Studies of the Offspring of Parents Treated by Pelvic Radio-therapy

R. Turpin, J. Lejeune and M. O. Réthoré

Supplement Volume of Cytologia International Journal of Cytology, Proceedings of the International Genetics Symposia, 1956 : 85-91, Issued July 30, 1957.


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With a view of bringing out possible sex linked lethal mutation induced by ionizing energy, we have studied the off springs of parents treated by pelvic radio-therapy.

The present report will be restricted on the study of the sex ratio of the offspring of irradiated parents.

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I. The data

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A. Selection of Patients

Thanks to material help from the " Securité Sociale " and the " Institut National d'Hygiéne " radio-therapy files of all hospitals in and around paris have been examined.

All in all, out of 238,800 complete files checked in twenty differents hospitals, 4428 cases of pelvic irradiation were found. The irradiations were carried out on account of various complaints, of a non-cancerous character, among adults younger than 35 for the women and 40 for the men.

These treatments were carried out before the month of December 1952, the years checked on dating from 1940 in the case of most hospitals but going back to 1930 and even 1925 in certain instances.

In all cases considered, the skin /dose was greater than 300 r and the characteristics of the radiation were known.

Of these 4428 cases :

3579 related to men

849 related to women

This is doubtless due to the different frequency of pelvic radio-therapy indications according to sex, but may also result from the reluctance of radiologists to use a therapy liable quickly to give rise to amenorrhoea.

A questionnaire, enabling the offspring of individual cases to be established, was therefore sent to each of these 4428 subjects, followed by as many reminders as proved necessary.

It may be pointed out that r doses, mentioned hereafter, always represent the amount of ionizing radiation reaching the skip as the radio-therapist, giving the treatment, had calculated. The average doses given here are therefore skin /doses and not gonad /doses.

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B. The offspring of irradiated males

Of 3579 questionnaires send out, 1334 or 37,4% suitable for our purpose were returned.

These 1334 answers obviously concerned with the cases treated for different reasons and under varying conditions, a fact which induced us to divide them into the following three categories :

a) 368 irradiated, either high up on the lumbar région, or on the thigh

For the most part (320), these cases suffering from sciatic neuralgia were irradiated an the upper lumbar region ; the remainder (48) on the thigh for various reasons. This group is therefore excluded from the present statistics.

b) 180 cases irradiated on the pelvic area, whose gonads being probably shielded

In actual fact, during radiations through the forelimbs, it is customary to shield the testicules by means of a strip of lead placed an the thighs. Unfortunately, there is no way of ascertaining how faithfully this rule was observed.

These 180 subjects comprise :

109, rheumatism or coxo-femoral arthrosis cases ;

64, inguinal adenopathic complaints (chiefly Nicolas Favre);

7, cases of pubic or super pubic dermatosis.

The above subjects, who doubtless received a weak dose of r since they had been probably protected, had offspring before and after treatment.

Sex ratio :

Before treatment 0.554 ± 0. 050 (115 children)

After treatment 0.437 ± 0.051 (101 children)

This rather special post-X ray s.r. makes it hard to differentiate this sample from the test of the present statistics.

However, as these fluctuations do not exceed what might be expected by chance, the exclusion of this data on grounds of irradiation conditions would not seem unwarranted.

c) 786 subjects irradiated on the pelvic area under conditions making protection of the gonads impossible

These 786 cases comprise :

517 all treated by test-limb radio-therapy, focused on the sacro-lumbar region and the two initial sacrum vertebrae, for sciatic neuralgia, on the one hand :

269 treated for various reasons :

either by sacra-lumbar rear-limb treatment

or by ano-genital fore-limb treatment

for different causes :

pruritic dermatoses : 120

sacra-iliac neuralgia : 59

sacra-lumbar rheumatisn : 79

spina bifida : 11

These two samples, 517 and 269, cannot be considered as strictly comparable and we shall therefore consider them separately.

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C. The offspring of irradiated women

Of 849 women questioned, 284 or 33,5 % sent answers suitable to our purpose (a percentage similar to that of the male), but obtained after two and sometimes three reminders.

All the data available for the present study can be summarized in the following table :

TotalStill-birthsAbortionsAbnormals Twins
MFMFMFMMMFFF
Before treatment Men (137) Various cases116115001711000
Men (284) Sciatica cases2422234329 33303
Women (154) All cases130106231810012
After treatment Men (95) Various cases (1461 r)6862222022301
Men (194) Sciatica cases (1295 r)15711831 2723112
Women (97) All cases ; (1360 r)6373612614110

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II. Study of the sex ratio

From the chromosomic determination of the sex it follows that in case of female subjects dominant lethal mutations induced on X can not be detected, because both sexes of the offspring should be equally affected, but recessive one will affect selectively the orale offspring, i.e. cause decrease of s.r. While, in case of male subjects, dominant lethal mutations only should be detected and affect selectively female offspring, i.e. cause increase of s.r.

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A. Sex ratio of the progeny of irradiated males

For reasons already stated, this study was carried out on sample of 786 subjects treated for sciatic neuralgia or other complaints without receiving gonad protection.

a) Now 92 cases treated for sciatic neuralgia had children before and after treatment and thus make an ideal subject-matter for the study of s.r. variations following treatment and previously

Before : s.r. 0.526 ± 0.042 (150 children)

After : s. r. 0.555 ± 0.045 (119 children)

b) Similarly 42 cases treated for various reasons had children before and after treatment.

Before : s.r. 0.448 ± 0.060 (67 children)

After : s.r. 0.530 ±0.071 (51 children)

Pooling these two samples, we find 134 fathers who has prior to treatment : 217 children : s.r. 0.502 ± 0.035

Following treatment : 170 children : s. r. 0.547 ± 0.083

The s.r. difference is not statistically significant, but, as might be expected, the trend of variation is towards an increase.

c) on combining the progeny of all cases who had children previous to treatment, with a view to comparising them with that of subjects who had children after treatment, we find on combining both samples

s. r. before treatment : 0.514 ± 0.019 (696 children)

s.r. after treatment : 0.555 ± 0.026 (405 children)

an increasing s.r. as before, but still not significant.

These data can be analysed according the following facts.

1) The fertility after radio-therapy as appraised by the increase of the sibship after treatment

Accepting the hypothesis of dominant lethals induced on the chromosome X, deviation should indeed be the more striking since the individual is more nearly sterile. This study, being focused on the increase of the sibship after treatment, is obviously a preliminary approach to the problem, for it does not enable the following phenomena to be taken into account :

Physiological sterility due to the increasing age of couples birth control

Size of the sibship after treatment
12345
Neuralgia sciatic (194 cases)Male645918115
Female454017115
Total
(Sciatic + varia) (289 cases)Male878026248
Female726225165
159142514013

In agreement with hypothesis, the s.r. variation peak is reached with sibships having the lowest increase 1 or 2 children, in the sciatica sub-sample.

This variation is not so great in the general sample.

2) Moment of conception after radio-therapy

s.r. distribution, according to the interval between the end of irradiation and date of child-birth, leads to the following figure :

Year0-12-34-56-78-9
Male3367553238
Female3751323129

These variations show that, if there really exists a s.r. increase due to the production of dominant lethals the chromosome X, there is no reason to suppose that it essentially affects children born soon after treatment.

In other words, if the female deficit is a real one its occurrence essentially concerns with children resulting from paternel gametes irradiated in the spermatogonial stage

3) Variation of s.r. according to dose received for the total same of treated fathers

s. r. before treatment : 0.514 ± 0.019 (696 children)

s. r. after treatment : < 1000 r (moyenne = 721) : 0.528 ± 0.039 (161 children)

s.r. after treatmeng : > 1000 r (Moyenne = 1730) : 0.574 ± 0.032 (244 children)

To summarize :

1) The observed deviations are not significant but show a trend toward increase in keeping with the genetic hypothesis of dominant lethals induced on the chromosome.

2) The s.r. increase seems more marked when the sibship is smaller and the amount of radiation higher.

3) There is no reason for supposing that this s.r. deviation, if it is real, is due to peculiar spermatozoid sensitivity, for the vast majority of children observed were resulted from gametes irradiated in the spermatogonial stage.

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B. Sex ratio of the offspring of irradiated women

45 mothers had children before and after treatment.

s. r. before : 0.606 ± 0.06 (61 children)

s.r. after 0.510 ± 0.07 (51 children)

If one considers the offspring of all the women

BeforeMFs.r.
154 mothers130106 = 2360.551 ± 0.034
Afters.r.
97 mothers6373 = 1360.463 ± 0.044
(Moyenne = 1.360)

This deficit is not significant although the s.r. deviation follows the trend expected. ?2 is 2.74 corresponding to a probability 10 % that the observed difference is purely fortuitous.

If we study s.r. variations, as done with further, in terms of :

The sise of the sibship after treatment

The deficit is found to affect mainly women who have borne two children only.

The period of conception

There is no ground for supposing that the genetic effect is stronger soon after treatment than afterwards.

However, subdividing the material too much creates very small groups with limited statistical value.

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Discussion

First of all we must admitt that the heterogeneous nature of both father and mother samples and the small number of observations available, considerably impair the general significance of this inquiry.

However, if we consider the s.r. of the progeny before treatment, of men who received pelvic radio-therapy treatment without gonad protection and of women who were submitted to pelvic radio-therapy, we find the offspring before any treatment :

s.r.
Of male 0.514 ± 0.019 (696 children)
Of female 0.551 ± 0.034 (236 children)
?2 = 962 ; 0.50>P>0.30

As both these instances of male and female prior to treatment can be considered homogeneous, it is possible to compare their offspring after treatment : Hence

s.r. of male(sciatica patients)0.571 ± 0.030(275 children)
s.r. of male(all cases)0.555 ± 0.026(405 children)
s.r. of female(various complaints)0.463 ± 0.044(136 children)

It will be noted that the difference between s. r. of children of female treated and s.r. of children of male treated for sciatica is significant.

?2 = 4.24 ; 0.05 > P > 0.02

Comparing now the progeny of female treated with total male treated, we do not reach the level of 0.05.

?2 = 3.49; P # 0.06

If we compare, in the last resort, the children of male who received more than 1000 r with these of female treated, the difference becomes relevant again. We then find :

For male 140 maleagainst 104 female
For female63 maleagainst 73 female
?2 = 4,15; 0,05 > P > >0,02

The following conclusion can be drawn from our data: it is likely that, the s.r. is increased in male and decreased in female after pelvic irradiation.

However, this conclusion cannot be regarded as certain since these comparisons are not free from possible distortions, due mainly to the existence of monosexual sibships which are known to occur more frequently than would be predicted by chance.

Thus, on confining our figures to the first child born after irradiation, we find :

First child form after treatment malefemales.r.
Fathers(sciatica cases)102760.573 ± 0.037
(various conditions)39420.482 ± 0.055
Mothers(various conditions)37440.457 ± 0.055

Comparison between offspring of female and offspring of male treated for sciatica yields ?2 = 3.04 or 0.10 > P > 0.05.

Comparison between the offspring of female and total progeny of male ?2 = 1.49

This decrease in the discrepancy between samples when comparison is limited to the first child is largely due to sibships with a higher s.r. at the 2nd, 3rd and 4th birth rank in the sample of patients treated for various conditions.

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Conclusion

The variation of s. r. in the off spring of female and male treated by pelvic ratio-therapy are well in agreement with the hypothesis based on the induction of dominant lethal sex-linked mutations detectable in the progeny of male and the induction of recessive lethal sex-linked mutations detectable in the progeny of female submitted to the same treatment.

Considering the uncertainties attending on our sampling, and the small size of the material, we realize that our data do not constitute a formal proof that mutations are produced by ionizing energy. However, this hypothesis seems the only likely explanation of the peculiarities observed.