Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring: A prospective nested case-control study.

Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.

Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study.

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy.

Breast cancer rate after oophorectomy: A Prospective Danish Cohort Study.

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of our study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24 409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, emigration or end of follow-up at 31 December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502 463 person-years of follow-up, 1975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with a reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (95% confidence interval): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift work.

Long-term air pollution and road traffic noise exposure and COPD: the Danish Nurse Cohort.

BACKGROUND: While air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence. METHODS: We defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence. RESULTS: 977 nurses developed COPD during a mean of 18.6 years' follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01-1.41) per 6.26 µg·m-3 for PM2.5, 1.13 (1.05-1.20) per 8.19 µg·m-3 for NO2 and 1.15 (1.06-1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise. CONCLUSION: Long-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

Long-term exposure to road traffic noise and stroke incidence: a Danish Nurse Cohort study.

BACKGROUND: Road traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution. METHODS: Twenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (Lden [dB]) and air pollutants (particulate matter with diameter < 2.5 µm and < 10 µm [PM2.5 and PM10], nitrogen dioxide [NO2], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of Lden preceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government's maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential Lden thresholds. RESULTS: Of 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of Lden and overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98-1.14) per 10 dB, which attenuated to 1.01 (0.93-1.09) and 1.00 (0.91-1.09) in models further adjusted for PM2.5 or NO2, respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between Lden and stroke. CONCLUSIONS: Long-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

Weight affects survival of primary total knee arthroplasty: study based on the Danish Knee Arthroplasty Register with 67,810 patients and a median follow-up time of 5 years.

Background and purpose - Obesity is a rising issue worldwide and growing evidence supports poor outcome amongst obese patients following total knee arthroplasty (TKA). Using nationwide registries we investigated the association between bodyweight and risk of revision of primary TKA. Patients and methods - All primary TKA performed during 1997-2015, weight at time of primary TKA and subsequent TKA revisions were identified in the Danish Knee Arthroplasty Register (DKR). Data on comorbidities and a priori selected confounding variables were collected from nationwide registries. The association between weight and 1st time TKA revision was calculated as both crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) using Cox regression. Results - Of 67,810 identified primary TKAs, 4.8% were revised within a median follow-up time of 5.4 years. No association between weight and risk of any revision in patients aged 18-54 and 55-70 years was found. Increased risk of any revision was seen in patients >70 years, 80-89 kg (aHR =1.5, CI 1.2-1.8), 90-99 kg (aHR =1.7, CI 1.3-2.1) and patients >99 kg (aHR =1.6, CI 1.3-2.1), as well as those weighing 45-60 kg (aHR =1.4, CI 1.1-1.9) compared with same aged patients weighing 70-79 kg. Interpretation - We found a complex association between weight and knee arthroplasty survival. There was an increased risk of any revision in patients older than 70 years of age weighing <60 kg and >80 kg. Patients aged 18-55 years weighing 60-69 kg had a lower risk of revision compared with all other weight groups, whereas weight was not found to affect risk of any revision in patients aged 55-70 years.

Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women.

Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29-0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer.

Is male gynaecomastia associated with an increased risk of death? A nationwide register-based cohort study.

OBJECTIVE: Recent evidence supports that gynaecomastia may predict long-term morbidity, but evidence on the association with death and causes of death in males with gynaecomastia is lacking. The objective of this work is to estimate the risk of death in men diagnosed with gynaecomastia and evaluate whether this was conditional on underlying aetiologies of gynaecomastia. DESIGN: A nationwide register-based cohort study. SETTING: Nationwide Danish national health registries. PARTICIPANTS: Males were diagnosed with incident gynaecomastia (n=23 429) from 1 January 1995 to 30 June 2021, and each was age and calendar matched to five randomly population-based males without gynaecomastia (n=117 145). INTERVENTIONS: Not applicable. PRIMARY AND SECONDARY OUTCOMES: Gynaecomastia was distinguished between males without (idiopathic) and males with a known pre-existing risk factor. Cox regression models and Kaplan-Meier analyses estimated associations between gynaecomastia and death (all cause/cause specific). RESULTS: We identified a total of 16 253 males with idiopathic gynaecomastia and 7176 with gynaecomastia and a known pre-existing risk factor. Of these, 1093 (6.7%) and 1501 (20.9%) died during follow-up, respectively. We detected a 37% increased risk of all-cause death in males with gynaecomastia in the entire cohort (HR 1.37; 95% CI 1.31 to 1.43). Death risk was highest in males diagnosed with gynaecomastia and a known pre-existing risk factor (HR 1.75; 95% CI 1.64 to 1.86) compared with males with idiopathic gynaecomastia (HR 1.05; 95% CI 0.98 to 1.13). Specific causes of increased death were malignant neoplasms and circulatory, pulmonary and gastrointestinal diseases. Of the latter, an over fivefold risk of death from liver disease was detected (HR 5.05; 95% CI 3.97 to 6.42). CONCLUSIONS: Males diagnosed with gynaecomastia are at higher risk of death, observed mainly in males with a known pre-existing risk factor of gynaecomastia. These findings will hopefully stimulate more awareness among healthcare providers to potentially apply interventions that aid in alleviating underlying risk factors in males with this condition.

Increased Morbidity in Males Diagnosed With Gynecomastia: A Nationwide Register-based Cohort Study.

CONTEXT: Evidence on the long-term and general health of males with gynecomastia is lacking. OBJECTIVES: To assess health before and following a diagnosis of gynecomastia. METHODS: A register-based cohort study of 140 574 males, of which 23 429 were diagnosed with incident gynecomastia and age- and calendar-matched (1:5) to 117 145 males without gynecomastia from the background population. Males with gynecomastia were stratified into males without (idiopathic) or with a known preexisting risk factor (disease/medication). Cox and logistic regression models investigated associations of disease risk according to International Classification of Diseases 10th revision sections following and before gynecomastia diagnosis. RESULTS: A total of 16 253 (69.4%) males in the cohort were identified with idiopathic gynecomastia. These males had a statistically significant higher risk of future disease across all included disease chapters (hazard ratio [HR], 1.19-1.89), with endocrine diseases representing the greatest disease risk (HR, 1.89; 95% CI, 1.76-2.03). The highest subchapter disease risk was observed for disorders of the endocrine glands (odds ratio [OR], 7.27; 95% CI, 6.19-8.54). Similarly, the ORs of comorbidities were higher across all included disease sections (OR, 1.05-1.51), except for psychiatric disease (OR, 0.72; 95% CI, 0.68-0.78), with the highest association with musculoskeletal/connective tissue (OR, 1.51; 95% CI, 1.46-1.57) and circulatory (OR, 1.36; 95% CI, 1.29-1.43) diseases. CONCLUSIONS: The presence of idiopathic gynecomastia is an important first clinical symptom of an underlying disease and a significant predictor of future disease risk. These findings should stimulate more awareness among health care providers to increase identification of gynecomastia and its causes in males.

Maternal Exposure to Cigarette Smoke during Pregnancy and Testicular Cancer in Offspring: A Systematic Review and Meta-Analysis.

BACKGROUND: Maternal exposure to cigarette smoke in pregnancy may play a role in the development of testicular cancer in offspring. An updated and comprehensive systematic review of the available evidence is needed. OBJECTIVE: To identify and evaluate current evidence on maternal exposure to cigarette smoke during pregnancy and testicular cancer in offspring. METHODS: A systematic search of English peer-reviewed original literature in PubMed through a block search approach. Publications were considered if assessing maternal exposure to cigarette smoke and the risk of testicular cancer in offspring. RESULTS: Among the 636 identified records, 14 publications were eligible for review and 10 for meta-analysis. Quality assessment of the publications was conducted. Most included publications were case-control studies (n = 11, 79%), while the remaining were ecological studies (n = 3, 21%). Completeness of reporting was high, but more than half were considered subject to potential bias. The trend synthesis showed that half (n = 7) of the included publications demonstrated a higher risk of testicular cancer in the sons of mothers exposed to cigarette smoke during pregnancy. The meta-analysis generated an overall summary risk estimate of 1.00 (95% CI: 0.88; 1.15) (n = 10 publications), with a lower risk for seminoma (0.79, 95% CI: 0.59; 1.04) and nonseminoma (0.96, 95% CI: 0.74; 1.26) (n = 4 publications). CONCLUSIONS: This systematic review did not provide evidence of an association between maternal exposure to cigarette smoke and risk of testicular cancer in offspring. An overall positive trend was suggested, but it had low statistical precision. The methodological limitations across publications encourage further research based on valid exposure data.

Prenatal paraben exposures and birth size: Sex-specific associations in a healthy population - A study from the Odense Child Cohort.

OBJECTIVES: To investigate the sex-specific associations between maternal paraben concentrations in second trimester urine and birth size of the offspring. METHODS: A prospective cohort study of 529 mother-child pairs within the Odense Child Cohort. Pregnant women were recruited to the cohort from 2010 to 2012 and provided fasting spot urine samples in second trimester (median 28.7 weeks). Concentrations of methylparaben (MeP), ethylparaben (EtP), iso-propylparaben (i-PrP), n-propylparaben (n-PrP), n-butylparaben (n-BuP) and benzylparaben (BzP) were analyzed by isotope diluted liquid-chromatography tandem-mass-spectrometry and osmolality adjusted. Exposures were categorized into tertiles or above/below level of detection. Data on maternal and birth characteristics were extracted from hospital records. Sex-stratified multiple linear regression analyses were performed according to relevant birth outcomes (length, weight, head/abdominal circumference) adjusting for a priori defined confounders. RESULTS: Higher paraben levels were detected in pregnant women who were older, more obese, who smoked and were primigravidae. Generally, higher maternal paraben exposure was consistently associated with lower birth size in female but not in male offspring, but with few substantial or statistically significant. Higher maternal exposure to n-BuP during pregnancy was associated with a statistically significant lower birth size in female offspring only [birth weight: -137 g (95 % CI -256; -19), head circumference: -0.48 cm (95 % CI -0.90; -0.05), abdominal circumference: -0.65 cm (95 % CI -1.21; -0.08)]. No differences in birth size were observed for other parabens. CONCLUSION: Higher maternal exposure to n-butylparaben was associated with lower birth size in female but not male offspring.

Self-Reported Asthma Is Associated with Reduced Sperm Count-A Cross-Sectional Study of More than 6000 Young Men from the General Population.

Asthma is driven by an inflammatory response that may impact testicular function. In this cross-sectional study, we investigated the association between self-reported asthma and testicular function (semen parameters, reproductive hormone levels), and determined whether potential further inflammation due to self-reported allergy modified this association. A total of 6177 men from the general population completed a questionnaire including information on doctor-diagnosed asthma or allergy, had a physical examination, delivered a semen sample, and had a blood sample drawn. Multiple linear regression analyses were performed. A total of 656 (10.6%) men reported having ever been diagnosed with asthma. Generally, self-reported asthma was consistently associated with a poorer testicular function; however, few estimates were statistically significant. Specifically, self-reported asthma was associated with statistically significant lower total sperm count [median: 133 vs. 145 million; adjusted ß (95% CI): -0.18 (-0.33 to -0.04) million on cubic-root-transformed scale] and borderline statistically significant lower sperm concentration compared with no self-reported asthma. The association between asthma and total sperm count was of similar magnitude among men with and without allergy. In conclusion, men with self-reported asthma had poorer testicular function than men without asthma. However, the cross-sectional design of the study limits ascertainment of causality.

Depression in Mid- and Later-Life and Risk of Dementia in Women: A Prospective Study within the Danish Nurses Cohort.

BACKGROUND: Depression and dementia confer substantial global health burdens, particularly in women. Understanding the association between depression and dementia may inform new targets for prevention and/or early intervention. OBJECTIVE: To investigate the association between depression in mid- and later-life and dementia (all-cause, Alzheimer's disease (AD) or vascular dementia (VaD)) in women. METHODS: A prospective study design. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration, or end of follow-up, whichever came first. Cox regression models with age as the underlying timeline were used to estimate the associations between time-varying depression and incident dementia. RESULTS: The study included 25,651 female Danish nurses (≥45 years) participating in the Danish Nurse Cohort. During an average of 23 years of follow-up, 1,232 (4.8%) nurses developed dementia and 8,086 (31.5%) were identified with at least two episodes of treated depression. In adjusted analyses, nurses with depression were at a statistically significant 5.23-fold higher risk of all-cause dementia (aHR 5.23:95% CI, 4.64-5.91) compared to those with no history of depression. The differential effects of depression were greater for VaD (aHR 7.96:95% CI, 5.26-12.0) than AD (aHR 4.64:95% CI, 3.97-5.42). Later life depression (>60 years) (aHR 5.85:95% CI, 5.17-6.64) and recurrent depression (aHR 3.51:95% CI, 2.67-4.61) elevated dementia risk. Severe depression tripled the risk of all cause dementia (aHR 3.14:95% CI, 2.62-3.76). CONCLUSION: Both later life and severe depression substantially increase dementia risk in women, particularly VaD.

Risk of Fracture After Bilateral Oophorectomy.

Fragility fractures, resulting from low-energy trauma, occur in approximately 1 in 10 Danish women aged 50 years or older. Bilateral oophorectomy (surgical removal of both ovaries) may increase the risk of fragility fractures due to loss of ovarian sex steroids, particularly estrogen. We investigated the association between bilateral oophorectomy and risk of fragility fracture and whether this was conditional on age at time of bilateral oophorectomy, hormone therapy (HT) use, hysterectomy, physical activity level, body mass index (BMI), or smoking. We performed a cohort study of 25,853 female nurses (≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from age 50 years or entry into the cohort, whichever came last, until date of first fragility fracture, death, emigration, or end of follow-up on December 31, 2018, whichever came first. Cox regression models with age as the underlying time scale were used to estimate the association between time-varying bilateral oophorectomy (all ages, <51/≥51 years) and incident fragility fracture (any and site-specific [forearm, hip, spine, and other]). Exposure and outcome were ascertained from nationwide patient registries. During 491,626 person-years of follow-up, 6600 nurses (25.5%) with incident fragility fractures were identified, and 1938 (7.5%) nurses had a bilateral oophorectomy. The frequency of fragility fractures was 24.1% in nurses who were <51 years at time of bilateral oophorectomy and 18.1% in nurses who were ≥51 years. No statistically significant associations were observed between bilateral oophorectomy at any age and fragility fractures at any site. Neither HT use, hysterectomy, physical activity level, BMI, nor smoking altered the results. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Evaporation of serum after long-term biobank storage: A chemical analysis of maternal serum from a large Danish pregnancy screening registry.

BACKGROUND: Relying on freezer stored biospecimens is preferred in epidemiolocal studies exploring environmental pregnancy exposures and later offspring health. Storage duration may increase the pre-analytical variability, potentially adding measurement uncertainty. We investigated evaporation of maternal serum after long-term biobank storage using ions (sodium, Na+; chloride, Cl-) recognized for stability and relatively narrow normal biological reference ranges in human serum. METHODS: A chemical analysis study of 275 biobanked second trimester maternal serum from a large Danish pregnancy screening registry. Serum samples were collected between 1985-1995 and stored at -20°C. Ion concentrations were quantified with indirect potentiometry using a Roche Cobas 6000 analyzer and compared according to storage time and normal biological ranges in second trimester. Ion concentrations were also compared with normal biological variation assessed by baseline Na+ and Cl- serum concentrations from a separate cohort of 24,199 non-pregnant women measured before freezing with the same instrument. RESULTS: The overall mean ion concentrations in biobanked serum were 147.5 mmol/L for Na+ and 109.7 for Cl-. No marked linear storage effects were observed according to storage time. Ion concentrations were consistently high across sampling years, especially for specific sampling years, and a relatively large proportion were outside respective normal ranges in second trimester: 38.9% for Na+ and 43.6% for Cl-. Some variation in concentrations was also evident in baseline serum used as quality controls. CONCLUSIONS: Elevated ion concentrations suggest evaporation, but independent of storage duration in the present study (27-37 years). Any evaporation may have occurred prior to freezer storage or during the first 27 years. Other pre-analytical factors such as low serum volume have likely influenced the concentrations, particularly given the high within year variability. Overall, we consider the biobanked serum samples internally comparable to enable their use in epidemiological studies.

Residential radon and lung cancer incidence in a Danish cohort.

High-level occupational radon exposure is an established risk factor for lung cancer. We assessed the long-term association between residential radon and lung cancer risk using a prospective Danish cohort using 57,053 persons recruited during 1993-1997. We followed each cohort member for cancer occurrence until 27 June 2006, identifying 589 lung cancer cases. We traced residential addresses from 1 January 1971 until 27 June 2006 and calculated radon at each of these addresses using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for lung cancer risk associated with residential radon exposure with and without adjustment for sex, smoking variables, education, socio-economic status, occupation, body mass index, air pollution and consumption of fruit and alcohol. Potential effect modification by sex, traffic-related air pollution and environmental tobacco smoke was assessed. Median estimated radon was 35.8 Bq/m(3). The adjusted IRR for lung cancer was 1.04 (95% CI: 0.69-1.56) in association with a 100 Bq/m(3) higher radon concentration and 1.67 (95% CI: 0.69-4.04) among non-smokers. We found no evidence of effect modification. We find a positive association between radon and lung cancer risk consistent with previous studies but the role of chance cannot be excluded as these associations were not statistically significant. Our results provide valuable information at the low-level radon dose range.

Maternal Serum α-Fetoprotein Levels during Pregnancy and Testicular Cancer in Male Offspring: A Cohort Study within a Danish Pregnancy Screening Registry.

Testicular cancer is believed to originate from disruptions of normal androgen-estrogen balance in-utero. α-fetoprotein (AFP) may modify fetal response to estrogens via estrogen interaction. In a cohort study, we investigated the association between circulating maternal pregnancy AFP and testicular cancer risk in offspring. Of the 56,709 live-born males from a pregnancy screening registry in 1980-1995, our study included 50,519 singleton males with available second trimester blood samples from their mothers and complete covariate ascertainment. Testicular cancer diagnoses and covariate data were obtained from nationwide Danish health registries. Cox regression and Kaplan-Meier analyses estimated the prospective risk of testicular cancer (all, seminoma, nonseminoma) by AFP multiples of the median. During follow-up, 163 (0.3%) of the included males developed testicular cancer, of which 89 (54.6%) were nonseminomas. Maternal serum AFP levels greater than/equal to the median were associated with a relative risk of testicular cancer close to unity (RR 1.04, 95% CI 0.76; 1.41) compared to AFP below the median. Associations differed by type of testicular cancer (RRseminoma 0.81, 95% CI 0.51; 1.29, RRnonseminoma 1.31, 95% CI 0.85; 2.02). On balance, our findings do not support that serum AFP in pregnancy can be used as a predictor of testicular cancer in offspring.

Sex-specific associations between maternal exposure to parabens, phenols and phthalates during pregnancy and birth size outcomes in offspring.

Current evidence on the effects of prenatal exposure to endocrine disrupting chemicals on birth size remains largely inconclusive. We aimed to investigate sex-specific associations between maternal exposure to parabens, phenols and phthalates during pregnancy and birth weight, length and head/abdominal circumferences. We performed a prospective study of 88 pregnant women who underwent amniocentesis in the period 2012 to 2014. Maternal urine samples were collected during pregnancy in weeks 12 to 36 (median: 18 weeks). The concentrations of parabens, phenols and individual phthalate diester metabolites were analyzed by isotope-diluted liquid chromatography-tandem mass spectrometry and osmolality adjusted. Linear regression models estimated the associations between urinary levels of selected compounds (tertile(T2-T3)medium/high versus T1low exposure) and birth size, stratified by offspring sex. A total of three parabens, two phenols, four individual phthalate metabolites and four sums of diester metabolites were detectable above limits of detection in at least 60% of urine samples. Overall, we observed few statistically significant associations, but medium/high exposure to bisphenol A (BPA) in male offspring was associated with statistically significant lower birth size across most outcomes [birth weight: -428 g (95% CI -756 to -99.4); birth length: -1.76 cm (95% CI -3.28 to -0.25); abdominal circumference: -1.97 cm (95% CI -3.55 to -0.39)]. Similarly, medium/high exposure to methyl paraben (MeP) in male offspring was associated with lower birth weight (-661 g, 95% CI -1251 to -70.7) and length (-3.11 cm, 95% CI -5.76 to -0.46) compared to low exposure. None of these associations were statistically significant in female offspring. Across all compounds, individual exposures were associated with more negative estimates of birth weight for male than for female offspring. Our study indicates that prenatal exposure to BPA and MeP may negatively affect birth size outcomes, with a possible sex effect. Given the small sample size, these findings need to be replicated in future larger studies.

Presence of parabens, phenols and phthalates in paired maternal serum, urine and amniotic fluid.

OBJECTIVE: To examine whether selected endocrine disrupting chemicals were present in pregnant women and passed through the placental barrier to amniotic fluid, potentially exposing the developing fetus. METHODS: Paired samples of maternal serum, urine and amniotic fluid were concurrently collected (<1 h) from 200 pregnant women (age >18 years) with a singleton pregnancy and undergoing amniocentesis between gestational weeks 12 - 36. The concentration of six different parabens, seven phenols, 31 metabolites from 15 phthalate diesters and the polychlorinated substance triclocarban were analyzed by isotope diluted TurboFlow-liquid chromatography-tandem mass spectrometry. RESULTS: Concentrations of all included compounds were highest in maternal urine followed by serum, and lowest in amniotic fluid. Of the six parabens measured in amniotic fluid, methylparaben (MeP) and ethylparaben (EtP) were detectable most often (87% and 33% of the samples, respectively). Of the seven phenols measured, three (2,4-dichlorphenol, 2,5-dichlorphenol, 2-propylphenol) were detectable in the range of 14-21% of the amniotic fluid samples, at low concentrations (<0.12 ng/ml). Two secondary phthalates metabolites, mono-(2-carboxymethyl-hexyl) phthalate and mono-carboxy-iso-octyl phthalate were each present in ≤15% of the amniotic fluid samples at concentrations 2-5 times lower than in maternal serum and 20-100 times lower than in maternal urine. A modest statistically significant correlation between the levels of MeP and EtP was detected in paired maternal urine-amniotic fluid samples was detected (Spearman rMeP: 0.246; rEtP: 0.364). Likewise, the concentration of mono-ethyl phthalate (MEP) in paired maternal urine and amniotic fluid samples indicated a modest statistically significant correlation (Spearman rMEP: 0.264), driven by detectable levels of MEP in only 3% of the amniotic fluid samples. CONCLUSIONS: In general, the included parabens, phenols and phthalates were effectively metabolized and excreted via the urine, which was the matrix that reflected the highest detectable levels. The detectable levels of several included parabens and phthalates in human amniotic fluid calls for further investigations of the toxicokinetic and potential endocrine disrupting properties of individual and multiple endocrine disruptors in order to better assess the risk to the developing fetus.

The long-term association between bilateral oophorectomy and depression: a prospective cohort study.

OBJECTIVE: Depression is a leading cause of disability globally and affects more women than men. Ovarian sex steroids are thought to modify depression risk in women and interventions such as bilateral oophorectomy that permanently change the sex steroid milieu may increase the risk of depression. This study aimed to investigate the associations between unilateral and bilateral oophorectomy and depression over a 25-year period (1993-2018) and whether this varied by age at oophorectomy or use of menopausal hormone therapy. METHODS: Twenty-five thousand one hundred eighty-eight nurses aged ≥45 years from the Danish Nurse Cohort were included. Nurses with depression prior to baseline were excluded. Poisson regression models, with log-transformed person-years as offset, were used to assess the associations between oophorectomy and incident depression. Nurses who retained their ovaries were the reference group. RESULTS: Compared with nurses with retained ovaries, bilateral oophorectomy was associated with a slightly higher rate of depression (rate ratio [RR], 1.08; 95% confidence interval [CI], 0.95-1.23), but without statistical significance. However, when stratified by age at oophorectomy, compared with nurses with retained ovaries, bilateral oophorectomy at age ≥51 years was associated with higher rates of depression (RR 1.16; 95% CI, 1.00-1.34), but not bilateral oophorectomy at age <51 years (RR 0.86; 95% CI, 0.69-1.07); P value for difference in estimates = 0.02. No association between unilateral oophorectomy and depression was observed. CONCLUSIONS: In this cohort of Danish female nurses, bilateral oophorectomy at age ≥51 years, but not at younger ages, was associated with a slightly higher rate of depression compared with those who retained their ovaries.