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Parents' cigarette smoking and childhood cancer
Medical
Hypotheses
PARENTS’
12:
17-20,
CIGARETI’R
1983
SMOKING
AND CHILDHOOD
CANCER
S. Grufferman, ES. Delzell, MC. Maile, G. Michalopoulos. Box 3958, Duke University Medical Center, Durham, North Carolina 27710.
ABSTRACT In our recent study of childhood rhabdomyosarcoma (RMS) we found an increase in the risk of RMS among children whose fathers smoked cigarettes. However, there was no association between RMS and mothers’ We hypothesize that differential germ cell damage from smoking. cigarette smoking underlies our observations and that this risk of germ cell damage from cigarette smoking and from other environmental exposures is greater for men than for women. The increased susceptibility for male germ cells may be due to the number and timing of meiotic and mitotic cell divisions. In males, germ cells undergo large numbers of meiotic and In contrast, in mitotic divisions throughout the reproductive years. females, generally only one oocyte matures and completes meiosis each Thus, there are very large male-female month of the reproductive years. differences in the number of rapidly dividing germ cells during the reproductive years, and it is rapidly proliferating cells which are mast susceptible to genetic damage. We conclude that fathers’ environmental exposures before conception of their children may play a role in the etiology of childhood cancer.
INTRODUCTION We recently reported a four-fold increase in the risk of rhabdomyosarcoma (RMS) among children whose fathers smoked cigarettes (1). We considered two explanations for this finding: first, that childrens’ passive exposure to cigarette smoke increases their risk of RMS; and second, that cigarette smoke causes heritable genetic damage in parents which subsequently increases the risk of RMS in their children. If passive exposure of children to their parents’ cigarette smoke were responsible, there should be a similar association with mothers’ smoking. However, we found no excess of RMS among children whose mothers smoked cigarettes. Thus, passive exposure is not a likely explanation for the observed association with fathers’ smoking. In addition, the absence of an effect of mothers’ smoking suggests either that cigarette smoking produces heritable genetic damage in the father but not in the mother or that the carcinogenic
17
effects of such damage occurring in the mother are masked. To interpret these findings, we reviewed the available information on the carcinogenic, teratogenic and physiologic effects of parents’ smoking on their offspring. OBSERVATIONS FROM THE LITERATURE We found little evidence that mothers’ cigarette smoking increases the rate of cancer among their children (2,3), and the evidence linking congenital malformations with mothers’ cigarette smoking is weak and inconsistent (4,5,6). It has been shown that there are excesses of spontaneous abortions, placental abnormalities and low birth weight infants However, it has not been possible to among smoking mothers (7). determine whether these effects are due to heritable genetic damage in the mother or to direct effects on the developing fetus (8). In either case, these conditions may adversely affect the survival of fetuses of smoking mothers and thus prevent the expression of carcinogenic or teratogenic damage. There are few studies of the effects of fathers’ smoking on their offspring. Two studies found morphologic abnormalities of the sperm in men who were heavy smokers (9,101. One of these demonstrated a doseresponse relationship between the amount smoked and proportion of sperm which were abnormal (10). A third study did not confirm these results (11). A study by Mau and Netter (12) found a two-fold statistically significant increase in major congenital malformations in children of fathers who were heavy smokers. We could find only one study in addition to ours that considered the relationship between fathers’ cigarette smoking and cancer in their children (2). It found essentially no increased risk of leukemia in the children of men who smoked cigarettes. HYPOTHESIS AND CONCLUSIONS Although we cannot exclude the possibility that cigarette smoking produces genetic damage in female germ cells, we believe that the following hypothesis should be considered: the risk of germ cell damage from environmental exposures is greater for men than for women, and the greater susceptibility of male germ cells is related to the number and timing of meiotic and mitotic cell divisions. In the early female embryo, primordial germ cells proliferate by mitotic divisions. The resulting primary oocytes enter prophase of the first meiotic division. Then meiosis is arrested in the dictyotene stage, and the oocytes remain in this stage until sexual maturity. In the adult, one oocyte, usually, undergoes maturation and completes meiosis shortly before ovulation each month throughout the woman’s reproductive years. In contrast to this, spermatogenesis involves large numbers of meiotic and mitotic divisions throughout the male’s reproductive years. Because rapidly proliferating cell populations are most susceptible to genetic damage (13,141, the greater number of germ cell divisions during adulthood in men could place them at a higher risk than women for germ cell damage by cigarette smoking and other recurrent environmental exposures. In fact, the recognized susceptibility of sperm to mutagenic agents is the basis of the sperm Our hypothesis is further abnormality assay for mutagenicity (151. supported by the observation that inhaled tobacco smoke disrupts normal spermatogenesis in rats by specifically affecting mitoses in spermatocytes (16). 18
Etiologic studies of congenital malformations and childhood cancer have not adequately evaluated the role of fathers’ environmental exposures before conception of their children. We think that such exposures may play a role in the etiology of childhood cancer. was supported by PHS grant number ROlCA-21244, Cancer Institute, DHHS.
This investigation
awarded by the National
References
1.
Grufferman S, Wang HH, DeLong ER, Kimm SYS, Delzell Falletta JM. Environmental factors in the etiology of rhabdomyosarcoma in childhood. JNCI 1982; 68:107-113,
2.
Stewart A, Webb J, Hewitt D. A survey Br Med J 1958; 1:1495-1508.
3.
Neutel
of childhood
CI, Buck C. Effect of smoking during JNCI 1971; 47:59-63.
ES, 1982
malignancies.
pregnancy
on the risk
of cancer in children. 4.
U.S. Public Health Service. The health consequences of smoking. report of the Surgeon General. Washington, D.C.: U.S. Govt Print off, 1973:136-137 (DHEW publication No. (HSM) 73-8704).
5.
U.S. Public Health Service. Smoking and health. A report of the Surgeon General. Washington, D.C.: U.S. Govt Print Off, 1979, part 8:39 (DHEW publication No. (PHS) 79-50066).
6.
Kelsey JL, Dwyer T, Holford TR, Bracken MB. Maternal smoking and congenital malformations: an epidemiological study. J EpidemioI Community HeaIth 1978; 32:102-107.
7.
U.S. Public Health Service. The health consequences of smoking. A report of the Surgeon General. Washington, D.C.: U.S. Govt Print Off, 1981:157-159 (DHHS publication No. (PHS) 81-50156).
8.
Bridges BA, Clemmesen J, Sugimura T. Cigarette smoking carry a genetic risk? Mutation Research 1979; 65:71-81.
9.
Evans HJ, Fletcher J, Torrance M, Hargreave abnormalities and cigarette smoking. Lancet
-- does it
TB. Sperm 1981; i:627-629.
10.
Viczian M. Ergebnisse von Spermauntersuchungen bei Zigarettenrauchern. Z Haut Geschlechtskr 1969; 44:183-187.
11.
Godfrey
12.
Mau G, Netter P. Die Auswirkungen des vaterlichen Zigarettenkonsums auf die perinatale Sterblichkeit und die Missbildungshaufigkeit. Dtsch Med Wochenschr 1974; 99:1113-I
B. Sperm
morphology
in smokers.
19
A
Lancet
1981; i:948.
118.
13.
Cayama E, Tsuda H, Sarma DSR, Farber E. Initiation of chemical carcinogenesis requires ceII proliferation. Nature 1978; 275:80-62.
14.
Columbano A, Rajalakshmi S, Sarma DSR. Requirement of cell proliferation for the initiation of liver carcinogenesis as assayed by three different procedures. Cancer Research 1981; 41:2079-2083.
15.
Wyrobek AJ, Bruce WR. The induction of sperm-shape abnormalities in mice and humans. In: HoIlaender A, de Serres FJ, eds. Chemical Mutagens. Principles and Methods for their Detection. New York: Plenum Press, 1978:257-285.
16.
Viczian M. The effect of cigarette smoke inhalation on spermatogenesis in rats. Experientia 1968; 24:511-513.
20
Hypotheses
PARENTS’
12:
17-20,
CIGARETI’R
1983
SMOKING
AND CHILDHOOD
CANCER
S. Grufferman, ES. Delzell, MC. Maile, G. Michalopoulos. Box 3958, Duke University Medical Center, Durham, North Carolina 27710.
ABSTRACT In our recent study of childhood rhabdomyosarcoma (RMS) we found an increase in the risk of RMS among children whose fathers smoked cigarettes. However, there was no association between RMS and mothers’ We hypothesize that differential germ cell damage from smoking. cigarette smoking underlies our observations and that this risk of germ cell damage from cigarette smoking and from other environmental exposures is greater for men than for women. The increased susceptibility for male germ cells may be due to the number and timing of meiotic and mitotic cell divisions. In males, germ cells undergo large numbers of meiotic and In contrast, in mitotic divisions throughout the reproductive years. females, generally only one oocyte matures and completes meiosis each Thus, there are very large male-female month of the reproductive years. differences in the number of rapidly dividing germ cells during the reproductive years, and it is rapidly proliferating cells which are mast susceptible to genetic damage. We conclude that fathers’ environmental exposures before conception of their children may play a role in the etiology of childhood cancer.
INTRODUCTION We recently reported a four-fold increase in the risk of rhabdomyosarcoma (RMS) among children whose fathers smoked cigarettes (1). We considered two explanations for this finding: first, that childrens’ passive exposure to cigarette smoke increases their risk of RMS; and second, that cigarette smoke causes heritable genetic damage in parents which subsequently increases the risk of RMS in their children. If passive exposure of children to their parents’ cigarette smoke were responsible, there should be a similar association with mothers’ smoking. However, we found no excess of RMS among children whose mothers smoked cigarettes. Thus, passive exposure is not a likely explanation for the observed association with fathers’ smoking. In addition, the absence of an effect of mothers’ smoking suggests either that cigarette smoking produces heritable genetic damage in the father but not in the mother or that the carcinogenic
17
effects of such damage occurring in the mother are masked. To interpret these findings, we reviewed the available information on the carcinogenic, teratogenic and physiologic effects of parents’ smoking on their offspring. OBSERVATIONS FROM THE LITERATURE We found little evidence that mothers’ cigarette smoking increases the rate of cancer among their children (2,3), and the evidence linking congenital malformations with mothers’ cigarette smoking is weak and inconsistent (4,5,6). It has been shown that there are excesses of spontaneous abortions, placental abnormalities and low birth weight infants However, it has not been possible to among smoking mothers (7). determine whether these effects are due to heritable genetic damage in the mother or to direct effects on the developing fetus (8). In either case, these conditions may adversely affect the survival of fetuses of smoking mothers and thus prevent the expression of carcinogenic or teratogenic damage. There are few studies of the effects of fathers’ smoking on their offspring. Two studies found morphologic abnormalities of the sperm in men who were heavy smokers (9,101. One of these demonstrated a doseresponse relationship between the amount smoked and proportion of sperm which were abnormal (10). A third study did not confirm these results (11). A study by Mau and Netter (12) found a two-fold statistically significant increase in major congenital malformations in children of fathers who were heavy smokers. We could find only one study in addition to ours that considered the relationship between fathers’ cigarette smoking and cancer in their children (2). It found essentially no increased risk of leukemia in the children of men who smoked cigarettes. HYPOTHESIS AND CONCLUSIONS Although we cannot exclude the possibility that cigarette smoking produces genetic damage in female germ cells, we believe that the following hypothesis should be considered: the risk of germ cell damage from environmental exposures is greater for men than for women, and the greater susceptibility of male germ cells is related to the number and timing of meiotic and mitotic cell divisions. In the early female embryo, primordial germ cells proliferate by mitotic divisions. The resulting primary oocytes enter prophase of the first meiotic division. Then meiosis is arrested in the dictyotene stage, and the oocytes remain in this stage until sexual maturity. In the adult, one oocyte, usually, undergoes maturation and completes meiosis shortly before ovulation each month throughout the woman’s reproductive years. In contrast to this, spermatogenesis involves large numbers of meiotic and mitotic divisions throughout the male’s reproductive years. Because rapidly proliferating cell populations are most susceptible to genetic damage (13,141, the greater number of germ cell divisions during adulthood in men could place them at a higher risk than women for germ cell damage by cigarette smoking and other recurrent environmental exposures. In fact, the recognized susceptibility of sperm to mutagenic agents is the basis of the sperm Our hypothesis is further abnormality assay for mutagenicity (151. supported by the observation that inhaled tobacco smoke disrupts normal spermatogenesis in rats by specifically affecting mitoses in spermatocytes (16). 18
Etiologic studies of congenital malformations and childhood cancer have not adequately evaluated the role of fathers’ environmental exposures before conception of their children. We think that such exposures may play a role in the etiology of childhood cancer. was supported by PHS grant number ROlCA-21244, Cancer Institute, DHHS.
This investigation
awarded by the National
References
1.
Grufferman S, Wang HH, DeLong ER, Kimm SYS, Delzell Falletta JM. Environmental factors in the etiology of rhabdomyosarcoma in childhood. JNCI 1982; 68:107-113,
2.
Stewart A, Webb J, Hewitt D. A survey Br Med J 1958; 1:1495-1508.
3.
Neutel
of childhood
CI, Buck C. Effect of smoking during JNCI 1971; 47:59-63.
ES, 1982
malignancies.
pregnancy
on the risk
of cancer in children. 4.
U.S. Public Health Service. The health consequences of smoking. report of the Surgeon General. Washington, D.C.: U.S. Govt Print off, 1973:136-137 (DHEW publication No. (HSM) 73-8704).
5.
U.S. Public Health Service. Smoking and health. A report of the Surgeon General. Washington, D.C.: U.S. Govt Print Off, 1979, part 8:39 (DHEW publication No. (PHS) 79-50066).
6.
Kelsey JL, Dwyer T, Holford TR, Bracken MB. Maternal smoking and congenital malformations: an epidemiological study. J EpidemioI Community HeaIth 1978; 32:102-107.
7.
U.S. Public Health Service. The health consequences of smoking. A report of the Surgeon General. Washington, D.C.: U.S. Govt Print Off, 1981:157-159 (DHHS publication No. (PHS) 81-50156).
8.
Bridges BA, Clemmesen J, Sugimura T. Cigarette smoking carry a genetic risk? Mutation Research 1979; 65:71-81.
9.
Evans HJ, Fletcher J, Torrance M, Hargreave abnormalities and cigarette smoking. Lancet
-- does it
TB. Sperm 1981; i:627-629.
10.
Viczian M. Ergebnisse von Spermauntersuchungen bei Zigarettenrauchern. Z Haut Geschlechtskr 1969; 44:183-187.
11.
Godfrey
12.
Mau G, Netter P. Die Auswirkungen des vaterlichen Zigarettenkonsums auf die perinatale Sterblichkeit und die Missbildungshaufigkeit. Dtsch Med Wochenschr 1974; 99:1113-I
B. Sperm
morphology
in smokers.
19
A
Lancet
1981; i:948.
118.
13.
Cayama E, Tsuda H, Sarma DSR, Farber E. Initiation of chemical carcinogenesis requires ceII proliferation. Nature 1978; 275:80-62.
14.
Columbano A, Rajalakshmi S, Sarma DSR. Requirement of cell proliferation for the initiation of liver carcinogenesis as assayed by three different procedures. Cancer Research 1981; 41:2079-2083.
15.
Wyrobek AJ, Bruce WR. The induction of sperm-shape abnormalities in mice and humans. In: HoIlaender A, de Serres FJ, eds. Chemical Mutagens. Principles and Methods for their Detection. New York: Plenum Press, 1978:257-285.
16.
Viczian M. The effect of cigarette smoke inhalation on spermatogenesis in rats. Experientia 1968; 24:511-513.
20