Donatella Placidi

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 × 10−12). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 × 10−7).

GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high‐risk population

Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione S‐transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N‐acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N‐acetylation and O‐acetylation of aromatic amines. Cytochrome P450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital‐based case‐control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997–2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR‐RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11–2.56) and 1.74 (95% CI = 1.02–2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08–7.10). We observed a trend (p‐value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16–2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27–5.23). NAT2 slow acetylator was associated with marginally increased risk of bladder cancer (OR = 1.50, 95% CI = 0.99–2.27), and the OR for the joint effect with occupational exposure of aromatic amines was 3.26 (95% CI = 1.06–9.95). SULT1A1 Arg213His polymorphism showed a marginal protective effect. These findings suggest that individual susceptibility to bladder cancer may be modulated by GSTM1, GSTT1 and NAT2 polymorphisms.

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the International Consortium of Bladder Cancer

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis.

Bladder cancer, GSTs, NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case–control study

The aim of the study was to investigate NAT1, NAT2, GSTM1, GSTT1, GSTP1, SULT1A1, XRCC1, XRCC3 and XPD genetic polymorphisms, coffee consumption and risk of bladder cancer (BC) through a hospital-based case–control study. The study population included 197 incident BC cases and 211 controls. The association between genetic polymorphisms, coffee drinking and BC risk was assessed by logistic regression taking into account age, education, tobacco smoking and occupational exposures to polycyclic aromatic hydrocarbons and aromatic amines. No association was found between the genetic polymorphisms investigated and BC risk according to coffee consumption apart of a significant increased BC risk among GSTP1 105-114 Val carriers heavy coffee drinkers (>3 cups/day) (OR 3.18, 95%CI 1.06–9.55). In conclusion our findings suggest a very limited role, if any, of genetic polymorphisms investigated in modulating the BC risk in coffee drinkers.

Primary liver cancer and occupation in men: A case‐control study in a high‐incidence area in northern Italy

The objective of our study was to evaluate the association between occupation and risk of liver cancer. A hospital‐based case‐control study was carried out during 1997–1999 in the Province of Brescia, a highly industrialized area in Northern Italy with a high incidence of this neoplasm. The cases were 144 male patients with incident liver cancer (96% hepatocellular carcinoma). Controls were 283 male patients, matched to cases on age (±5 years), period and hospital of admission. Information on lifetime occupational history and alcohol consumption was obtained via interview. Specific occupational exposures to pesticides, solvents and other suspected hepatocarcinogens were evaluated. A blood sample was collected to detect hepatitis B and C infections. Odds ratios (OR) of occupational exposure and 95% confidence intervals (CI), adjusted for age, residence, education, heavy alcohol intake, hepatitis B surface antigen and hepatitis C virus antibodies positivity were computed. A statistically significant increased OR was observed for employment in repair of motor vehicles (OR 3.7; 95% CI 1.1–12.3; 9 exposed cases, 10 exposed controls). Increased ORs, although not statistically significant, were found for field‐crop farm workers, food and beverage processors, blacksmiths and machine‐tool operators, electrical fitters, clerical workers, manufacture of industrial machinery and personal and household services. A slightly increased OR was noted in workers exposed to toluene and xylene (OR 1.4; 95% CI 0.7–3.0, 23 cases, 36 controls); the OR was 2.8 (95% CI 1.0–7.6, 11 cases, 12 controls) for 20 or more years of exposure and 2.0 (95% CI 0.9–4.1, 21 cases, 28 controls) for 30 or more years of time since first exposure. The increase in OR seemed to be independent from that of alcohol or viral infections. Our study showed that the role of occupational exposures in liver carcinogenesis is limited. However, prolonged exposure to organic solvents such as toluene and xylene may represent a risk factor for liver cancer.

Mechanism of neurobehavioral alteration

Behavioral toxicology is an emerging field which is becoming increasingly important in risk assessment of exposure to neurotoxic substances, due to the high sensitivity of behavior towards neurotoxic action and the integration in behavioral functions of several underlying processes and neurofunctions, such as motor, sensory, attention, motivational. Whenever it is difficult to isolate the relative contribution of sensory, motor, arousal, or cognitive factors that contribute to an observed behavioral change, possible mechanism of behavioral alteration may rely on the involvement of neurotransmitters, such as the dopaminergic system and catecholamines metabolism. Examples are given of different behavioral types of changes induced in humans by organic solvents (styrene), metals (manganese) and anaesthetic gases, based on a possible common underlying mechanism of toxicity.

Hidden effectiveness? Results of hand-searching Italian language journals for occupational health interventions.

Objective To compare the yield of hand-searching with optimised electronic search strategies in retrieving occupational health (OH) intervention studies published in a language other than English. Methods The authors systematically hand-searched and screened reports of OH intervention studies published in Italian in peer-reviewed scientific journals between 1990 and 2008. The authors evaluated how many of them met the Cochrane Occupational Safety and Health Review Groups (OSHRG) definition of being an OH intervention study and how many potentially relevant studies retrieved by hand-searching would not be found by PubMed alone using the OSHRGs most specific and most sensitive search strings. Results Hand-searching retrieved 25 articles (reporting 27 studies), including nine not indexed in MEDLINE. Most studies (81%, 22/27) had a before–after design and only one was a randomised trial. The OSHRGs most sensitive search string retrieved all 16 articles published in the Italian language journals that were indexed in MEDLINE, while the most specific search strategy retrieved nine articles (56%, 9/16). The most specific search string showed a lower ‘number needed to read’ value than the most sensitive one (60 vs 132). Conclusions These findings suggest that a sensitive electronic search strategy may be able to find most of the OH interventions published in languages other than English that are indexed in MEDLINE. Hand-searching of important national journals not indexed in MEDLINE should be considered when conducting particularly in-depth research.

Manganese and Developmental Neurotoxicity

Manganese (Mn) is an essential metal that plays a fundamental role for brain development and functioning. Environmental exposure to Mn may lead to accumulation in the basal ganglia and development of Parkinson-like disorders. The most recent research is focusing on early-life overexposure to Mn and the potential vulnerability of younger individuals to Mn toxicity also in regard to cognitive and executive functions through the involvement of the frontal cortex.Neurodevelopmental disturbances are increasing in the society, and understanding the potential role of environmental determinants is a key for prevention. Therefore, assessing the environmental sources of Mn exposure and the mechanisms of developmental neurotoxicity and defining appropriate biomarkers of exposure and early functional alterations represent key issues to improve and address preventive strategies. These themes will be reviewed in this chapter.

Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents

Introduction: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school‐age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. Methods: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right‐handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11–14 years old. We examined the relationships of tooth Mn (ln‐transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. Results: We found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn × sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye‐hand coordination in boys compared to girls in sex‐stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right‐hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). Conclusions: This study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex‐specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex‐specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period. HighlightsLiterature on perinatal Mn exposure and motor function in adolescents is limited.We used a novel tooth biomarker to reconstruct prenatal and childhood Mn exposure.Sex‐specific association between Mn exposure and neuromotor functions was observed.Prenatal Mn was associated with better body stability in boys but instability in girls.