Michael Gamborg

Biomarkers for exposure to ambient air pollution--comparison of carcinogen-DNA adduct levels with other exposure markers and markers for oxidative stress.

Human exposure to genotoxic compounds present in ambient air has been studied using selected biomarkers in nonsmoking Danish bus drivers and postal workers. A large interindividual variation in biomarker levels was observed. Significantly higher levels of bulky carcinogen-DNA adducts (75.42 adducts/10(8) nucleotides) and of 2-amino-apidic semialdehyde (AAS) in plasma proteins (56.7 pmol/mg protein) were observed in bus drivers working in the central part of Copenhagen, Denmark. In contrast, significantly higher levels of AAS in hemoglobin (55.8 pmol/mg protein), malondialdehyde in plasma (0. 96 nmol/ml plasma), and polycyclic aromatic hydrocarbon (PAH)-albumin adduct (3.38 fmol/ microg albumin) were observed in the suburban group. The biomarker levels in postal workers were similar to the levels in suburban bus drivers. In the combined group of bus drivers and postal workers, negative correlations were observed between bulky carcinogen-DNA adduct and PAH-albumin levels (p = 0.005), and between DNA adduct and [gamma]-glutamyl semialdehyde (GGS) in hemoglobin (p = 0.11). Highly significant correlations were found between PAH-albumin adducts and AAS in plasma (p = 0.001) and GGS in hemoglobin (p = 0.001). Significant correlations were also observed between urinary 8-oxo-7, 8-dihydro-2-deoxyguanosine and AAS in plasma (p = 0.001) and PAH-albumin adducts (p = 0.002). The influence of the glutatione S-transferase (GST) M1 deletion on the correlation between the biomarkers was studied in the combined group. A significant negative correlation was only observed between bulky carcinogen-DNA adducts and PAH-albumin adducts (p = 0.02) and between DNA adduct and urinary mutagenic activity (p = 0.02) in the GSTM1 null group, but not in the workers who were homozygotes or heterozygotes for GSTM1. Our results indicate that some of the selected biomarkers can be used to distinguish between high and low exposure to environmental genotoxins.

Childhood height and birth weight in relation to future prostate cancer risk: a cohort study based on the Copenhagen School Health Records Register

Background: Adult height has been positively associated with prostate cancer risk. However, the exposure window of importance is currently unknown and assessments of height during earlier growth periods are scarce. In addition, the association between birth weight and prostate cancer remains undetermined. We assessed these relationships in a cohort of the Copenhagen School Health Records Register (CSHRR). Methods: The CSHRR comprises 372,636 school children. For boys born between the 1930s and 1969, birth weight and annual childhood heights—measured between ages 7 and 13 years—were analyzed in relation to prostate cancer risk. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: There were 125,211 males for analysis, 2,987 of who were subsequently diagnosed with prostate cancer during 2.57 million person-years of follow-up. Height z-score was significantly associated with prostate cancer risk at all ages (HRs, 1.13 to 1.14). Height at age 13 years was more important than height change (P = 0.024) and height at age 7 years (P = 0.024), when estimates from mutually adjusted models were compared. Adjustment of birth weight did not alter the estimates. Birth weight was not associated with prostate cancer risk. Conclusions: The association between childhood height and prostate cancer risk was driven by height at age 13 years. Impact: Our findings implicate late childhood, adolescence, and adulthood growth periods as containing the exposure window(s) of interest that underlies the association between height and prostate cancer. The causal factor may not be singular given the complexity of both human growth and carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(12); 2232–40. ©2013 AACR.

Childhood body mass index in relation to future risk of oesophageal adenocarcinoma.

Background:Middle-aged obese adults are at substantially elevated risk of oesophageal adenocarcinoma. It is unclear whether this risk originates earlier in life.Methods:We assessed associations between childhood body mass index (BMI) and height—measured annually between ages 7 and 13—with adult oesophageal adenocarcinoma in a cohort from the Copenhagen School Health Records Register. Analyses included 255u2009053 children born during 1930–1971. Danish Cancer Registry linkage provided outcomes. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression.Results:During 5.4 million person-years of follow-up, 254 (216 males) incident oesophageal adenocarcinomas occurred. At each examined age, cancer risk increased linearly per unit BMI z-score, although associations were only statistically significant for ages 9–13. The HR for the age of 13 years was 1.31 (95% CI: 1.13, 1.51) per unit BMI z-score. Associations were similar in men and women and across birth cohorts. Childhood height was not related to cancer risk in men but was in women, although these analyses included just 38 female cases. HRs per unit height z-score at the age of 13 years were 1.04 (0.90, 1.19) in males and 1.77 (1.27, 2.47) in females, with similar results observed at the other examined ages.Conclusion:Individuals with higher childhood BMI were at elevated risk of oesophageal adenocarcinoma, even though these cancers occurred many decades later in life. Although the mechanisms require further investigation, our findings provide additional evidence for the long-term health risks of childhood obesity.

Assortative marriages by body mass index have increased simultaneously with the obesity epidemic

Background: The genetic predisposition to obesity may have contributed to the obesity epidemic through assortative mating. We investigated whether spouses were positively assorted by body mass index (BMI; = kg/m2) in late childhood, and whether changes in assorted marriage by upper BMI-percentiles occurred during the obesity epidemic. Methods: In the Copenhagen School Health Records Register (CSHRR) boys and girls with measures of BMI at age 13 years later became 37,792 spousal-pairs who married between 1945 and 2010. Trends in the spousal BMI correlations using sex-, age-, and birth cohort-specific BMI z-scores across time were investigated. Odds ratios (ORs) of marriage among spouses both with BMI z-scores >90th or >95th percentile compared with marriage among spouses ≤90th percentile were analyzed for marriages entered during the years prior to (1945–1970), and during the obesity epidemic (1971–2010). Findings: Spousal BMI correlations were around 0.05 and stayed similar across time. ORs of marriage among spouses with BMIs >90th percentile at age 13 were 1.21, 1.05–1.39, in 1945–1970, and increased to 1.63, 1.40–1.91, in 1971–2010 (p = 0.006). ORs of marriage among spouses both >95th BMI percentile were higher and increased more; from 1.39, 1.10–1.81, to 2.39, 1.85–3.09 (p = 0.004). Interpretation: Spousal correlations by pre-marital BMIs were small and stable during the past 65 years. Yet, there were assorted marriages between spouses with high BMI at age 13 years and the tendency increased alongside with the obesity epidemic which may increase the offsprings predisposition to obesity.

Time course and determinants of leptin decline during weight loss in obese boys and girls

OBJECTIVEnTo investigate whether changes in leptin concentrations during weight loss can be explained by gender, puberty, baseline adiposity and changes in adiposity, body composition, rate of weight loss, physical activity and insulin concentrations.nnnDESIGNnA longitudinal study with 9 repeated measures during a 12-week weight loss programme.nnnSUBJECTSnFifty-three boys and 62 girls (7.9-15.2 years) with body mass index (BMI) standard deviation scores (SDS) of median 2.78 and 2.70, respectively.nnnMEASUREMENTSnHeight, weight, fat mass percentage assessed by bioimpedance, Tanner stages, testicular size, physical activity scores, blood leptin (ng/ml) and insulin concentrations (pmol/l) were measured at baseline, and except for Tanner stage and testicular size, repeated regularly during the programme.nnnRESULTSnThe weight loss was accompanied by a steep decline in leptin concentrations during the first 10-11 days, followed by a less steep decline until day 82. Leptin declined to 39% in boys and 51% in girls of the level that was expected given the relationship at baseline between leptin and BMI SDS, and the BMI SDS changes during weight loss. The biphasic leptin decline was independent of gender, puberty, baseline adiposity or concomitant changes in BMI SDS, fat mass percentage, rate of weight loss, physical activity scores or insulin concentrations.nnnCONCLUSIONnThe biphasic leptin decline, which exceeded the level expected, was independent of puberty, baseline adiposity and changes in adiposity, body composition, rate of weight loss, physical activity scores and insulin concentrations. The dissociation of the leptin-weight relationship during weight loss may contribute to the general leptin variability in obese subjects.

Childhood body mass index and the risk of prostate cancer in adult men

Background:Prostate cancer aetiology is poorly understood. It may have origins early in life; previously we found a positive association with childhood height. The effects of early life body mass index (BMI; kgu2009m−2) on prostate cancer remain equivocal. We investigated if childhood BMI, independently and adjusted for height, is positively associated with adult prostate cancer.Methods:Subjects were a cohort of 125u2009208 boys formed from the Copenhagen School Health Records Register, born 1930–1969 with height and weight measurements at 7–13 years. Cases were identified through linkage to the Danish Cancer Registry. Cox proportional hazards regressions were performed.Results:Overall, 3355 men were diagnosed with prostate cancer. Body mass index during childhood was positively associated with adult prostate cancer. The hazard ratio of prostate cancer was 1.06 (95% confidence interval (CI): 1.01–1.10) per BMI z-score at age 7, and 1.05 (95% CI: 1.01–1.10) per BMI z-score at age 13. Estimates were similar and significant at all other ages. However, adjustment for childhood height attenuated the associations at all but the youngest ages as most estimates became nonsignificant.Conclusions:These results suggest that at most childhood ages, BMI does not confer an additional risk for prostate cancer beyond that of height.

Childhood height increases the risk of prostate cancer mortality

BACKGROUNDnAdult body size is positively associated with aggressive and fatal prostate cancers. It is unknown whether these associations originate in early life. Therefore, we investigated if childhood height, body mass index (BMI; kg/m(2)) and growth are associated with prostate cancer-specific mortality and survival.nnnMETHODSnSubjects were 125,208 men from the Copenhagen School Health Records Register, born 1930-1969 with height and weight measurements at ages 7-13years. Linkage to the Danish Cancer Registry and the Register of Causes of Death enabled identification of incident and fatal prostate cancers. Cox proportional hazards regressions were performed.nnnRESULTSn630 men had prostate cancer recorded as the underlying cause of death. Childhood height at age 13years was positively associated with prostate cancer-specific mortality (hazard ratio [HR]per z-score=1.2, 95% confidence interval [CI]: 1.1-1.3). Associations were significant at all other childhood ages. Growth analyses showed that height at age 13years had a stronger association with prostate cancer-specific mortality than height at age 7, suggesting the association at age 7 is largely mediated through later childhood height. The tallest boys at age 13years had a significantly worse survival, but only when restricted to a diagnosis at <60years of age (HRz-score of 1=1.7, 95% CI: 1.3-2.4). These associations were significant at all other childhood ages. Childhood BMI was not associated with prostate cancer mortality or survival.nnnCONCLUSIONnChildhood height was positively associated with the hard end-point of prostate cancer-specific mortality, which strengthens prior epidemiologic observations of a positive association with prostate cancer incidence.