Maternal Cigarette Smoking, Metabolic Enzyme Polymorphism, and Developmental Events in the Early Stages of Extrauterine Life

Human Biology, Apr 2004 by Bottini, N, Gloria-Bottini, F, Magrini, A, Stefanini, L, Et al

Abstract

The recent observation that maternal ACP1 genotype has an interactive effect with smoking on intrauterine development prompted us to search for a possible interaction effect between smoking and ACP1 genotype on haptoglobin (Hp) development in the neonatal period. ACP1 is a highly polymorphic protein tyrosine phosphatase involved in signal transduction of several growth factor receptors. The enzyme is composed of two isoforms, F and S. We studied 299 infants born in the Department of Obstetrics of the University Hospital of Rome La Sapienza. We found that an interaction between ACP1 genotype and smoking has an effect on haptoglobin development: A significant delay of haptoglobin development in infants born to smoking mothers is observed only in infants with the ACP1*B/*B genotype, which shows the highest concentration of the ACP1 F isoform. The results indicate that the ACP1 genotype modifies the deleterious effects of smoking on development not only during intrauterine life but also during the early stage of extrauterine life.

KEY WORDS: ACP1, HP, SMOKING, HAPTOGLOBIN DEVELOPMENT, NEWBORNS

Recent evidence has shown that the deleterious effects of maternal cigarette smoking on intrauterine growth are influenced by genetic variability in metabolic enzymes (E. Bottini et al. 2001; Hong et al. 2001; Wang et al. 2002; Pound 2002). We have shown that the negative effects of maternal smoking on intrauterine growth depend on the genotype of ACP1, also named cLMPTP (cytosolic low-molecular-weight phosphotyrosine phosphatase). cLMPTP is a highly polymorphic enzyme involved in signal transduction of several growth factor receptors. The liver is particularly rich in this enzyme, which is composed of two isoforms, F and S, each of which shows strong quantitative variation among genotypes (E. Bottini et al. 1995).

Haptoglobin is an [alpha]^sub 2^-sialoglycoprotein that shows immunomodulatory properties (Langlois and Delanghe 1996). According to the original methods described by Smithies (1955), haptoglobin displays three common phenotypes-HP 1,1, HP 1,2, and HP 2,2-as a result of the presence of two codominant alleles, HP*1 and HP*2, at an autosomal locus.

Haptoglobin develops gradually during the first weeks of life. In normal infants its plasma concentration, which is low at birth, rises steadily during the first 2-3 days of life (Watson and Porter 1963; Eaton et al. 1982). Haptoglobin development has been proposed as a postnatal maturation index.

Haptoglobin has an antioxidant role that protects against the action of free radicals (Gutteridgc 1987; Miller et al. 1997; Saeed et al. 1997). The newborn is susceptible to oxidative damage, and Moison et al. (1993) suggested that the absence of haptoglobin favors lipid peroxidation of pulmonary surfactant in preterm babies. Because of its property of complexing iron, haptoglobin limits the use of hemoglobin by adventitious bacteria, preventing Hb-threatening hemoglobin-driven bacterial infections (Eaton et al. 1982). Haptoglobin behaves as an aspecific bacteriostat (Lewis and Dyer 199; Otto et al. 1994); thus a delayed haptoglobin appearance might increase the risk of bacterial infections in the newborn.

In adult subjects tobacco smoke influences the serum level of haptoglobin (Shima and Adachi 1996).

In a previous paper we showed that haptoglobin development during the early stages of extrauterine life depends on the neonatal ACP1 genotype (E. Bottini et al. 1985). In particular, the lowest rate of haptoglobin development in the first few days after birth is observed in the ACP1 B phenotype, which shows the highest concentration of the F isoform.

For the present paper we reasoned that ACP1 might modify not only the effect of smoking on intrauterine growth but also the possible effects of smoking on developmental events that occur during the early stages of intrauterine life. Thus we revisited our clinical records to search for possible influences of ACP1 genotype on the effect of smoking on haptoglobin development in the neonatal period.

Materials and Methods

The sample is composed of 299 infants born in the Department of Obstetrics of the University Hospital of Rome Ea Sapienza. These are the same infants that we considered in our previous report (E. Bottini et al. 1985).

Serum haptoglobin was studied by starch gel electrophoresis at birth and on the third day of life. For our experimental conditions the minimum detectable haptoglobin concentration was about 5 mg/dl for hemoglobin-binding capacity. This limit was established by serial dilutions of several adult plasma samples in which haptoglobin concentration had been previously determined. Using this semiquantitative method, we were able to classify subjects into two categories: those with a haptoglobin concentration less than 5 mg/dl and those with a haptoglobin concentration greater than 5 mg/dl for hemoglobin-binding capacity.

The ACP1 phenotype of infants was determined using the original method of Hopkinson et al. (1964). At present, we determine ACP1 genotype using DNA analysis. The results obtained from the classical method using starch gel electrophoresis and from the new method are practically identical, suggesting a 100% correlation between phenotype (classical analysis) and genotype (DNA analysis).