Submitted to: Biofactors
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/22/1999
Publication Date: 3/1/2000
Citation: Johnson, W.T., Prohaska, J.R. 2000. Gender influences the effect of perinatal copper deficiency on cerebellar PKC gamma content. Biofactors. 11:163-169. Interpretive Summary: Menke's disease is an inherited disorder of copper metabolism that leads to low copper concentrations in the infant brain. Severe retardation of neurological development and early death accompany this disease which provides evidence that copper is essential for normal brain development in humans. Because severe copper deficiency is rare in humans, it is unlikely that the extremely low brain copper concentrations that characterize Menke's disease would occur in newborns. However, a substantial portion of people in the industrialized world consume diets that do not provide the recommended daily intake of copper and it is not clear if and how the consumption of these diets during pregnancy and nursing affects brain development in infants. A class of regulatory enzymes called protein kinases are important mediators of brain growth and development. One of these protein kinases, protein kinase C, modulates the growth of nerves and the formation of contacts between nerves in the developing brain. The present study shows that copper deficiency during pregnancy and nursing lowers a form of protein kinase C in a region of the brain, called the cerebellum, in newborn rats. Furthermore, the reduction in protein kinase C was greater in female than male newborns. The reduction in this form of protein kinase C, because it occurs at a time when protein kinase C is involved in regulating the formation of contacts between nerves in the cerebellum, could adversely affect normal maturation of the cerebellum. The cerebellum controls motor functions and impairment of its maturation by copper deficiency could have long-term, functional consequences on motor coordination. The findings indicate that such consequences may be more pronounced in females than in males.
Technical Abstract: Change in cerebellar protein kinase C gamma (PKC gamma) content caused by perinatal copper (Cu) deficiency was determined in 22-day old rats. The offspring of dams with low Cu intake during gestation and lactation exhibited signs characteristic of Cu deficiency including anemia, greater than 90% reduction in liver Cu concentration, and undetectable serum ceruloplasmin. In addition, brain Cu concentrations were reduced 80%. No differences in the signs of Cu deficiency were observed between female and male offspring. However, cerebellar PKC gamma content was reduced 54% (P<0.05, Tukey's test) in female offspring but only 18% (P>0.05) in male offspring. Following 6 weeks of Cu supplementation, brain Cu concentrations remained depressed in female and male rats that experienced perinatal Cu deficiency, but cerebellar PKC gamma content was completely restored to control levels. Postnatal expression of PKC gamma in the cerebellum coincides with and regulates cerebellar maturation. The results of the present study indicate perinatal Cu deficiency may impair cerebellar maturation to a greater extent in females than in males. However, it is not clear whether supression of PKC gamma by perinatal Cu deficiency produces permanent neuropathology in the cerebellum because the effects were reversed by Cu supplementation.