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 intake of paracetamol during pregnancy and biomarkers of male fecundity in young adult sons.

Paracetamol is suggested to have endocrine disrupting properties possibly affecting fetal programming of reproductive health that might lead to impaired semen quality and changes in reproductive hormones. In this longitudinal study, we included 1058 young adult men born 1998-2000 into the Danish National Birth Cohort with follow-up at 18-21 years of age. The exposure, maternal intake of paracetamol, was modelled in three ways: dichotomized, trimester-specific, and as duration of exposure categorized into: short (1-2 weeks), medium (3-9 weeks) or long duration (>9 weeks) vs. no intake. Outcomes included semen characteristics, self-measured testis volume, and reproductive hormone levels. We used negative binominal regression to estimate the percentage difference and 95% confidence interval (CI) for each outcome. In total, 547 (48%) sons were prenatally exposed to paracetamol due to maternal intake at least once. Maternal intake of paracetamol during pregnancy was not associated with any of the biomarkers in the dichotomized or trimester-specific exposure models. For duration of exposure, sons of mothers with long duration of maternal intake of paracetamol showed tendencies towards lower semen concentration (-14% [95% CI: -31%; 8%]), a higher proportion of nonprogressive and immotile spermatozoa (8% [95% CI: -4%; 21%]) and higher DNA Fragmentation Index (16% [95% CI: -1%; 36%]) compared to son of mothers with no intake. Maternal intake of paracetamol during pregnancy was not clearly associated with biomarkers of male fecundity in adult sons. However, it cannot be ruled out that long duration of maternal intake of paracetamol might be associated with impaired semen characteristics.

Birth by caesarean section and semen quality in adulthood: a Danish population-based cohort study.

BACKGROUND: The caesarean section (CS) rate has increased worldwide and there is an increasing public and scientific interest in the potential long-term health consequences for the offspring. CS is related to persistent aberrant microbiota colonization in the offspring, which may negatively interfere with sex hormone homeostasis and thus potentially affect the reproductive health. It remains unknown whether adult sons' semen quality is affected by CS. We hypothesize that CS is associated with lower semen quality. METHODS: This study was based on the Fetal Programming of Semen Quality cohort (FEPOS, enrolled from 2017 to 2019) nested within the Danish National Birth Cohort (DNBC, enrolled from 1996 to 2002). A total of 5697 adult sons of mothers from the DNBC were invited to the FEPOS cohort, and 1044 young men participated in this study. Information on mode of delivery was extracted from the Danish Medical Birth Registry, and included vaginal delivery, elective CS before labor, emergency CS during labor and unspecified CS. The young men provided a semen sample for analysis of semen volume, sperm concentration, motility and morphology. Negative binomial regression models were applied to examine the association between CS and semen characteristics with estimation of relative differences in percentages with 95% confidence intervals (CIs). RESULTS: Among included sons, 132 (13%) were born by CS. We found a slightly lower non-progressive sperm motility (reflecting higher progressive sperm motility) among sons born by CS compared to sons born by vaginal delivery [relative difference (95% CI): - 7.5% (- 14.1% to - 0.4%)]. No differences were observed for other sperm characteristics. When CS was further classified into elective CS, emergency CS and unspecified CS in a sensitivity analysis, no significant differences in non-progressive motility were observed among sons born by any of the three types of CS compared to sons born vaginally. CONCLUSIONS: This large population-based cohort study found no significant evidence for an adverse effect on semen quality in adult sons born by CS.

Caesarean section is one of the most frequently used interventions during childbirth and global cesarean delivery rates continue to increase. The rising cesarean delivery rate has been reported to be related with series of adverse health outcomes in children, such as asthma, allergies, obesity, diabetes and even poor emotional, behavioral and educational outcomes. Still, it remains unknown whether children's reproductive health is affected by this delivery mode.Based on data from the Fetal Programming of Semen Quality cohort (FEPOS,) nested within the Danish National Birth Cohort, we have therefore analyzed the potential effect of caesarean section on son's semen quality in 1044 young men. We found a slightly higher progressive sperm motility among sons born by caesarean section compared to sons born by vaginal delivery. No differences, however, were observed for semen volume, sperm concentration and morphology between the two delivery modes.The FEPOS cohort is the largest population-based male offspring cohort worldwide. This is the first study aiming to examine the association between caesarean section and semen quality in adulthood. Although the findings need to be confirmed in other studies, it is reassuring that this large population-based cohort study finds no significant evidence for an adverse effect on semen quality in adult sons born by caesarean section.

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.

Sleep duration and biomarkers of fecundity in young men: a cross-sectional study from a population-based cohort.

BACKGROUND: Poor male fecundity is of concern and warrants the identification of potential modifiable risk factors. Short and long sleep duration might be risk factors for poor male fecundity although evidence in this research field is inconsistent. OBJECTIVES: To investigate the association between sleep duration and biomarkers of male fecundity in young men. MATERIALS AND METHODS: We conducted a cross-sectional study of 1,055 young men from the Fetal Programming of Semen Quality (FEPOS) cohort, Denmark, 2017-2019. Sleep duration was obtained from an online survey answered by the participants prior to the clinical visit, where semen and blood samples were obtained, and testis volume was self-assessed using an Orchidometer. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analysed according to sleep duration using multivariable negative binomial regression models. Sleep duration was dichotomised (recommended (6-9 h/night) versus deviant sleep) and visualised continuously as restricted cubic spline plots. RESULTS: Deviation from recommended sleep duration was associated with higher high DNA stainability (HDS) of 5% (95% CI: -1%; 13%), higher testosterone of 3% (95% CI: 0%; 7%) and higher free androgen index (FAI) of 6% (95% CI: 0%; 13%). The spline plots overall supported these results, suggesting u-shaped associations between sleep duration and HDS, testosterone and FAI, a linear association between sleep duration and semen volume and sex hormone binding globulin (SHBG) and an inverse u-shaped association with normal morphology. DISCUSSION: Information on sleep duration was obtained by self-report in broad categories with at least 3 h intervals. We were not able to investigate short or long sleep duration separately, since only few participants reported this. CONCLUSION: Sleep duration was associated with some biomarkers of fecundity in young men. Maintaining a recommended sleep duration may thus be beneficial for young men with regard to reproductive health.

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.

Exposure to airborne polychlorinated biphenyls and type 2 diabetes in a Danish cohort.

BACKGROUND: Previous research indicates an association between higher-chlorinated polychlorinated biphenyls (PCBs) and type 2 diabetes (T2D). However, less is known about the extent to which PCB exposure in indoor air, composed primarily of lower-chlorinated PCBs, affects T2D risk. We assessed the association between indoor air exposure to PCBs in residential buildings and T2D incidence. METHODS: The register-based 'Health Effects of PCBs in Indoor Air' (HESPAIR) cohort comprises 51,921 Danish residents of two residential areas with apartments built with and without PCB-containing materials (reference apartments). We assessed exposure status by combining register-based information on relocation history with extrapolated values of exposure based on PCB-measurements in indoor air from subsets of the apartments. T2D cases were identified in the Danish registers during 1977-2018. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression analyses with time-varying exposure. RESULTS: We identified 2737 incident T2D cases during the follow-up. Exposure to ≥3300 ng/m3 PCB × year (3rd tertile of PCByear) was associated with higher risk of T2D (HR 1.15, 95% CI 1.02-1.30) compared with exposure to <300 ng/m3 PCB × year (reference). However, among individuals with lower cumulated PCByear, the risk was similar to residents with exposure <300 ng/m3 PCB × year (300-899 ng/m3 PCB × year: HR 0.98, 95% CI 0.87-1.11; 900-3299 ng/m3 PCB × year: HR 0.96, 95% CI 0.83-1.10). DISCUSSION: We observed a marginally higher risk of T2D, but there was no evidence of an exposure-response relationship. The results should be interpreted with caution until confirmed in other independent studies of PCB exposure in indoor air.

Maternal alcohol intake in early pregnancy and biomarkers of fecundity in adult sons: A cohort study.

Male fecundity may be largely determined through fetal programming and therefore potentially be sensitive to exposure to maternal alcohol intake during pregnancy. We investigated whether maternal alcohol intake in early pregnancy was associated with biomarkers of fecundity in adult sons. In total, 1058 sons from the Fetal Programming of Semen Quality (FEPOS) cohort nested in the Danish National Birth Cohort (DNBC) provided blood and semen samples at around 19 years of age. Information on maternal weekly average alcohol intake (0 drinks [ref], >0-1 drinks, >1-3 drinks, >3 drinks) and binge drinking episodes (intake of ≥5 drinks on one occasion: (0 [ref], 1-2, ≥3 episodes)) was self-reported at around gestational week 17. Outcomes included semen characteristics, testes volume and reproductive hormones. We found some small tendencies towards lower semen characteristics and an altered hormone level profile in sons of mother who had an intake of > 3 drinks/week in early pregnancy and sons of mother who had ≥ 3 episodes of binge drinking in pregnancy. However, the effect estimates were overall small and inconsistent and with no indication of a dose dependent association. Due to the limited number of mothers with a high weekly alcohol intake, we cannot exclude whether prenatal exposure to higher doses than 4.5 drinks/week of alcohol in early pregnancy might have a detrimental effect on the biomarkers of fecundity in adult sons..

Reduction in hippocampal GABAergic transmission in a low birth weight rat model of depression.

Prenatal stress is believed to increase the risk of developing neuropsychiatric disorders, including major depression. Adverse genetic and environmental impacts during early development, such as glucocorticoid hyper-exposure, can lead to changes in the foetal brain, linked to mental illnesses developed in later life. Dysfunction in the GABAergic inhibitory system is associated with depressive disorders. However, the pathophysiology of GABAergic signalling is poorly understood in mood disorders. Here, we investigated GABAergic neurotransmission in the low birth weight (LBW) rat model of depression. Pregnant rats, exposed to dexamethasone, a synthetic glucocorticoid, during the last week of gestation, yielded LBW offspring showing anxiety- and depressive-like behaviour in adulthood. Patch-clamp recordings from dentate gyrus granule cells in brain slices were used to examine phasic and tonic GABAA receptor-mediated currents. The transcriptional levels of selected genes associated with synaptic vesicle proteins and GABAergic neurotransmission were investigated. The frequency of spontaneous inhibitory postsynaptic currents (sIPSC) was similar in control and LBW rats. Using a paired-pulse protocol to stimulate GABAergic fibres impinging onto granule cells, we found indications of decreased probability of GABA release in LBW rats. However, tonic GABAergic currents and miniature IPSCs, reflecting quantal vesicle release, appeared normal. Additionally, we found elevated expression levels of two presynaptic proteins, Snap-25 and Scamp2, components of the vesicle release machinery. The results suggest that altered GABA release may be an essential feature in the depressive-like phenotype of LBW rats.

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.

Risk of cardiovascular diseases following residential exposure to airborne polychlorinated biphenyls: A register-based cohort study.

BACKGROUND: Indoor air in buildings constructed with materials containing polychlorinated biphenyls (PCBs) may be contaminated with especially lower-chlorinated PCBs. So far, the cardiovascular consequences of living with such contamination are unknown. OBJECTIVES: To determine the risk of cardiovascular disease (CVD) following residential exposure to predominantly lower-chlorinated PCBs in indoor air. METHODS: The Health Effects of PCBs in Indoor Air (HESPAIR) cohort is register-based with 51 921 residents of two residential areas near Copenhagen: Farum Midtpunkt and Brøndby Strand Parkerne. Here, indoor air was contaminated with PCB in one third of the apartments due to construction with materials containing PCB. Individual PCB exposure was estimated based on register-based information on relocation dates and indoor air PCB measurements in subsets of the apartments. Information on CVD was retrieved from the Danish National Patient Register for the follow-up period of 1977-2018. We estimated adjusted hazard ratios using Cox regression with time-varying exposure. RESULTS: Cumulative residential exposure to airborne PCB was not associated with a higher overall risk for CVD (HR for highly exposed (≥3300 ng/m3 PCB × year): 1.02, 95% CI 0.94-1.10). This was also the case for most of the specific cardiovascular diseases, apart from acute myocardial infarction where a higher risk was observed for residents exposed to ≥3300 ng/m3 PCB × year compared to the reference group (HR 1.17, 95% CI 1.00-1.35). However, no exposure-response relationship was apparent and additional adjustment for education attenuated the risk estimate. DISCUSSION: In this, to our knowledge, first study ever to examine the risk of CVD following residential exposure to PCBs in indoor air, we observed limited support for cardiovascular effects of living in PCB-contaminated indoor air. Considering the prevalence of exposure to airborne PCBs and lack of literature on their potential health effects, these findings need to be corroborated in other studies.

Maternal intake of folate and folic acid during pregnancy and markers of male fecundity: A population-based cohort study.

BACKGROUND: Poor male fecundity is of concern, and a prenatal origin has been proposed. Folate, a methyl donor involved in DNA methylation, is essential for normal fetal development by regulating gene expression during different periods of fetal development. Thus, prenatal exposure to low maternal folate intake might have a programing function of the developing reproductive organs. OBJECTIVES: To examine the association between maternal intake of folate from diet and folic acid from supplements during pregnancy and markers of fecundity in young men. MATERIALS AND METHODS: We conducted a follow-up study using a Danish mother-son cohort of 787 young men born 1998-2000. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analyzed according to total folate calculated as dietary folate equivalents from diet and supplements in midpregnancy, using multivariable negative binomial regression models. Total folate was analyzed in quintiles, continuous per standard deviation decrease (SD: 318 µg/day) and as restricted cubic splines. RESULTS: Low maternal intake of total folate was associated with lower total sperm count (-5% (95% confidence intervals [CI]: -11%; 2%)), a lower proportion of non-progressive and immotile spermatozoa (-5% [95% CI: -8%; -3%]), and lower testes volume (-4% [95% CI: -6%; -2%]) per SD decrease in total folate intake. Spline plots supported these findings. DISCUSSION: The finding of a lower proportion of non-progressive and immotile spermatozoa, and hence a higher proportion of motile spermatozoa, in men of mothers with a lower intake of total folate in midpregnancy was surprising and may be a chance finding. CONCLUSION: Lower maternal intake of total folate in midpregnancy was associated with lower sperm count and lower testes volume, however, also with a lower proportion of non-progressive and immotile spermatozoa in adult men. Whether this actually affects the ability to obtain a pregnancy warrants further investigation.

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.

Nitrate in Maternal Drinking Water during Pregnancy and Measures of Male Fecundity in Adult Sons.

Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers' residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization's (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity.

Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS.

BACKGROUND: Concerns remain about the human reproductive toxicity of the widespread per- and polyfluoroalkyl substances (PFAS) during early stages of development. OBJECTIVES: We examined associations between maternal plasma PFAS levels during early pregnancy and male offspring reproductive function in adulthood. METHODS: The study included 864 young men (age range:18.9-21.2 y) from the Fetal Programming of Semen Quality (FEPOS) cohort established between 2017 and 2019. Plasma samples from their mothers, primarily from the first trimester, were retrieved from the Danish National Biobank and levels of 15 PFAS were measured. Seven PFAS had detectable levels above the limit of detection in >80% of the samples and were included in analyses. Semen quality, testicular volume, and levels of reproductive hormones and PFAS were assessed in the young men. We used weighted quantile sum (WQS) regression to estimate the associations between combined exposure to maternal PFAS and reproductive function, and negative binomial regression to estimate the associations of single substances, while adjusting for a range of a priori-defined fetal and postnatal risk factors. RESULTS: By a 1-unit increase in the WQS index, combined maternal PFAS exposure was associated with lower sperm concentration (-8%; 95% CI: -16%, -1%), total sperm count (-10%; 95% CI: -17%, -2%), and a higher proportion of nonprogressive and immotile sperm (5%; 95% CI: 1%, 8%) in the young men. Different PFAS contributed to the associations with varying strengths; however, perfluoroheptanoic acid was identified as the main contributor in the analyses of all three outcomes despite the low concentration. We saw no clear association between exposure to maternal PFAS and testicular volume or reproductive hormones. DISCUSSION: In a sample of young men from the general Danish population, we observed consistent inverse associations between exposure to maternal PFAS and semen quality. The study needs to be replicated in other populations, taking combined exposure, as well as emerging short-chain PFAS, into consideration. https://doi.org/10.1289/EHP10285.

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.

Developmental exposure to the brominated flame retardant DE-71 reduces serum thyroid hormones in rats without hypothalamic-pituitary-thyroid axis activation or neurobehavioral changes in offspring.

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants for which human exposure remains ubiquitous. This is of concern since these chemicals can perturb development and cause adverse health effects. For instance, DE-71, a technical mixture of PBDEs, can induce liver toxicity as well as reproductive and developmental toxicity. DE-71 can also disrupt the thyroid hormone (TH) system which may induce developmental neurotoxicity indirectly. However, in developmental toxicity studies, it remains unclear how DE-71 exposure affects the offspring's thyroid hormone system and if this dose-dependently relates to neurodevelopmental effects. To address this, we performed a rat toxicity study by exposing pregnant dams to DE-71 at 0, 40 or 60 mg/kg/day during perinatal development from gestational day 7 to postnatal day 16. We assessed the TH system in both dams and their offspring, as well as potential hearing and neurodevelopmental effects in prepubertal and adult offspring. DE-71 significantly reduced serum T4 and T3 levels in both dams and offspring without a concomitant upregulation of TSH, thus inducing a hypothyroxinemia-like effect. No discernible effects were observed on the offspring's brain function when assessed in motor activity boxes and in the Morris water maze, or on offspring hearing function. Our results, together with a thorough review of the literature, suggest that DE-71 does not elicit a clear dose-dependent relationship between low serum thyroxine (T4) and effects on the rat brain in standard behavioral assays. However, low serum TH levels are in themselves believed to be detrimental to human brain development, thus we propose that we lack assays to identify developmental neurotoxicity caused by chemicals disrupting the TH system through various mechanisms.