Pulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation.

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.

Maternal pre-pregnancy BMI and reproductive health in adult sons: a study in the Danish National Birth Cohort.

STUDY QUESTION: Is maternal pre-pregnancy BMI associated with semen quality, testes volume, and reproductive hormone levels in sons? SUMMARY ANSWER: Maternal pre-pregnancy BMI was associated with an altered reproductive hormone profile in young adult sons, characterized by higher levels of oestradiol, LH, and free androgen index (FAI) and lower levels of sex hormone-binding globulin (SHBG) in sons born of mothers with pre-pregnancy overweight and obesity. WHAT IS KNOWN ALREADY: Evidence suggests that maternal pre-pregnancy BMI may influence reproductive health later in life. Only one pilot study has investigated the association between maternal pre-pregnancy BMI and reproductive health outcomes in sons, suggesting that a high BMI was associated with impaired reproductive function in the adult sons. STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 1058 young men from the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019, was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1058 adult sons (median age 19 years, 2 months), born 1998-2000 by mothers included in the DNBC, participated in FEPOS. At a clinical examination, they provided a semen and blood sample, measured their testes volume, and had height and weight measured. Maternal pre-pregnancy BMI was obtained by self-report in early pregnancy. Semen characteristics, testes volume, and reproductive hormone levels were analysed according to maternal pre-pregnancy BMI categories and as restricted cubic splines using negative binomial and ordinary least square regression models. Mediation analyses examined potential mediation by the sons' birthweight, pubertal timing, fat mass, and BMI. Additional analyses investigated the role of paternal BMI in the potential associations between maternal BMI and reproductive health outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We found no consistent associations between maternal pre-pregnancy BMI and semen characteristics or testes volume. Sons of mothers with higher pre-pregnancy BMI had higher oestradiol and lower SHBG levels, both in a dose-dependent manner. Sons of mothers with pre-pregnancy obesity (≥30 kg/m2) had higher LH levels and a higher FAI than sons born by mothers with normal pre-pregnancy BMI (18.5-24.9 kg/m2). The mediation analyses suggested that the effect of maternal pre-pregnancy BMI on higher levels of oestrogen, LH, and FAI was partly mediated by the sons' birthweight, in addition to adult fat mass and BMI measured at the clinical examination, whereas most of the effect on lower levels of SHBG was primarily mediated by the sons' own fat mass and BMI. Paternal BMI was not a strong confounder of the associations in this study. LIMITATIONS, REASONS FOR CAUTION: This study was based in a population-based cohort with a low prevalence of overweight and obesity in both mothers and adult sons. Some men (10%) had blood for reproductive hormone assessment drawn in the evening. While several potential confounding factors were accounted for, this study's inherent risk of residual and unmeasured confounding precludes provision of causal estimates. Therefore, caution should be given when interpreting the causal effect of maternal BMI on sons' reproductive health. WIDER IMPLICATIONS OF THE FINDINGS: Given the widespread occurrence of overweight and obesity among pregnant women, it is imperative to thoroughly examine the potential consequences for reproductive hormone levels in adult sons. The potential effects of maternal pre-pregnancy obesity on sons' reproductive hormone profile may potentially be partly avoided by the prevention of overweight and obesity in the sons. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University, Independent Research Fund Denmark (9039-00128B), and the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Paternal pre-conceptional smoking and semen quality in the adult son.

BACKGROUND: Growing evidence suggests intergenerational effects of paternal pre-conceptional smoking through the germ line, but its specific impact on offspring semen quality remains uncertain because of challenges in isolating paternal exposure from maternal passive smoking or underreporting. METHODS: We reran previous analyses estimating differences in semen parameters and testicular size according to paternal smoking in 867 young adult men, adding first-trimester maternal plasma cotinine to the original adjustment for maternal self-reported smoking. We also estimated differences in sperm DNA fragmentation. Paternal smoking was reported by the pregnant women around gestational week 16. Analyses were additionally adjusted for household occupational status, parental ages at birth, maternal pre-pregnancy body mass index and alcohol consumption, and abstinence time, and accounted for spillage, minutes from ejaculation to analysis, and son's own smoking. RESULTS: We found no association between paternal preconceptional smoking and any of the semen parameters or testicular size. Adjustment for son's own smoking did not change results. DISCUSSION: While maternal plasma cotinine offers an objective measure of tobacco exposure and allows for a more thorough adjustment of maternal smoking, the high correlation between paternal pre-conceptional smoking and maternal cotinine exposure may, have resulted in overadjustment removing some paternal effect. Inability to distinguish between paternal never smokers and former smokers, may have led to misclassification of paternal pre-conceptional smoking and underestimation of associations. CONCLUSION: We found no support for an independent association between paternal pre-conceptional smoking and semen quality in young adult sons, but studies with more detailed paternal smoking history are needed before firm conclusions can be drawn.

Maternal vitamin D levels and male reproductive health: a population-based follow-up study.

Maternal vitamin D levels during pregnancy may be important for reproductive health in male offspring by regulating cell proliferation and differentiation during development. We conducted a follow-up study of 827 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, nested in the Danish National Birth Cohort to investigate if maternal vitamin D levels were associated with measures of reproductive health in adult sons. These included semen characteristics, testes volume, and reproductive hormone levels and were analysed according to maternal vitamin D (25(OH)D3) levels during pregnancy. In addition, an instrumental variable analysis using seasonality in sun exposure as an instrument for maternal vitamin D levels was conducted. We found that sons of mothers with vitamin D levels < 25 nmol/L had 11% (95% CI - 19 to - 2) lower testes volume and a 1.4 (95% CI 1.0 to 1.9) times higher risk of having low testes volume (< 15 mL), in addition to 20% (95% CI - 40 to 9) lower total sperm count and a 1.6 (95% CI 0.9 to 2.9) times higher risk of having a low total sperm count (< 39 million) compared with sons of mothers with vitamin D levels > 75 nmol/L. Continuous models, spline plots and an instrumental variable analysis supported these findings. Low maternal vitamin D levels were associated with lower testes volume and lower total sperm count with indications of dose-dependency. Maternal vitamin D level above 75 nmol/L during pregnancy may be beneficial for testes function in adult sons.

Maternal fever during pregnancy and male offspring reproductive health: A longitudinal cohort study in young Danish males.

BACKGROUND: Maternal fever during pregnancy has been associated with an increased risk of genital malformations, but the implication for long-term reproductive health in the offspring is unknown. OBJECTIVES: To investigate associations between timing, duration, and temperature of fetal exposure to maternal fever and sons' semen quality, testicular volume, and levels of reproductive hormones in early adulthood. Further, to examine whether concurrent use of antipyretics and/or antibiotics modified the effect. MATERIALS AND METHODS: We used the Fetal Programming of Semen Quality cohort consisting of men born to women enrolled in the Danish National Birth Cohort. Self-reported information on maternal fever was collected twice during pregnancy (median 16 and 31 pregnancy weeks) and categorized as any fever during pregnancy, fever during early pregnancy (weeks 1-15), and fever exclusively during late pregnancy (weeks 16-42). Semen quality and concentrations of reproductive hormones were measured at a clinical examination at the age of 18.9 years. We used negative binomial regression to examine the associations, adjusting for maternal age at birth, maternal smoking, family occupational status, and precision variables related to semen quality and hormonal levels, for example, abstinence time. RESULTS: 986 men were included in the study, of which 23% had mothers reporting at least one episode of fever. We found no strong indications of associations between maternal fever during pregnancy and male reproductive health in young men. Concurrent use of antipyretics and antibiotics did not modify the association. DISCUSSION: Strengths include the large sample size, prospectively collected data, and the adjustment for maternal factors during pregnancy and important precision variables. A limitation is the crude self-reported information on maternal fever. CONCLUSION: We found no evidence to support that timing, duration, or temperature of maternal fever during pregnancy has a long-term impact on semen characteristics, testicular volume, or level of reproductive hormones in male offspring.

Selection bias in a male-offspring cohort investigating fecundity: is there reason for concern?

STUDY QUESTION: Is there risk of selection bias in etiological studies investigating prenatal risk factors of poor male fecundity in a cohort of young men? SUMMARY ANSWER: The risk of selection bias is considered limited despite a low participation rate. WHAT IS KNOWN ALREADY: Participation rates in studies relying on volunteers to provide a semen sample are often very low. Many risk factors for poor male fecundity are associated with participation status, and as men with low fecundity may be more inclined to participate in studies of semen quality, a risk of selection bias exists. STUDY DESIGN, SIZE, DURATION: A population-based follow-up study of 5697 young men invited to the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998-2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Young men (age range: 18 years, 9 months to 21 years, 4 months) born 1998-2000 by mothers included in the DNBC were invited to participate in FEPOS. In total, 1173 men answered a survey in FEPOS (n = 115 participated partly); of those, 1058 men participated fully by also providing a semen and a blood sample at a clinical visit. Differential selection according to parental baseline characteristics in the first trimester, the sons' own characteristics from the FEPOS survey, and urogenital malformations and diseases in reproductive organs from the Danish registers were investigated using logistic regression. The influence of inverse probability of selection weights (IPSWs) to investigate potential selection bias was examined using a predefined exposure-outcome association of maternal smoking in the first trimester (yes, no) and total sperm count analysed using adjusted negative binomial regression. A multidimensional bias analysis on the same association was performed using a variety of bias parameters to assess different scenarios of differential selection. MAIN RESULTS AND THE ROLE OF CHANCE: Participation differed according to most parental characteristics in first trimester but did not differ according to the prevalence of a urogenital malformation or disease in the reproductive organs. Associations between maternal smoking in the first trimester and male fecundity were similar when the regression models were fitted without and with IPSWs. Adjusting for other potential risk factors for poor male fecundity, maternal smoking was associated with 21% (95% CI: -32% to -9%) lower total sperm count. In the bias analysis, this estimate changed only slightly under realistic scenarios. This may be extrapolated to other exposure-outcome associations. LIMITATIONS, REASONS FOR CAUTION: We were unable to directly assess markers of male fecundity for non-participants from, for example an external source and therefore relied on potential proxies of fecundity. We did not have sufficient power to analyse associations between prenatal exposures and urogenital malformations. WIDER IMPLICATIONS OF THE FINDINGS: The results are reassuring when using this cohort to identify causes of poor male fecundity. The results may be generalized to other similar cohorts. As the young men grow older, they can be followed in the Danish registers, as an external source, to examine, whether participation is associated with the risk of having an infertility diagnosis. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis's Grant, Axel Muusfeldt's Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall's Fond, Aarhus University and Independent Research Fund Denmark (9039-00128B). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Cancer Risk following Residential Exposure to Airborne Polychlorinated Biphenyls: A Danish Register-Based Cohort Study.

BACKGROUND: Polychlorinated biphenyls (PCBs) are biopersistent chemicals classified as human carcinogens. This classification is primarily based on evidence on higher-chlorinated PCBs found in food. The carcinogenic potential of airborne lower-chlorinated PCBs remains largely unexplored. OBJECTIVES: We aimed to investigate cancer risk following residential exposure to airborne PCBs. METHODS: Cancer risk was examined in the Health Effects of PCBs in Indoor Air (HESPAIR) cohort of 38,613 residents of two partly PCB-contaminated residential areas in Greater Copenhagen, identified by nationwide registries. PCB exposure was based on relocation dates and indoor air PCB measurements in subsets of apartments. Cancer diagnoses were extracted from the Danish Cancer Registry for the follow-up period of 1970-2018. We estimated adjusted hazard ratios with time-varying cumulative exposure and a 10-y lag using Cox regression. RESULTS: Overall risk of cancer was not associated with PCByear, [hazard ratio (HR) for high-exposed vs. low-exposed =0.98; 95% confidence interval (CI): 0.88, 1.09], but residents exposed to ≥3,000 ng/m3 PCB×year had higher risk of liver cancer (HR =2.81; 95% CI: 1.28, 6.15) and meningiomas (HR =3.49; 95% CI: 1.84, 6.64), with indications of exposure-response relationships. Results were suggestive of a higher risk of pancreatic cancer (HR =1.59; 95% CI: 0.95, 2.64) at the highest aggregated PCB level. For testis cancer, a higher risk was observed among residents exposed to 300-949 ng/m3 PCB×year relative to residents exposed to <300 ng/m3 PCB×year (HR =2.97; 95% CI: 1.41, 6.28), but the risk was not higher for residents exposed to ≥950 ng/m3 PCB×year. Apart from this, the risk of specific cancers was similar across exposure groups. DISCUSSION: In this, to our knowledge, first population-based cohort study of residential exposure to airborne PCBs, we found no association between exposure to PCBs in indoor air in private homes and the risk for most of the specific cancers. Higher risk of liver cancer and meningiomas were observed. https://doi.org/10.1289/EHP10605.

Fetal exposure to maternal cigarette smoking and male reproductive function in young adulthood.

Maternal smoking during pregnancy constitutes a potential, major risk factor for adult male reproductive function. In the hitherto largest longitudinal cohort, we examined biomarkers of reproductive function according to maternal smoking during the first trimester and investigated whether associations were mitigated by smoking cessation prior to the fetal masculinization programming window. Associations between exposure to maternal smoking and semen characteristics, testicular volume and reproductive hormones were assessed among 984 young men from the Fetal Programming of Semen Quality (FEPOS) cohort. Maternal smoking was assessed through interview data and measured plasma cotinine levels during pregnancy. We applied negative binomial, logistic and linear regression models to estimate differences in outcomes according to levels of maternal smoking. Sons of light smokers (≤ 10 cigarettes/day) had a 19% (95% CI - 29%, - 6%) lower sperm concentration and a 24% (95% CI - 35%, - 11%) lower total sperm count than sons of non-smokers. These estimates were 38% (95% CI - 52%, - 22%) and 33% (95% CI - 51%, - 8%), respectively, for sons of heavy smokers (> 10 cigarettes/day). The latter group also had a 25% (95% CI 1%, 54%) higher follitropin level. Similarly, sons exposed to maternal cotinine levels of  > 10 ng/mL had lower sperm concentration and total sperm count. Smoking cessation prior to gestational week seven was not associated with a higher reproductive capacity. We observed substantial and consistent exposure-response associations, providing strong support for the hypothesis that maternal smoking impairs male reproductive function. This association persisted regardless of smoking cessation in early pregnancy.

Lead (Pb) and neurodevelopment: A review on exposure and biomarkers of effect (BDNF, HDL) and susceptibility.

Lead (Pb) is a ubiquitous environmental pollutant and a potent toxic compound. Humans are exposed to Pb through inhalation, ingestion, and skin contact via food, water, tobacco smoke, air, dust, and soil. Pb accumulates in bones, brain, liver and kidney. Fetal exposure occurs via transplacental transmission. The most critical health effects are developmental neurotoxicity in infants and cardiovascular effects and nephrotoxicity in adults. Pb exposure has been steadily decreasing over the past decades, but there are few recent exposure data from the general European population; moreover, no safe Pb limit has been set. Sensitive biomarkers of exposure, effect and susceptibility, that reliably and timely indicate Pb-associated toxicity are required to assess human exposure-health relationships in a situation of low to moderate exposure. Therefore, a systematic literature review based on PubMed entries published before July 2019 that addressed Pb exposure and biomarkers of effect and susceptibility, neurodevelopmental toxicity, epigenetic modifications, and transcriptomics was conducted. Finally included were 58 original papers on Pb exposure and 17 studies on biomarkers. The biomarkers that are linked to Pb exposure and neurodevelopment were grouped into effect biomarkers (serum brain-derived neurotrophic factor (BDNF) and serum/saliva cortisol), susceptibility markers (epigenetic markers and gene sequence variants) and other biomarkers (serum high-density lipoprotein (HDL), maternal iron (Fe) and calcium (Ca) status). Serum BDNF and plasma HDL are potential candidates to be further validated as effect markers for routine use in HBM studies of Pb, complemented by markers of Fe and Ca status to also address nutritional interactions related to neurodevelopmental disorders. For several markers, a causal relationship with Pb-induced neurodevelopmental toxicity is likely. Results on BDNF are discussed in relation to Adverse Outcome Pathway (AOP) 13 ("Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities") of the AOP-Wiki. Further studies are needed to validate sensitive, reliable, and timely effect biomarkers, especially for low to moderate Pb exposure scenarios.

Urinary Bisphenol A, F and S Levels and Semen Quality in Young Adult Danish Men.

Bisphenol A (BPA) is considered an endocrine disruptor and has been associated with deleterious effects on spermatogenesis and male fertility. Bisphenol F (BPF) and S (BPS) are structurally similar to BPA, but knowledge of their effects on male fertility remains limited. In this cross-sectional study, we investigated the associations between exposure to BPA, BPF, and BPS and semen quality in 556 men 18-20 years of age from the Fetal Programming of Semen Quality (FEPOS) cohort. A urine sample was collected from each participant for determination of BPA, BPF, and BPS concentrations while a semen sample was collected to determine ejaculate volume, sperm concentration, total sperm count, sperm motility, and sperm morphology. Associations between urinary bisphenol levels (continuous and quartile-divided) and semen characteristics were estimated using a negative binomial regression model adjusting for urine creatinine concentration, alcohol intake, smoking status, body mass index (BMI), fever, sexual abstinence time, maternal pre-pregnancy BMI, and first trimester smoking, and highest parental education during first trimester. We found no associations between urinary bisphenol of semen quality in a sample of young men from the general Danish population.

Exposure to psychosocial work strain and changes in smoking behavior during pregnancy - a longitudinal study within the Danish National Birth Cohort.

Objective Knowledge of the relationship between psychosocial strain in the work environment and smoking during pregnancy is scarce. This study aimed to examine the association between psychosocial job strain and change in smoking behavior during pregnancy. Methods The cohort included 65 645 pregnancies from the Danish National Birth Cohort (1996-2002), where pregnant women were interviewed on job factors and lifestyle during the first and third trimesters. Smoking was categorized into non-, non-daily, and daily smoking at each interview. Psychosocial job strain was categorized into four groups based on the concept of Karasek's demand-control model: low strain (reference), passive, active and high strain. Associations between psychosocial strain and change in smoking status between the first and second interviews were analyzed by multinomial logistic regression, separately for each smoking category at first interview. Results Non-smoking women exposed to high strain work were more likely to become daily smokers [adjusted odds ratio (OR adj) 1.41, (95% confidence interval (CI) 1.08-1.83)] compared to non-smoking women exposed to low strain work. Non-smoking women exposed to passive work were more likely to become both non-daily and daily smokers [OR adj1.59 (95% CI 1.21-2.08) and OR adj1.32 (95% CI 1.03-1.70), respectively]. Daily smoking women exposed to high strain work were less likely to decrease their smoking [OR adj0.57 (95% CI 0.32-0.99)] compared to daily smoking women exposed to low strain work. Conclusions Psychosocial strain influenced the women's smoking behavior during pregnancy, especially in job types with low control.

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

Parvalbumin-positive (PV+ ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV+ interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV+ interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV+ interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.

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.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

BACKGROUND: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE: The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS: A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES: The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS: The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

Risk of congenital malformations among children of construction painters in Denmark: a nationwide cohort study.

OBJECTIVES: Painters' occupational exposure is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous studies have shown increased risk of congenital malformations among children of women exposed to organic solvents and paint emissions during pregnancy. In Denmark, women comprise half of those enrolled in vocational paint training. We investigated the association between maternal and paternal occupational painting, respectively, and the risk of congenital malformations among children. METHODS: National register data were used to link childbirths, malformations, and parental occupation. The cohort included >1,300,000 children born to occupationally active women in Denmark 1980-2010. Cases were hospital-diagnosed with malformations within the first year of life. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using multiple logistic regression with adjustment for potential confounders. RESULTS: Among 3444 children of female construction painters, we found no increased risk of malformations overall (126 cases, OR 0.88, 95% CI 0.74-1.05) or in organ-specific subgroups compared to children of women in all other occupations (55 045 cases). Sensitivity analyses restricted to severe malformations, children of maternal painters with ≥2 years of pre-pregnancy exposure, and firstborn children, and analyses with maternal healthcare assistants and kitchen workers as reference supported the main results. Also, no associations were found when including diagnoses within the first 10 years of life, when stratifying by maternal age, birth year, and sex, or for paternal construction painters. CONCLUSIONS: This nationwide cohort study is reassuring with no indications of increased risk of congenital malformations among children of male or of female construction painters.

In utero exposure to nanosized carbon black (Printex90) does not induce tandem repeat mutations in female murine germ cells.

Inhalation of particles has been shown to induce mutations in the male germline in mice following both prenatal and adult exposures in several experiments. In contrast, the effects of particles on female germ cell mutagenesis are not well established. Germline mutations are induced during active cell division, which occurs during fetal development in females. We investigated the effects of prenatal exposure to carbon black nanoparticles (CB) on induction of mutations in the female mouse germline during fetal development, spanning the critical developmental stages of oogenesis. Pregnant C57BL/6J mice were exposed four times during gestation by intratracheal instillation of 67µg/animal of nanosized carbon black Printex90 or vehicle (gestation days 7, 10, 15 and 18). Female offspring were raised to maturity and mated with unexposed CBA males. Expanded simple tandem repeat (ESTR) germline mutation rates in the resulting F2 generation were determined from full pedigrees (mother, father, offspring) of F1 female mice (178 CB-exposed and 258 control F2 offspring). ESTR mutation rates in CB-exposed F2 female offspring were not statistically different from those of F2 female control offspring.

Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk.

BACKGROUND: Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. METHODS: We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. RESULTS: Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. CONCLUSIONS: Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease.

Maternal occupational exposure to asthmogens during pregnancy and risk of asthma in 7-year-old children: a cohort study.

OBJECTIVES: The objective of this study was to examine whether maternal exposure to asthmogens during pregnancy is associated with the development of asthma in 7-year-old Danish children, taking atopic status and sex into consideration. DESIGN: The study is a prospective follow-up of a birth cohort. SETTING AND PARTICIPANTS: A total of 41 724 women and their children from The Danish National Birth Cohort were categorised according to maternal occupational exposure. Exposure information was obtained by combining job title in pregnancy and 18 months after pregnancy with a commonly used asthma Job Exposure Matrix. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was parent-reported asthma among their 7-year-old children in an internet-based questionnaire. Secondary outcome was asthma among the same children with or without atopic dermatitis and among boys and girls, respectively. RESULTS: Prenatal exposure to low molecular weight (LMW) agents was borderline associated with asthma in children with OR 1.17 (0.95 to 1.44) for children with atopic dermatitis and 1.10 (0.98 to 1.22) for children without. Maternal postnatal exposure was associated with asthma (OR 1.15 (1.04 to 1.28). After mutual adjustment,postnatal exposure (OR 1.13 (0.99 to 1.29) and the combined effects of prenatal and postnatal exposure (OR 1.34 (1.19 to 1.51)) seem to increase the risk of asthma in children. No significant associations were observed for other prenatal or postnatal exposures. The gender of the child did not modify the aforementioned associations. CONCLUSIONS: Maternal occupational exposures during pregnancy do not seem to be a substantial risk factor for the development of asthma in 7-year-old children. Maternal prenatal and postnatal exposures to LMW agents may predispose the propensity of the children to develop asthma. Future studies should prioritise the characterisation of the timing of exposure in relation to the birth.

Daily sperm production: application in studies of prenatal exposure to nanoparticles in mice.

We investigated the influence of maternal airway exposure to nanoparticulate titanium dioxide (TiO2, UV-Titan) and carbon black (CB, Printex90), on male reproductive function in the two following generations. Time-mated C57BL/6J mice were exposed by inhalation to UV-Titan, or by intratracheal instillation with Printex90. Body and testicle weight, sperm content per g testicular parenchyma and daily sperm production (DSP) were assessed. The protocol for assessment of DSP was optimized for application in mice (C57BL/6J) and the influence of different parameters was studied. Maternal particulate exposure did not affect DSP statistically significantly in the F1 generation, although TiO2 tended to reduce sperm counts. Overall, time-to-first F2 litter increased with decreasing sperm production. There was no effect on sperm production in the F2 generation originating after TiO2 exposure. F2 offspring, whose fathers were prenatally exposed to Printex90, showed lowered sperm production. Furthermore, we report statistically significant differences in sperm production between mouse strains.

Occupational exposure during pregnancy and the risk of hay fever in 7-year-old children.

OBJECTIVES: The prevalence of allergic diseases including hay fever has increased in the last decades, especially in Westernised countries. The aim of this study was to analyse whether occupational exposure during pregnancy is associated with development of hay fever in 7-year-old Danish children. METHODS: A total of 42,696 women and their children from the Danish National Birth Cohort were categorised according to maternal occupational exposure. Exposure information was obtained by combining job title in pregnancy with a commonly used asthma Job Exposure Matrix. Information on hay fever in the child was obtained by an internet questionnaire at follow-up at 7 years of age. RESULTS: Adjusted logistic regression analyses showed no significant association between maternal occupational exposure during pregnancy and hay fever among the 7-year-old children. Stratifying for atopic status in the children did not change the results. The prevalence of hay fever was 10.0% in the atopic children compared with 3.6% in the non-atopic children. Maternal atopic disposition increased the risk of hay fever in the offspring, odds ratio (OR) 2.49 [95% confidence interval (CI) 2.26; 2.74]. Rural residence during pregnancy decreased the risk for hay fever [OR 0.74 (95% CI 0.59; 0.92)] as did parity, OR 0.72 (95% CI 0.66; 0.80) and 0.70 (95% CI 0.48; 1.00) for 2nd and 3rd child, respectively, compared with the firstborn child. CONCLUSION: The results suggest that occupational exposure among pregnant women in Denmark is not a risk factor for hay fever among young children.