Experimental studies evaluating the ability of chemopreventive agents, given during pregnancy, to inhibit transplacental carcinogenesis are available in the literature (7
). The present data provide the first demonstration that it is possible to inhibit postnatally induced cancer by administering a chemopreventive agent during pregnancy.
The results of our previous studies give a mechanistic base to the herein reported findings. In fact, the particular vulnerability at birth is amenable to the paraphysiological nucleotide alterations consequent to oxidative stress in the lung (4
). The high sensitivity of the newborn to carcinogens may also depend on additional factors, such as an increased proliferation rate in neonatal organs, also including the lung (10
), alterations of xenobiotic metabolism (11
) and a lower efficiency of certain DNA repair mechanisms (12
). Indeed, 60 years of research have supported the view that tobacco smoke is negative or weakly carcinogenic in rodents (13
), in contrast with the overwhelming epidemiological evidence showing that smoke is the most important human carcinogen. Yet, when exposure starts immediately after birth, as confirmed in the present study, MCS induces a potent carcinogenic response, which is characterized by a high incidence of benign lung tumors and occurrence of malignant tumors, within a short latency time, as well as by other degenerative changes in the lung and even in extra-respiratory tissues (3
). It should be noted that a neonatal tumorigenicity bioassay was proposed for the first time 50 years ago (15
). Although the liver is the main target in this model, encouraging results were also obtained with pulmonary carcinogens, also including smoke components (16
The impressive protection afforded by treatment with NAC throughout pregnancy demonstrates that the oxidative stress occurring at birth in the lung renders the organism particularly vulnerable to the action of carcinogens. Interestingly, prenatal NAC also prevented MCS-induced preneoplastic damage in the urinary bladder, which shows that treatment with this chemopreventive agent during pregnancy protects not only the lung but also another typical target of cigarette smoke. It is obvious that the dose of NAC used in the present study, which is the same dose used in a number of experimental studies with this agent (6
), is high if compared with a realistic intake by humans. Yet, this dose is not toxic to rodents (6
), and the need for using high doses both of carcinogens and protective agents is an inevitable drawback of all animal studies.
Parallel studies with environmental cigarette smoke (ECS) showed that exposure of mice since birth, for 5 weeks, results in a variety of early alterations, including cytogenetic damage in bone marrow and peripheral blood, formation of lipid peroxidation products in lung, increase of bulky DNA adducts and oxidatively generated DNA damage in lung, heart and aorta, overexpression of OGG1
in lung, stimulation of apoptosis, hyperproliferation and loss of Fhit protein in bronchial epithelial cells and pulmonary alveolar macrophages (18
). Interestingly, nucleotide alterations were even more pronounced when the mice were exposed to ECS during the first 5 weeks of life rather than during adulthood for an equivalent period of time (18
). It is also noteworthy that the expression levels of stem cell antigen-1
) gene are significantly higher in newborns than in adult mice, and exposure to ECS during the first 5 weeks of life significantly upregulated Sca-1
in lung, whereas no effect was observed in adults (20
). In vitro
, NAC inhibited the formation of DNA adducts and oxidatively generated DNA damage in transformed human mammary epithelial stem cells treated with 7,12-dimethylbenz(a
). In addition, exposure of neonatal mice to ECS produced, after 330 days, histopathological alterations in both lung and liver, which were not observed when exposure started 8 days later (22
). These findings highlight the crucial susceptibility soon after birth.
NAC and its derivatives have a variety of protective mechanisms in carcinogenesis, the primary one being the ability of their thiol molecules to scavenge reactive oxygen species and other free radicals (6
). It is probably that the protective environment created by NAC during pregnancy and at birth may both counteract the physiological birth-related oxidative stress and block the nucleophilic and oxidative species consequent to exposure to MCS immediately after birth. Moreover, we cannot rule out the hypothesis that prenatal NAC may have some ‘imprinting’ effect by influencing reduced glutathione metabolism in the offspring. Our previous studies have demonstrated that, in adult mice and rats, oral NAC is able to inhibit an impressive array of smoke-induced alterations of molecular, biochemical and cytogenetic endpoints (reviewed in ref. 23
). When given during pregnancy to ECS-exposed mice, NAC protected the fetus liver against the formation of bulky DNA adducts, oxidatively generated DNA damage, cytogenetic damage and overexpression of a number of genes (24
). Treatment during pregnancy of dams with NAC inhibited the increase of reduced glutathione and malondialdehyde in fetus lung (25
), and administration of NAC to dams prevented oxidative stress associated with birth in neonatal rats (26
). Moreover, administration of NAC during pregnancy protected Ku86-deficient mice from developmental cell death in the liver (27
). Although the issue of the transplacental transport of NAC has been questioned by using an ovine model (28
), all the above data lend support to the conclusion that this drug can indeed protect the fetus and the newborn from paraphysiological and toxicological alterations. A broad clinical experience shows that NAC is safe in pregnancy and can be administered, either orally or intravenously, according to the standard protocols in case of acetaminophen overdose during pregnancy (29
In conclusion, administration of NAC and presumably of other antioxidant drugs or foods during pregnancy defends the newborn both from oxidatively generated nucleotide alterations (4
) and, as shown here, from susceptibility to noxious exposures occurring soon after birth, including inhibition of smoke-induced lung cancer. Maternal diet and supplements should be taken into account as confounding factors in epidemiological studies evaluating the effects of involuntary smoking in children. The results of the present study have obvious implications in preventive medicine and may be the premise for practical applications in maternal child health care and cancer prevention.