Interaction between cadmium and aromatic DNA adducts in hprt mutagenesis during foetal development

Abstract

The foetus is exposed to multiple xenobiotics through the mother's circulation and this is possibly involved in the development of diseases in later life. Heavy metals and lipophilic genotoxins in umbilical cord blood of newborns may have synergistic effects on mutagenesis in the hypoxanthine-phosphoribosyltransferase (HPRT) reporter gene. Concentrations of zinc (Zn), lead (Pb) and cadmium (Cd) were determined in the peripheral and cord blood of 16 non-smoking and 9 smoking healthy mothers by atomic absorption spectrometry. Lipophilic DNA adducts in lymphocytes were determined in the same subjects by 32P-postlabelling and the HPRT-variant frequency was assessed by the evaluation of 6-thioguanine resistant cells. Although the Cd/Zn ratio was 2.5-fold higher in the blood of smoking women than in non-smoking women (1.0 +/- 0.2 and 0.4 +/- 0.1, respectively, P = 0.007), this difference could not be observed in umbilical cord blood (0.3 +/- 0.1 and 0.3 +/- 0.1, respectively, P = 0.66). Similarly, mean DNA adduct levels were increased in the lymphocytes of smoking women compared with non-smoking controls (0.99 +/- 0.31 adducts/10(8) nt and 0.43 +/- 0.12, respectively, P = 0.009), but were only marginally higher in the neonates of smokers than in their non-smoking counterparts (0.57 +/- 0.29 and 0.24 +/- 0.09, respectively, P = 0.38). Since Cd is known to effectively inhibit DNA repair, we hypothesized that concomitant exposure of neonates to Cd and genotoxic compounds may result in an increased fixation of DNA damage into somatic mutations. Indeed, the number of HPRT-variants per adduct (i.e. the mutagenic efficiency of adducts) correlated positively with the Cd concentrations in cord blood (r = 0.61, P = 0.001). These data suggest a molecular link between DNA damage, inhibition of DNA repair by Cd and in vivo mutagenesis during foetal development. Thus, exposure to heavy metals may enhance the mutagenic potential of DNA-damaging compounds and results in biologically relevant genotoxic effects in neonates.

The associations between metals/metalloids concentrations in blood plasma of Hong Kong residents and their seafood diet, smoking habit, body mass index and age

“…Other studies also revealed higher Cd and Pb levels in smokers' blood (Navas-Acien et al 2004), as well as in milk and hair (Mortada et al 2004;Godschalk et al 2005). In accordance with the findings of Gundacker et al (2002), the present results also indicated that smoking had no significant influence on the blood Hg level.…”

Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother–Child Study (NewGeneris)

“…Bulky DNA adducts are a widely accepted and sensitive biomarker of the biologically effective dose of genotoxic agents in complex environmental exposures, including those in ambient air, tobacco smoke, and diet (Godschalk et al 2005; Karttunen et al 2010; Kovács et al 2011). They reflect individual exposure, absorption, and metabolic activation of heterogeneous adduct-forming compounds, in combination with the ability to repair induced DNA damage (Farmer 1994), and may be predictive of cancer risk (Veglia et al 2008).…”

“…A positive correlation between DNA adducts in blood and PAH exposure has been reported in adult populations exposed to high levels of PAHs in ambient air or food (Nielsen et al 1996; van Maanen et al 1994), which suggests that bulky DNA adducts reflect DNA damage caused by genotoxic PAHs. Bulky DNA adducts and more specific PAH-related DNA adducts have been detected in human umbilical cord white blood cells (Godschalk et al 2005; Hansen et al 1993; Pedersen et al 2009; Perera et al 1998, 2005; Topinka et al 2009), in human placenta (Everson et al 1988; Hansen et al 1993; Sram et al 2006) and in ex vivo human placental perfusions (Karttunen et al 2010), which suggests that PAHs and other environmental genotoxic agents are capable of forming DNA adducts in utero .…”

“…Intake of meat with a blackened surface (Pedersen et al 2012a), exposure to traffic-related air pollution during pregnancy (Pedersen et al 2009), and smoking during pregnancy (Godschalk et al 2005; Hansen et al 1993; Pedersen et al 2009) have been associated with higher levels of bulky DNA adducts in human cord blood. However, evidence regarding associations between bulky DNA adducts and birth outcomes is conflicting.…”

Prenatal, Early Life, and Childhood Exposure to Genotoxicants in the Living Environment

“…Cadmium, lead, and arsenic, from tobacco smoke have 10 times higher absorption than from food or water (74). In a study by Godschalk et al (75), foetal exposure to heavy metals such as cadmium correlated positively with the number of HPRT-variants per adduct in cord blood. The authors suggest that by inhibiting DNA repair, cadmium may enhance the genotoxic effect of other carcinogens.…”