interrupted the normal rate of development of definite parts of the embryo, the wide range of structural abnormality being accounted for by the different periods of prenatal development at which the vascular disturbances occurred and by their severity.
These facts have been given at some length not only because similar eye and kidney defects have occurred in the stock of rats used by us, but the interval of time which elapsed between the first appearance of each of the two defects was the same as was observed in Bagg’s mice, viz. four generations. There is, however, no association of irradiation with the ancestors of any of this stock, or with any member of the stock itself. Moreover, microphthalmia first appeared in the original American stock of Wistar rats (of which the Edinburgh stock is a branch) in 1913, and a study of its inheritance and of other eye defects was made by Dr Helen Dean King (1931). No other structural anomalies were found in association with the eye defects, but Dr Hammett of the Wistar Institute is reported by Bagg (1926) as having found a single adult female rat with a solitary kidney, “ which was the only animal found with this condition in a group of several thousand autopsies”.
The similarity between the expression of the developmental arrests described in our rats and Bagg’s mice is sufficiently striking to admit the possibility of the same causal agency, the outward expression of the arrest being dependent on the “critical period” (Stockard, 1920) at which this operated. Certain features prominent in Bagg’s mice do not exist in our rats:
(a) Whereas almost invariably two or more defects existed in the same mouse, only one—either eye or kidney—was found in our rats.
(b) By inbreeding, the incidence of the defects was immeasurably increased in mice (Bagg, 1926). An increase was also observed in the rats, but this was by no means commensurate with Bagg’s figures. According to him, the characters appeared as recessives following Mendelian laws, and no abnormaleyed animals were found in the first generation of an abnormal by normal outcross. This was strictly contrary to the findings of Hain (1987) as is shown by two examples on the pedigree chart between pp. 100 and 101, viz. rats
(c) It is remarkable that in none of Bagg’s defective mice were renal defects associated with genital defects on the same side of the body such as have been a prominent feature in the rats herein described.
(d) Whereas the renal defects in rats were confined to the left side, in mice they were almost evenly distributed, though with a tendency to occur more often on the right side; however, a marked tendency for clubbing of limbs to occur on the left side of the body is recorded by Bagg (1929).
From a study of the facts presented by the pedigree chart and Tables I and IT it is concluded that, although the evidence indicates that renal anomalies are inherited characters, their mode of inheritance, as in the case of microphthalmia, is not a straightforward one. The data are consistent with the existence of multiple factors or of a dominant factor with poor expression, the manifestation of which is determined both by genetic and physiological factors. A comparison of the charts for microphthalmia (Hain, 1987) and urogenital anomalies indicates a more straightforward mode of inheritance for the latter than for the former.
Summary
- As the result of the inbreeding of rats related to animals showing urogenital defects, the incidence of the latter has been increased. Additional forms of the anomaly have been obtained and are described.
- An attempt is made to relate the nature and degree of renal and genital anomaly to the conjectured arrest of renal development in early embryonic life.
- The abnormalities are inherited and are probably associated with microphthalmia although they have not appeared in rats having eye defects. It is probable that both anomalies are due to arrests in the development of the embryo, the outward manifestation being determined by the stage at which the disturbance occurred.
- The similarity between effects produced by Bagg as the result of irradiating mice and those that have been found in the rats here described is discussed.
References
Baaa, H. J. (1922). Amer. J. Anat. vol. xxx, p. 133. (1924). Amer. J. Obstet. Gynaec. vol. vim, p. 131.
—— (1926). Amer. J. Anat. vol. XxxVI, p. 275.
—— (1929). Amer. J. Anat. vol. xLm, p. 167. Baga, H. J. & Lirtzg, C. C. (1924). Amer. J. Anat. vol. xxxm, p. 119. Braver, D. C. (1933). Arch. Path. Lab. Med. vol. xv, p. 51. Brown, A. L. (1931). Amer. J. Anat. vol. xLvu, p. 117. CaMPBELL, M. (1928). Ann. Surg. vol. Lxxxvm, p. 1039. Cotuins, D. C. (1932). Ann. Surg. vol. xov, p. 715. Donatpson, H. H. (1915). The Rat. (Monograph of the Wistar Institute.) Harn, A. M. (1934a). Anat. Rec. vol. Ix, p. 383.
—— (1934b). J. exp. Biol. vol. x1, p. 279.
—— (1937). Proc. roy. Soc. Edinb. vol. LVI, p. 64.
Harn, A. M. & Rosertson, E. M. (1936). J. Anat. vol. Lxx, p. 566. Jackson, C. M. (1924). Proc. Soc. exp. Biol., N.Y., vol. xxu, p. 410. Kina, H. D. (1931). Amer. J. Anat. vol. xivim, p. 231.
Strocxarp, C. R. (1920). Amer. J. Anat. vol. xxvm, p. 115.
Cite this page: Hill, M.A. (2024, April 16) Embryology Paper - Congenital urogenital anomalies in rats including unilateral renal agenesia: further data in support of their inheritance (1937). Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Paper_-_Congenital_urogenital_anomalies_in_rats_including_unilateral_renal_agenesia:_further_data_in_support_of_their_inheritance_(1937)
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