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Pregnant Swiss Webster mice were fed a diet moderately deficient in zinc from day 7 of gestation until parturition. Offspring of these mice showed depressed immune function through 6 months of age. In addition, the second and third filial generations, all of which were fed only the normal control diet, continued to manifest reduced immunocompetence, although not to the same degree as in the first generation.

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The effects of zinc deprivation upon the normal immunologic ontogeny of outbred N:NIH(S) mice was investigated by feeding lactating dams, from the day of parturition, and their pups to 8 weeks of age, a diet containing EDTA-washed isolated soy protein and 9 ppm (marginal zinc deficiency), 5 ppm (moderate zinc deficiency) or 2.5 ppm (severe zinc deficiency) zinc. Two groups of controls were provided with the same diet, but containing 100 ppm zinc; one group was fed ad libitum, the other was pair-fed to the level of food intake observed in the moderately deprived animals (5 ppm zinc). Severe growth retardation of lymphoid tissues, most notably thymus, was observed in all mice deprived of zinc. Indeed, the magnitude of splenic and thymic hypogenesis was directly dependent upon the severity of the dietary zinc deficit. Furthermore, zinc-deprived pups exhibited a significantly decreased splenic cellularity whether assessed per spleen or as a function of spleen weight, including a sharp reduction in both red and white cell counts. Similarly, at 4 weeks of age direct splenic plaque-forming cell responses to sheep erythrocyte immunization were dramatically diminished in mice that were moderately and severely deprived of zinc during the postnatal period. Finally, a striking and indicative feature of the critical import of zinc in immune maturation was the observation that these zinc-deficient mice at 4 weeks of age exhibited a highly disordered serum immunoglobulin profile, with absence of detectable IgM, IgG2a and IgA along with greatly elevated serum levels of IgG1. We suggest that deficiency of zinc during growth and development may predispose in a major way to acquired immune deficiency and opportunistic infection.

To investigate the effects and reversibility of moderate prenatal zinc deprivation, pregnant mice were fed, beginning on day 7 of gestation, a diet containing either 100 ppm (control) or 5 ppm zinc; pair-fed controls were also studied. Nutritional manipulation was limited to the prenatal period. Zinc-deprived dams had significantly smaller litters than did controls, and postnatal survival was markedly compromised. Progeny of zinc-deprived dams displayed significant growth retardation, as reflected by lower body weight and length than controls, whether ad libitum-fed or pair-fed. Growth of spleen and thymus was affected by zinc deprivation to a significantly greater extent than was growth of heart, kidney or brain. Cross-fostering of control pups to zinc-deprived dams resulted in delayed growth; however, retardation was not as great as that observed in deprived pups allowed to suckle their natural mothers. Cross-fostering of zinc-deprived pups to control dams improved growth of most organs, but did little to improve growth of spleen and, most notably, thymus. Zinc-deprived pups exhibited considerable "catch up" growth following neonatal zinc repletion, and by 6-8 weeks of age, no significant differences between control and deprived offspring were observed.

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Recent work has shown that offspring of outbred mice deprived of adequate dietary zinc during the latter two-thirds of gestation exhibited a defective direct plaque-forming cell response to immunization with heterologous erythrocytes, as well as impaired ontogenesis of serum IgM. Moreover, such aberrant immunological measurements continued to be observed, although to a lesser degree, in F2 and F3 progeny. We now demonstrate that offspring of mice moderately deprived of zinc (5 ppm zinc diet) between days 7 and 20 of gestation also show an aberrant pattern of development of serum levels of IgG2a and IgA, despite complete nutritional rehabilitation beginning at birth. Only by 6 months of age were concentrations of these serum immunoglobulins similar to those in offspring of control dams. In contrast, levels of IgG1 and IgG2b were within normal ranges by 6 wk of age. Cross-fostering of zinc-deprived offspring to dams adequately nourished during pregnancy did little to ameliorate their aberrant pattern of serum immunoglobulin development. Defective maturation of serum IgG2a and IgA did not persist in F2 and F3 progeny. Nonetheless such 2nd and 3rd generation offspring continued to have higher than normal perinatal mortality. The alterations of immune ontogenesis in these mice could not be attributed to the persistence of abnormal plasma zinc levels, as these were within normal ranges. It would appear that zinc deficiency during gestation may alter the basic mechanism of development of immunological competence.

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