Maternal use of nitrosatable drugs during pregnancy and adult male reproductive health: A population-based cohort study.

BACKGROUND: Prenatal exposures to xenobiotics during the masculinization programming window are suggested to impact male fecundity later in life. Frequently used nitrosatable drugs, such as penicillins and beta2-agonists, contain amines or amides that may form teratogenic compounds in reaction with nitrite. OBJECTIVES: We explored whether maternal nitrosatable drug use during gestation was associated with biomarkers of male fecundity in adulthood; moreover, the potential modifiable effect of nitrate and vitamin intake was investigated. METHOD: We performed a cohort study in the Fetal Programming of Semen Quality cohort that includes semen characteristics, reproductive hormone concentrations, and measures of testis size on 1058 young adult sons in the Danish National Birth Cohort. Information on maternal use of nitrosatable drugs was obtained from questionnaires and interviews around gestational weeks 11 and 16. A multivariable negative binomial regression model was used to obtain relative differences in biomarkers of male fecundity for those whose mothers used nitrosatable drugs compared to those without such maternal use. In sub-analyses, the exposure was categorized according to nitrosatable drug type: secondary amine, tertiary amine, or amide. We investigated dose dependency by examining the number of weeks with intake and explored potential effect modification by low versus high maternal nitrate and vitamin intake from diet and nitrate concentration in drinking water. We added selection weights and imputed values of missing covariates to limit the risk of selection bias. RESULTS: In total, 19.6% of the study population were born of mothers with an intake of nitrosatable drugs at least once during early pregnancy. Relative differences in biomarkers related to male fecundity between exposed and unexposed participants were negligible. Imputation of missing covariates did not fundamentally alter the results. Furthermore, no sensitive subpopulations were detected. CONCLUSIONS: The results suggest that maternal use of nitrosatable drugs does not have a harmful influence on the male fecundity of the offspring.

High Exposure to Perfluoroalkyl Substances and Antibody Responses to SARS-CoV-2 mRNA Vaccine-an Observational Study in Adults from Ronneby, Sweden.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely used, environmentally ubiquitous, and stable chemicals that have been associated with lower vaccine-induced antibody responses in children; however, data on adults are limited. The drinking water from one of the two waterworks in Ronneby, Sweden, was heavily contaminated for decades with PFAS from firefighting foams, primarily perfluorohexane sulfonic acid and perfluorooctanesulfonic acid (PFOS). Vaccination against SARS-CoV-2 offered a unique opportunity to investigate antibody responses to primary vaccination in adults who had been exposed to PFAS. OBJECTIVES: Our objective was to evaluate associations between PFAS, across a wide range of exposure levels, and antibody responses in adults 5 wk and 6 months after a two-dose vaccination regime against SARS-CoV-2. METHODS: Adults age 20-60 y from Ronneby (n=309, median PFOS serum level 47 ng/mL, fifth to 95th percentile 4-213 ng/mL) and a group with background exposure (n=47, median PFOS serum level 4 ng/mL) received two doses of the Spikevax (Moderna) mRNA vaccine. The levels of seven PFAS were measured in serum before vaccination. Serum immunoglobulin G antibodies against the SARS-CoV-2 spike antigen (S-Abs) were measured before vaccination and at 5 wk (n=350) and 6 months (n=329) after the second vaccine dose. Linear regression analyses were fitted against current, historical, and prenatal exposure to PFAS, adjusting for sex, age, and smoking, excluding individuals with previous SARS-CoV-2-infection. RESULTS: PFAS exposure, regardless of how it was estimated, was not negatively associated with antibody levels 5 wk [current PFOS: -0.5% S-Abs/PFOS interquartile range (IQR); 95% confidence interval (CI): -8, 7] or 6 months (current PFOS: 3% S-Abs/PFOS IQR; 95% CI: -6, 12) after COVID-19 vaccination. DISCUSSION: Following a strict study protocol, rigorous study design, and few dropouts, we found no indication that PFAS exposure negatively affected antibody responses to COVID-19 mRNA vaccination for up to 6 months after vaccination. https://doi.org/10.1289/EHP11847.

Impact of a manager-oriented intervention on occupational exposures and well-being among pregnant hospital and day-care employees: A cluster randomised trial.

BACKGROUND: Pregnancy can make it difficult to cope with demands at work and may affect women's well-being. We investigated if a manager-targeted educational intervention reduced demanding occupational exposures and improved the psychosocial work environment and well-being among pregnant employees. METHODS: Data came from a cluster randomised trial in Danish hospitals and day-care institutions. Work units were assigned randomly and were non-blinded to the intervention, where managers were either invited to participate in a three-hour seminar addressing job adjustment in pregnancy or assigned to a control group undertaking their usual practice. Self-reported outcomes by pregnant employees at the work units were the proportion of pregnant employees with demanding occupational exposures, good psychosocial work environment and good well-being. Mixed logistic regression was applied in the population of responders and in intention-to-treat analyses using multiple imputations. RESULTS: We included 915 pregnant employees: 451 in the intervention group and 464 in the control group. Of 216 invited managers, 103 (48%) participated in the seminar. A total of 339 (37%) pregnant employees answered the questionnaire. The proportion of pregnant employees who had demanding occupational exposures, good psychosocial work environment and good well-being in the intervention versus the control group were 36% versus 39% (odds ratio (OR)=0.90, 95% confidence interval (CI) 0.57-1.44), 56% versus 59% (OR=1.01, 95% CI 0.60-1.71) and 77% versus 73% (OR=1.13, 95% CI 0.68-1.87), respectively. CONCLUSIONS: This manager-targeted educational intervention did not reduce demanding occupational exposures and did not improve the psychosocial work environment or the well-being among pregnant employees in hospital and day-care settings. Comprehensive and participatory interventions may be considered in future studies.

Male childlessness as independent predictor of risk of cardiovascular and all-cause mortality: A population-based cohort study with more than 30 years follow-up.

In a recent population-based study, an elevated risk of the Metabolic syndrome (MetS) and type 2 diabetes was found in childless men compared to those who have fathered one or more children. Therefore, by using a larger cohort of more than 22 000 men from the Malmo Preventive Project (MPP) we aimed to expand our observations in order to evaluate the metabolic profile of childless men and to evaluate if childlessness is an additional and independent predictor of major adverse cardiovascular events (MACE), mortality and incident diabetes when accounting for well-known biochemical, anthropometric, socio-economic and lifestyle related known risk factors. Logistic regression was used to assess risk of MACE, diabetes and MetS at baseline. Multivariate Cox regression was used to evaluate the risks of MACE and mortality following the men from baseline screening until first episode of MACE, death from other causes, emigration, or end of follow-up (31st December 2016) adjusting for age, family history, marital status, smoking, alcohol consumption, educational status, body mass index, prevalent diabetes, high blood lipids, increased fasting glucose and hypertension. Childless men presented with a worse metabolic profile than fathers at the baseline examination, with elevated risk of high triglycerides, odds ratio (OR) 1.24 (95%CI: 1.10-1.42), high fasting glucose OR 1.23 (95%CI: 1.05-1.43) and high blood pressure, OR 1.28 (95%CI: 1.14-1.45), respectively. In the fully adjusted prospective analysis, childless men presented with elevated risk of cardiovascular mortality, HR: 1.33 (95% CI: 1.18-1.49) and all-cause mortality, HR 1.23 (95%CI: 1.14-1.33), respectively. In conclusion, these results add to previous studies showing associations between male reproductive health, morbidity and mortality. Male childlessness, independently of well-known socio-economic, behavioral and metabolic risk factors, predicts risk of cardiovascular disease and mortality. Consequently, this group of men should be considered as target population for preventive measures.

Fetal exposure to paternal smoking and semen quality in the adult son.

BACKGROUND: The negative impact of maternal smoking during pregnancy on offspring semen quality is well established. Less is known about the impact of paternal smoking. METHODS: We estimated differences in semen parameters and testicle size according to paternal smoking in 772 adult sons of women enrolled in the Danish National Birth Cohort when pregnant. Parents' smoking was reported around gestational week 16, and analyses were adjusted for parents' ages at conception, maternal pre-pregnancy body mass index, maternal alcohol and caffeine intake, family occupational status, ejaculatory abstinence time, clinic of semen analysis, and season. RESULTS: Sons of smoking fathers and non-smoking mothers had a 10% (95% confidence interval: -24%, 7%) lower semen concentration and 11% (95% confidence interval: -27%, 8%) lower sperm count than sons of non-smoking parents. Having two smoking parents was associated with 19% reduction in sperm count (95% confidence interval: -37%, 3%). Paternal smoking was not associated with volume, motility, or morphology. Adjusting for maternal smoking, paternal smoking was associated with a 26% increased risk of small testicular volume (95% confidence interval: 0.89, 1.78). DISCUSSION: Exclusion of sons with a history of testicular cancer, chemotherapy, orchiectomy, and with only one or no testicles may have caused us to underestimate associations if these men's reproductive health including semen quality are in fact more sensitive to paternal smoking. CONCLUSION: The study provides limited support for slightly lower sperm concentration and total sperm concentration in sons of smoking fathers, but findings are also compatible with no association.

Risk of metabolic disorders in childless men: a population-based cohort study.

OBJECTIVE: To study whether male childlessness is associated with an increased risk of metabolic disorders such as metabolic syndrome (MetS) and diabetes. DESIGN: A population-based cohort study. SETTING: Not applicable. PARTICIPANTS: 2572 men from the population-based Malmö Diet and Cancer Cardiovascular Cohort. INTERVENTIONS: None. MAIN OUTCOME MEASURES: From cross-sectional analyses, main outcome measures were ORs and 95% CIs for MetS and diabetes among childless men. In prospective analyses, HRs and 95% CI for diabetes among childless men. RESULTS: At baseline, in men with a mean age of 57 years, the prevalence of MetS was 26% and 22% among childless men and fathers, respectively. Similarly, we observed a higher prevalence of diabetes of 11% among childless men compared with 5% among fathers. In the cross-sectional adjusted analyses, childless men had a higher risk of MetS and diabetes, with ORs of 1.22 (95% CI 0.87 to 1.72) and 2.12 (95% CI 1.34 to 3.36) compared with fathers. In the prospective analysis, during a mean follow-up of 18.3 years, we did not see any increase in diabetes risk among childless men (HR 1.02 (0.76 to 1.37)). CONCLUSION: This study provides evidence of an association between male childlessness and a higher risk of MetS and diabetes. However, as these associations were found in cross-sectional analyses, reverse causation cannot be excluded.