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Maternal and paternal alcohol use: Effects on the immune system of the offspring
Life Sciences, Vol. 48, pp. Printed in the U.S.A.
1-8
Pergamon Press
MINIREVIEW: MATERNAL AND PATERNAL ALCOHOL USE: EFFECTS ON THE IMMUNE SYSTEM OF THE OFFSPRING Zehava Gottesfeld* and Ernest L. Abel *Department of Neurobiology and Anatomy University of Texas Medical School P.O. Box 20708 Houston, Texas 77225 and C.S. Mott Center for Human Growth and Development Wayne State University, School of Medicine Detroit, Michigan 48201 (Received in final form October 29, 1990)
Summary There is no single mechanism which can account for such a complex biological phenomenon as immune regulation, nor is it clear how alcohol teratogenicity exerts its multiple adversive effects, including lasting immune deficits. Much of the research aimed at unravelling effects of pre- or early postnatal alcohol exposure on the organism's defense mechanisms and long-term health risks has been phenomenological. A better understanding of mechanisms which underlie alcohol effects on immune competency will require integrated studies of the neuro-immune-endocrine networks. Exposure to alcohol during early development has been associated with immune deficits in offspring, that may lead to increased vulnerability to infectious diseases or cancer. The purpose of this review is threefold: first, we present evidence that maternal alcohol consumption during pregnancy and/or lactation, and paternal consumption can influence immune competency in offspring; second, we review clinical evidence linking prenatal alcohol exposure to increased frequencies of malignancies; and third, we suggest possible mechanisms to account for the immune deficits associated with pre- or early postnatal-alcohol exposure, involving functional alterations in neuro-immuneendocrine networks.
* Address for correspondence 0024-3205/91 $3,00 + .00
Copyright (c) 1991 Pergamon Press plc
2
Parental Alcohol Use: Offspring Immunity
Vol. 48, No. I, 1991
EFFECTS OF MATERNAL OR PATERNAL ALCOHOL USE ON OFFSPRING IMMUNITY Effects of Maternal Alcohol Consumotion Durina Preanancv As indicated in Table 1 (refs 1-16), immune competency of humans and animals exposed to alcohol in utaro has been tested using a variety of immune parameters, e.g. mitogen-induced lymphocyte proliferation assays, several types of cellular and humoralmediated immune responses, lymphocyte cell count, thymic and splenic organ size, andsusceptibility to bacterial infection as well as to parasitic burden. Each of these assays measures only one aspect of immune function and may not necessarily account for immunocompetence or resistance to disease displayed by the organism. Overall, a marked suppression of one or another immune parameter in subjects exposed to alcohol in utaro has been noted by most, but not all investigators and certain immune deficits appear age-related (1,2). Furthermore, not all immune parameters were equally affected in the same subject (3,4,5,6). Inconsistencies in various studies may be related to factors such as type of immune parameters under study; species, sex and age differences; dose, route and duration of alcohol administration during prenatal development; gestational period, type of diet intake and nutritional status of the alcohol-consuming mother, as well as various maternal risk factors such as smoking, drug use, emotional and socioeconomic status. Clearly, this field of research will benefit from further systematic research. TABLE 1 Immune Effects of Prenatal Alcohol Exposure Immune Parameters
Results
References
~ ~
5,7,8 5
~ * ~
5 5 7
~ ~,
5,7 7
1' ~
5,7,8 7
Human stuclies Lymphocyte proliferation T cell proliferation B cell proliferation Cell count Eosinophil, neutrophil counts Lymphocyte count T cell count Humoral Immunity Immunoglobulins Miscellaneous Incidence of infections Thymus size
Vol. 48, No. I , 1991
Parental Alcohol Use: Offspring Immunlty
TABLE 1, continued Immune Parameters
Results
References
* ,*
1,2,9,10,11 1,6,12 1,6,10,12 2,6,9,10
Animal studies (rat. mouse~
Lymphocyte proliferation T cell proliferation B cell proliferation T blast response to IL-2 Cell count Thymus cell count Spleen cell count
* 1'
9,13 10 12
Antigenic expression L3T4, Lyt2 Thy 1 CD4, CD8
1'
3 3,4 4,14 14 4
*,
4,12
t ,. (Exp. 1) (Exp. 2)
4 4 4 15 15
~, **
Humoral Immunity Plaque-forming cells Cellular Immunity Cytotoxic T cells Delayed response to KLH Contact hypersensitivity Local graft vs host
Miscellaneous Thymus size Thymus: body ratio
•*
Spleen: body ratio Parasitic infection
•* 1'
1'
1' Increase; ~ decrease;., no change
3,9 11 11 11 11 16
3
4
Parental Alcohol Use: Offspring Immunity
Vol. 48, No. i, 1991
Effects of Lactational Alcohol Exoosura The consequences of alcohol exposure during early postnatal development are relatively unknown. In the rodent, this period is comparable to the human third trimester, and is characterized by rapid brain growth spurt (19) and development of immunocompetancy (20,21). Young adult mice exposed to alcohol during the suckling period exhibit cellular immune deficits, including suppressed local graft vs host and contact hypersensitivity responses (22). The magnitude of the immune deficits displayed by these animals is similar to that associated with prenatal alcohol exposure although blood alcohol concentrations occurring in suckling pups is considerably lower. This suggests that the nascent immune system is not only vulnerable to alcohol exposure during the critical period of early postnatal development, but may also be more sensitive to perturbation than at other times. It remains to be determined whether the same mechanisms underlie the immune deficits associated with adult alcohol consumption and perinatal alcohol exposure. Effects of Paternal Alcohol Consumption Rats and mice sired by alcohol-consuming males are also more susceptible to infection. In our studies, we scarify the corneas of these offspring and topically apply Pseudomonas .~.ugJgg.~, a gram negative opportunistic bacterium. Animals sired by alcohol-consuming fathers have a greater tendency to develop perforated corneas, and the days to perforation are shorter (23,24). This increased susceptibility, however, is observed only in Long-Evans and not Sprague-Dawley rats (25). In mice, the increased susceptibility to Pseudomonas infection occurs despite the presence of high titers of antibody specific to pseudomonas (24). This indicates that the differential susceptibility is not due to humoral factors. The most likely mechanism is a cellular defect possibly involving an alteration in phagocytosis. EVIDENCE THAT EXPOSURE TO ALCOHOL IN UTERO IS ASSOCIATED WITH INCREASED SENSITIVITY TO TUMORIGENESIS Several clinical studies have reported a link between in utero alcohol exposure and increased incidence of malignancies (Table 2, refs. 26-31, 35,36). Most of the reported tumors in these children were of embryonic origin, including neuroblastoma (26-29), ganglioneuroblastoma (30) and medulloblastoma (31). A noteworthy feature of these clinical reports is that no malignancies were observed in tissues of the oral cavity, esophagus or larynx which are characteristic of tumors found in adult alcoholics (32). This suggests that mechanisms involved in the oncogenic effects of alcohol during fetal life are different from those occurring in the adult. Weanling mice exposed to alcohol in utero and during lactation, display increased susceptibility to induction of primary Rous sarcoma (33). In this case, alcohol or its metabolites may be acting as carcinogens in utero, co-carcinogens predisposing the offspring to other carcinogens, or as teratogens promoting malignancy indirectly by suppressing the immune system. Further studies are necessary to determine the underlying mechanisms and whether the alcohol-exposed animals are equally susceptible to other carcinogens. We recently reported that prenatal alcohol exposure enhanced estrogen-induced growth of a prolactin-secreting pituitary tumor in adult rats (34). These animals displayed a further increase in immune deficits compared to those of the
Vol. 48, No. 1, 1991
Parental Alcohol Use: Offsprln 8 l~nunlty
5
estrogen-treated pair-fed cohorts (34). The potentiated immune suppression may be partly responsible for the increased susceptibility to tumorigenesis. TABLE 2 Incidence of Malignancies in Patients Exposed to Alcohol in utero
Case # 1 2 3 4 5 6 7 8 9 10 11 12
Age 27 months 12 years Unknown 3 months At birth Unknown 13 months 21 months 6 years 16 months 21 months 18-42 years
Type of tumor Hepatoblastoma Adrenal carcinoma Genglioneuroblastoma Neuroblastoma Sacrococcygeal teratoma Medulloblastoma (2 cases) Endodermal sinus tumor Rhabdomyosarcoma (bladder) Nephroblastoma Acute lymphocytic leukemia Nephroblastoma Testicular cancer (several cases)
References 28 35 30 26 31 31 31 29 29 29 27 36
In all cases, the mother consumed large amounts of alcohol prior to and during pregnancy. In case #1, the mother also used other illegal drugs and in case #11, both parents were heavy users of alcohol. EFFECTS OF PRENATAL ALCOHOL EXPOSURE ON NEURO-IMMUNE-ENDOCRINE NETWORKS The immune system plays a vital role in maintaining the host's homeostasis, end its complexity requires finely-tuned control mechanisms. Failure to regulate the immune system can compromise the well being of the organism, including offspring of alcoholconsuming mothers. Traditionally, the immune system has been viewed as an intrinsic mechanism. Increasing evidence has indicated, however, that immune responsiveness is also modulated by feedback signals from the central nervous system (37,38). According to these observations, activated immunocytes release lymphokines ('immunotrensmitters") which act as intrinsic regulators as well as signal-mediators to the brain (39,40). The latter, in turn, modulates responses of the challenged lymphocytes by sending signals via the autonomic (sympathetic end parasympathetic) neuronal efferents (41,42,43), as well as the neuroendocrine humoral axis (44,45,46). Altered communications in neuro-immune-endocrine networks may account, at least partly, for the immune deficits associated with alcohol exposure during early development. Few studies have addressed this issue. Our initial maternal studies were focused on the peripheral nervous system ('the sympatho-lymphoid axis'), because compelling evidence
6
Parental Alcohol U s e : Offspring Immunity
Vol. 48, No. 1, 1991
has also shown that the sympathetic system plays an important role in immune modulation (41,42). We found that young adult mice exposed to alcohol in utero had increased norepinephrine (NE) tumover in the spleen and thymus but not the heart, compared to the pair-fed cohorts (15). This increased amine release may reflect increased sympathetic neuronal activity, consistent with the down regulation of #adrenoceptors, as well as decreased concentration of NE selectively in lymphoid organs (15). The altered sympathetic synaptic transmission was noted as early as postnatal day one and increased in magnitude with age (47). We also found that young-eduit mice exposed to alcohol via the mother's milk during lactation displayed similar changes (22). The association between increased release of NE in lymphoid organs and immune deficits observed in alcohol exposed animals, is consistent with the suggestion that sympathetic innervation exerts immunosuppressive effects (48). It remains to be determined, however, whether the enhanced sympathetic neuronal activation directly accounts for immune incompetency, or whether this is a reflection of altered central mechanisms. Hormones released from the hypothalamo/pituitary-gonadal, -adrenal and -thyroid axes are thought to function as immunomodulators (44). It is possible, therefore, that changes in the hormonal milieu in some way mediate the effects of alcohol exposure in utero or early postnatal development (49-53). It is well known, for example, that corticosterioids have potent suppressive effects on lymphocyte number and function and on neutrophil activity (54-56). In this regard, the reports of increased serum glucocorticoid levels associated with prenatal alcohol exposure are especially interesting (57-59). Few studies, however, have attempted to link changes in activation of the hypothalamo-adrenal axis with immune deficits observed in offspring of alcohol-consuming mothers (11). This field of research remains a terra incognita. The effects of paternal alcohol consumption on offspring immunity are intriguing but as yet there are not enough data to even speculate as to mechanism(s) of action. Acknowledaements Work by the authors described in this review was partly supported by NIAAA #AA06158 (ZG), NIH-supported BRSG (ZG) and P50 AA07606 (ELA). The expert typing and secretarial assistance by Diana Parker is gratefully acknowledged. References 1. 2. 3. 4. 5. 6. 7.
A.A. MONJAN and W. MANDELL, Neurobehav. Toxicol. 2 213-215 (1980). D.C. Norman, M.-P. CHANG, S. CASTLE, C.M.K. WONG, B.J. BRANCH and A.N. TAYLOR, Alcoholism: Clin. Exp. Res. 14 324 (1990). S.J. EWALD and S.M. WALDEN, J. Leukocyte Biol. 44 434-440 (1988). S.J. EWALD, C. HUANG and L. BRAY, Drugs of Abuse, Immunity end Immunodeflciency, H. Friedman (ed), Plenum Pub. Corp., New York (in press). S. JOHNSON, R. KNIGHT, D.J. MARMIER and R. STEELE, Pediatr. Ras. 15 908-911 (1981). D.C. NORMAN, M.-P. CHANG, S.C. CASTLE, J.E. VAN ZUYLEN and A.N. TAYLOR, Alcoholism: Clin. Exp. Res. 13 69-72 (1989). A.J. AMMAN, E.W. WARA, M.Jo COWAN, D.J. BARRETI" and E.R. STIEHN, Am. J. Dis. Child 136 906-908 (1982).
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8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Parental Alcohol Use: Offspring Immunity
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M. CALVANI, D. GHIRELLI, M. CALVANI, C. FORTUNA, F. LALU and P. MARCOUNI, Minerva Pediatr. 37 77-88 (1985). S.J. EWALD and W.W. FROST, Thymus 9 211-215 (1987). T. JERRELLS and J. WEINBERG, Alcoholism: Clin. Exp. Res. 13 320 (1989). E. REDEI, W.R. CLARK and R.F. MCGIVERN, Alcoholism: Clin. Exp. Res. 13 439-443 (1989). R.H. ZlDELL, N.S. HATOUM and P.T. THOMAS, Fund Appl. Toxicol. 10 189-198 (1988). S.J. EWALD, Alcoholism: Clin. Exp. Res. 13 485-489 (1989). S.J. EWALD and C. HUANG, Alcohol. Immunomodulation and AIDS, Alan R. Uss Inc., New York, pp 191-200 (1990). Z. GOTTESFELD, R. CHRISTIE, D.L FELTEN and S.J. LEGRUE, Neurosci. 35 185194 (19~0). LL. 8EELIG JR, W.M. STEVEN and G.L STEWART, Alcoholism: Clin. Exp. Res. 14 336 (1990). R.R. MACGREGOR, JAMA 256 1474-1479 (1986). R.R. WATSON, C. ESKELSON and B.R. HARTMANN, Arizona Med. 41 665-668
(1984). 19. J. DOBBING and J. SANDS, Early Hum. Devl. 3 79-83 (1979). 20. J.H. KIMURA, S.M. ELDRIDGE, I. MICHALEK, I. MORISAKA, S. HAMADA and J.R. MCGHEE, J. Immunol. 134 2839-2845 (1985). 21. A.J.P. VEERMAN, Z. Immunitaeforsh. 150 45-59 (1975). 22. Z. GO'I-rESFELD and S.J. LEGRUE, Life Sci. 47 457-465 (1990). 23. LD. HAZLE'rr, R.P. BARRETr, R.S° BERK and E.L ABEL, Ophthal. Res. 21381-387 (1989). 24. R.J. BERK, I.N. MONTGOMERY, LD. HAZLETT and E.L ABEL, Alcoholism: Clin. Exp. Res. 13 795-798 (1989). 25. EoL ABEL, LD. HAZLETT, R.J. BERK and B. MUTCHNICK, Alcoholism: Clin. Exp. Res. 13 323 (1989). 26. H. KINNEY, R. FAIX and J. BRAZY, Pediatrics 66 130-132 (1980). 27. W. KIESS, Oo LINDERKAMP, H.-B. HADORN and R. HAAS, Eur. J. Pediatr. 14~1160161 (1984). 26. A. KAHN, J.L BADER, G.R. HOY and L.F. SINKS, The Lancat_l 1403-1404 (1979). 29. A. ZAUNSCHIRM and W. MUNTEAN, Eur. J. Pediatr. 141 256 (1984). :30. C.P. HOLT and B. FAVARA, Eleventh Annual Meeting of the Soc. Pediatr. Onc., Usbon, Portugal, p. 761 (1979). 31. M.N. COHEN, Neurobehav. Toxicol. and Teratol. 3 161-162 (1981). 32. K.J. ROTHMAN, Alcohol, Persons at Hioh Risk of Cancer: An ADoroa~l to Cancer Etiolo(~y~_and Control, J.F. Fraumeni Jr. (ed), Academic Press, New York, pp. 138-148 (1975). 33. G. HAUGHTON, K. MOHR and F. ELLIS, Alcoholism 5 347 (1981). 34. Z. GoI-rESFELD, Alcoholism: Clin. Exp. Res. 14 294 (1990). 35. L HORNSTEIN, C. CROEWE and R. GRUPPO, Lancat II 1292-1293 (1977). 36. LM. BROWN, LM. PO'I-rERN and R.N. HOOVER, Cancer Res. 46 4812-4816 (1986). 37. H.O. BESEDOVSKY, A.E. DEL REY and E. SORKIN, Immunol. Today 4 342-346 (1983). 38. R. GUILLEMIN, M. COHN and T. MELNECHUK (eds), Neural Modulation of Immunity, Raven Press, New York (1985). 39. A. DEI REY, H. BESEDOVSKY, E. SORKIN and C.A. DINARELLO, Ann. N.Y. Acad. Sci. 496 85-90 (1987).
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40. N.R. HALL, J.P. MCGILUS, B.L SPANGELO and A.L. GOLDSTEIN, J. Immunol. 135 806s-81 ls (1985). 41. D.L. FELTEN, S.Y. FEL'rEN, D.L BELUNGER, S.L CARLSON, K.D. ACKERMAN, K.S. MADDEN, J.A. OLSCHOWSKA and S. LIVNAT, Immunol. Rev. 100 225-260 (1987). 42. S. UVNAT, S.Y. FELTEN, S.L. CARLSON, D.L. BELLINGER and D.L FELTEN, J. Neuroimmunol. 10 5-30 (1985). 43. K. BULLOCK, R. GUILLEMIN, M. COHN and T. MELNECHUK (eds.), Neural Modulation of Immunitv. (eds), Raven Press, New York, pp. 111-139 (1985). 44. I. BERCZI (ed), Pituitarv Functions and Immunitv. Boca Raton, CRC Press (1986). 45. H.O. BESEDOVSKY, A.E. DEL REY and E. SORKIN, J. Immunol. 135 750s-754s (1985). 46. E.J. GOE'rZL, T. CHERNOV, F. RENOLD and D.G. PAYAN, J. Immunol. 135 802s805s (1985). 47. Z. GOTTESFELD, B. MORGANand J.R. PEREZ-POLO,J. Neurosci. Res. 26:308-316 (1980). 46. H.O. BESEDOVSKY, A. DEL REY, E. SORKIN, M. DAPRADA and H.H. KELLER, ImmunoL 48 848-855 (1979). 49. R.A. ANDERSON JR, Neurobehav. Toxicol. Teratol..~ 98-104 (1981). 50. Z. GOTTESFELD and P.B. SILVERMAN, Neurosci. Lett. 109 42-47 (1990). 51. J.C. ROSE, P.J. MEIS and M.I. CASTRO, Neurobehav. Toxicol. and Teratol..~ 105110 (1981). 52. J. WEINBERG, LR. NELSON and A.W. TAYLOR, Alcohol and Brain DeveloDment, J.R. West (ecl.), Oxford University Press, Oxford, pp 310-842 (1986). 5,3. A.N. TAYLOR, B.J. BRANCH and N. KOKKA, Prog. Bioohem. Pharmacol. 18 99-110 (1981). 54. M. ARNOLD, I_ SCHRIEBER and P. BROOKS, Drugs 36 340-363 (1988). 55. H.N. CLAMAN, New Engl. J. Med. 287 388-397 (1972). 56. T.R. CUPPS and A.S. FAUCI, Immunol. Rev. 65 133-155 (1982). 57. J. WEINBERG, Alcoholism: Clin. Exp. Res. 13 73-83 (1989). 58. J. WEINBERG and P.V. GALLO, Neurobehav. Toxicol. Teratol. 4 515-520 (1982). 59. A.N. TAYLOR, B.J. BRANCH, B. COOLEY-MATrHEWS and R.E. POLAND, Psychoneuroendocrinol..Z 49-56 (1982).
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Pergamon Press
MINIREVIEW: MATERNAL AND PATERNAL ALCOHOL USE: EFFECTS ON THE IMMUNE SYSTEM OF THE OFFSPRING Zehava Gottesfeld* and Ernest L. Abel *Department of Neurobiology and Anatomy University of Texas Medical School P.O. Box 20708 Houston, Texas 77225 and C.S. Mott Center for Human Growth and Development Wayne State University, School of Medicine Detroit, Michigan 48201 (Received in final form October 29, 1990)
Summary There is no single mechanism which can account for such a complex biological phenomenon as immune regulation, nor is it clear how alcohol teratogenicity exerts its multiple adversive effects, including lasting immune deficits. Much of the research aimed at unravelling effects of pre- or early postnatal alcohol exposure on the organism's defense mechanisms and long-term health risks has been phenomenological. A better understanding of mechanisms which underlie alcohol effects on immune competency will require integrated studies of the neuro-immune-endocrine networks. Exposure to alcohol during early development has been associated with immune deficits in offspring, that may lead to increased vulnerability to infectious diseases or cancer. The purpose of this review is threefold: first, we present evidence that maternal alcohol consumption during pregnancy and/or lactation, and paternal consumption can influence immune competency in offspring; second, we review clinical evidence linking prenatal alcohol exposure to increased frequencies of malignancies; and third, we suggest possible mechanisms to account for the immune deficits associated with pre- or early postnatal-alcohol exposure, involving functional alterations in neuro-immuneendocrine networks.
* Address for correspondence 0024-3205/91 $3,00 + .00
Copyright (c) 1991 Pergamon Press plc
2
Parental Alcohol Use: Offspring Immunity
Vol. 48, No. I, 1991
EFFECTS OF MATERNAL OR PATERNAL ALCOHOL USE ON OFFSPRING IMMUNITY Effects of Maternal Alcohol Consumotion Durina Preanancv As indicated in Table 1 (refs 1-16), immune competency of humans and animals exposed to alcohol in utaro has been tested using a variety of immune parameters, e.g. mitogen-induced lymphocyte proliferation assays, several types of cellular and humoralmediated immune responses, lymphocyte cell count, thymic and splenic organ size, andsusceptibility to bacterial infection as well as to parasitic burden. Each of these assays measures only one aspect of immune function and may not necessarily account for immunocompetence or resistance to disease displayed by the organism. Overall, a marked suppression of one or another immune parameter in subjects exposed to alcohol in utaro has been noted by most, but not all investigators and certain immune deficits appear age-related (1,2). Furthermore, not all immune parameters were equally affected in the same subject (3,4,5,6). Inconsistencies in various studies may be related to factors such as type of immune parameters under study; species, sex and age differences; dose, route and duration of alcohol administration during prenatal development; gestational period, type of diet intake and nutritional status of the alcohol-consuming mother, as well as various maternal risk factors such as smoking, drug use, emotional and socioeconomic status. Clearly, this field of research will benefit from further systematic research. TABLE 1 Immune Effects of Prenatal Alcohol Exposure Immune Parameters
Results
References
~ ~
5,7,8 5
~ * ~
5 5 7
~ ~,
5,7 7
1' ~
5,7,8 7
Human stuclies Lymphocyte proliferation T cell proliferation B cell proliferation Cell count Eosinophil, neutrophil counts Lymphocyte count T cell count Humoral Immunity Immunoglobulins Miscellaneous Incidence of infections Thymus size
Vol. 48, No. I , 1991
Parental Alcohol Use: Offspring Immunlty
TABLE 1, continued Immune Parameters
Results
References
* ,*
1,2,9,10,11 1,6,12 1,6,10,12 2,6,9,10
Animal studies (rat. mouse~
Lymphocyte proliferation T cell proliferation B cell proliferation T blast response to IL-2 Cell count Thymus cell count Spleen cell count
* 1'
9,13 10 12
Antigenic expression L3T4, Lyt2 Thy 1 CD4, CD8
1'
3 3,4 4,14 14 4
*,
4,12
t ,. (Exp. 1) (Exp. 2)
4 4 4 15 15
~, **
Humoral Immunity Plaque-forming cells Cellular Immunity Cytotoxic T cells Delayed response to KLH Contact hypersensitivity Local graft vs host
Miscellaneous Thymus size Thymus: body ratio
•*
Spleen: body ratio Parasitic infection
•* 1'
1'
1' Increase; ~ decrease;., no change
3,9 11 11 11 11 16
3
4
Parental Alcohol Use: Offspring Immunity
Vol. 48, No. i, 1991
Effects of Lactational Alcohol Exoosura The consequences of alcohol exposure during early postnatal development are relatively unknown. In the rodent, this period is comparable to the human third trimester, and is characterized by rapid brain growth spurt (19) and development of immunocompetancy (20,21). Young adult mice exposed to alcohol during the suckling period exhibit cellular immune deficits, including suppressed local graft vs host and contact hypersensitivity responses (22). The magnitude of the immune deficits displayed by these animals is similar to that associated with prenatal alcohol exposure although blood alcohol concentrations occurring in suckling pups is considerably lower. This suggests that the nascent immune system is not only vulnerable to alcohol exposure during the critical period of early postnatal development, but may also be more sensitive to perturbation than at other times. It remains to be determined whether the same mechanisms underlie the immune deficits associated with adult alcohol consumption and perinatal alcohol exposure. Effects of Paternal Alcohol Consumption Rats and mice sired by alcohol-consuming males are also more susceptible to infection. In our studies, we scarify the corneas of these offspring and topically apply Pseudomonas .~.ugJgg.~, a gram negative opportunistic bacterium. Animals sired by alcohol-consuming fathers have a greater tendency to develop perforated corneas, and the days to perforation are shorter (23,24). This increased susceptibility, however, is observed only in Long-Evans and not Sprague-Dawley rats (25). In mice, the increased susceptibility to Pseudomonas infection occurs despite the presence of high titers of antibody specific to pseudomonas (24). This indicates that the differential susceptibility is not due to humoral factors. The most likely mechanism is a cellular defect possibly involving an alteration in phagocytosis. EVIDENCE THAT EXPOSURE TO ALCOHOL IN UTERO IS ASSOCIATED WITH INCREASED SENSITIVITY TO TUMORIGENESIS Several clinical studies have reported a link between in utero alcohol exposure and increased incidence of malignancies (Table 2, refs. 26-31, 35,36). Most of the reported tumors in these children were of embryonic origin, including neuroblastoma (26-29), ganglioneuroblastoma (30) and medulloblastoma (31). A noteworthy feature of these clinical reports is that no malignancies were observed in tissues of the oral cavity, esophagus or larynx which are characteristic of tumors found in adult alcoholics (32). This suggests that mechanisms involved in the oncogenic effects of alcohol during fetal life are different from those occurring in the adult. Weanling mice exposed to alcohol in utero and during lactation, display increased susceptibility to induction of primary Rous sarcoma (33). In this case, alcohol or its metabolites may be acting as carcinogens in utero, co-carcinogens predisposing the offspring to other carcinogens, or as teratogens promoting malignancy indirectly by suppressing the immune system. Further studies are necessary to determine the underlying mechanisms and whether the alcohol-exposed animals are equally susceptible to other carcinogens. We recently reported that prenatal alcohol exposure enhanced estrogen-induced growth of a prolactin-secreting pituitary tumor in adult rats (34). These animals displayed a further increase in immune deficits compared to those of the
Vol. 48, No. 1, 1991
Parental Alcohol Use: Offsprln 8 l~nunlty
5
estrogen-treated pair-fed cohorts (34). The potentiated immune suppression may be partly responsible for the increased susceptibility to tumorigenesis. TABLE 2 Incidence of Malignancies in Patients Exposed to Alcohol in utero
Case # 1 2 3 4 5 6 7 8 9 10 11 12
Age 27 months 12 years Unknown 3 months At birth Unknown 13 months 21 months 6 years 16 months 21 months 18-42 years
Type of tumor Hepatoblastoma Adrenal carcinoma Genglioneuroblastoma Neuroblastoma Sacrococcygeal teratoma Medulloblastoma (2 cases) Endodermal sinus tumor Rhabdomyosarcoma (bladder) Nephroblastoma Acute lymphocytic leukemia Nephroblastoma Testicular cancer (several cases)
References 28 35 30 26 31 31 31 29 29 29 27 36
In all cases, the mother consumed large amounts of alcohol prior to and during pregnancy. In case #1, the mother also used other illegal drugs and in case #11, both parents were heavy users of alcohol. EFFECTS OF PRENATAL ALCOHOL EXPOSURE ON NEURO-IMMUNE-ENDOCRINE NETWORKS The immune system plays a vital role in maintaining the host's homeostasis, end its complexity requires finely-tuned control mechanisms. Failure to regulate the immune system can compromise the well being of the organism, including offspring of alcoholconsuming mothers. Traditionally, the immune system has been viewed as an intrinsic mechanism. Increasing evidence has indicated, however, that immune responsiveness is also modulated by feedback signals from the central nervous system (37,38). According to these observations, activated immunocytes release lymphokines ('immunotrensmitters") which act as intrinsic regulators as well as signal-mediators to the brain (39,40). The latter, in turn, modulates responses of the challenged lymphocytes by sending signals via the autonomic (sympathetic end parasympathetic) neuronal efferents (41,42,43), as well as the neuroendocrine humoral axis (44,45,46). Altered communications in neuro-immune-endocrine networks may account, at least partly, for the immune deficits associated with alcohol exposure during early development. Few studies have addressed this issue. Our initial maternal studies were focused on the peripheral nervous system ('the sympatho-lymphoid axis'), because compelling evidence
6
Parental Alcohol U s e : Offspring Immunity
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has also shown that the sympathetic system plays an important role in immune modulation (41,42). We found that young adult mice exposed to alcohol in utero had increased norepinephrine (NE) tumover in the spleen and thymus but not the heart, compared to the pair-fed cohorts (15). This increased amine release may reflect increased sympathetic neuronal activity, consistent with the down regulation of #adrenoceptors, as well as decreased concentration of NE selectively in lymphoid organs (15). The altered sympathetic synaptic transmission was noted as early as postnatal day one and increased in magnitude with age (47). We also found that young-eduit mice exposed to alcohol via the mother's milk during lactation displayed similar changes (22). The association between increased release of NE in lymphoid organs and immune deficits observed in alcohol exposed animals, is consistent with the suggestion that sympathetic innervation exerts immunosuppressive effects (48). It remains to be determined, however, whether the enhanced sympathetic neuronal activation directly accounts for immune incompetency, or whether this is a reflection of altered central mechanisms. Hormones released from the hypothalamo/pituitary-gonadal, -adrenal and -thyroid axes are thought to function as immunomodulators (44). It is possible, therefore, that changes in the hormonal milieu in some way mediate the effects of alcohol exposure in utero or early postnatal development (49-53). It is well known, for example, that corticosterioids have potent suppressive effects on lymphocyte number and function and on neutrophil activity (54-56). In this regard, the reports of increased serum glucocorticoid levels associated with prenatal alcohol exposure are especially interesting (57-59). Few studies, however, have attempted to link changes in activation of the hypothalamo-adrenal axis with immune deficits observed in offspring of alcohol-consuming mothers (11). This field of research remains a terra incognita. The effects of paternal alcohol consumption on offspring immunity are intriguing but as yet there are not enough data to even speculate as to mechanism(s) of action. Acknowledaements Work by the authors described in this review was partly supported by NIAAA #AA06158 (ZG), NIH-supported BRSG (ZG) and P50 AA07606 (ELA). The expert typing and secretarial assistance by Diana Parker is gratefully acknowledged. References 1. 2. 3. 4. 5. 6. 7.
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