Maternal concentrations of phthalates and Attention-Deficit Hyperactivity Disorder (ADHD-) related symptoms in children aged 2 to 4 years from Odense child cohort.

BACKGROUND: Phthalates are endocrine disrupting chemicals used in everyday consumer products. Several epidemiological studies have examined the association between prenatal phthalate concentration and Attention-Deficit Hyperactivity Disorder (ADHD) in offspring, but the findings have been inconclusive. OBJECTIVES: To investigate the association between maternal urinary concentrations of phthalate metabolites during pregnancy and ADHD related symptoms in children at 2 to 4 years in a large prospective cohort. METHODS: In the Odense Child Cohort from Denmark were women recruited in early pregnancy from 2010 to 2012. Phthalate concentrations were measured in urine samples collected in 3rd trimester and separated into low and high weight phthalates. Parents filled in the Child Behavior Checklist for ages 1.5 to 5 years (CBCL/1½-5), including a 6-item ADHD symptom scale at children aged 2 to 4 years. Data were analysed by use of adjusted negative binomial regression. RESULTS: A total of 658 mother-child pairs were included. Urinary phthalate metabolite concentrations were generally low compared to previous cohorts. A doubling in maternal concentration of the low-weighted phthalate metabolite MCPP was significantly associated with lower ADHD symptoms score in children (IRR: 0.95 (95 % CI 0.91-0.98)), strongest in girls (IRR: 0.92 (0.87-0.98)). Sex differences were observed. High maternal phthalate metabolite concentrations were associated with lower ADHD symptom score in girls, significant trends across tertile of MCPP and MnBP (p = 0.018, p = 0.038, respectively). In boys, maternal concentrations of high-molecular-weight phthalates (MBzP, ∑DiNP and ∑DEHP) were associated with an almost significantly higher ADHD symptom score (IRR for a doubling in concentration: 1.04 (95 % CI: 0.99-1.10), IRR: 1.05 (95 % CI: 0.97-1.13), IRR: 1.04 (95 % CI: 0.99-1.10), respectively). CONCLUSION: Maternal concentration of the low-weighted phthalate metabolite MCPP was significantly associated with a lower ADHD symptom score in children, strongest in girls. Maternal concentrations of high-molecular-weight phthalates were associated with non-significant increase in ADHD symptom score in boys.

Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021).

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures.

Concurrent Assessment of Phthalates/HEXAMOLL® DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL® DINCH biomarkers. The relation between phthalates/HEXAMOLL® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 ± 11 (NAC-II), 98 ± 12 (OCC), and 81 ± 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (ß = 2.56; 95% CI 0.58-4.55; N = 270), 5OH-MEHP+5cx-MEPP (ß = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (ß = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value ≥ 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children.

Harmonization of Human Biomonitoring Studies in Europe: Characteristics of the HBM4EU-Aligned Studies Participants.

Human biomonitoring has become a pivotal tool for supporting chemicals' policies. It provides information on real-life human exposures and is increasingly used to prioritize chemicals of health concern and to evaluate the success of chemical policies. Europe has launched the ambitious REACH program in 2007 to improve the protection of human health and the environment. In October 2020 the EU commission published its new chemicals strategy for sustainability towards a toxic-free environment. The European Parliament called upon the commission to collect human biomonitoring data to support chemical's risk assessment and risk management. This manuscript describes the organization of the first HBM4EU-aligned studies that obtain comparable human biomonitoring (HBM) data of European citizens to monitor their internal exposure to environmental chemicals. The HBM4EU-aligned studies build on existing HBM capacity in Europe by aligning national or regional HBM studies. The HBM4EU-aligned studies focus on three age groups: children, teenagers, and adults. The participants are recruited between 2014 and 2021 in 11 to 12 primary sampling units that are geographically distributed across Europe. Urine samples are collected in all age groups, and blood samples are collected in children and teenagers. Auxiliary information on socio-demographics, lifestyle, health status, environment, and diet is collected using questionnaires. In total, biological samples from 3137 children aged 6-12 years are collected for the analysis of biomarkers for phthalates, HEXAMOLL® DINCH, and flame retardants. Samples from 2950 teenagers aged 12-18 years are collected for the analysis of biomarkers for phthalates, Hexamoll® DINCH, and per- and polyfluoroalkyl substances (PFASs), and samples from 3522 adults aged 20-39 years are collected for the analysis of cadmium, bisphenols, and metabolites of polyaromatic hydrocarbons (PAHs). The children's group consists of 50.4% boys and 49.5% girls, of which 44.1% live in cities, 29.0% live in towns/suburbs, and 26.8% live in rural areas. The teenagers' group includes 50.6% girls and 49.4% boys, with 37.7% of residents in cities, 31.2% in towns/suburbs, and 30.2% in rural areas. The adult group consists of 52.6% women and 47.4% men, 71.9% live in cities, 14.2% in towns/suburbs, and only 13.4% live in rural areas. The study population approaches the characteristics of the general European population based on age-matched EUROSTAT EU-28, 2017 data; however, individuals who obtained no to lower educational level (ISCED 0-2) are underrepresented. The data on internal human exposure to priority chemicals from this unique cohort will provide a baseline for Europe's strategy towards a non-toxic environment and challenges and recommendations to improve the sampling frame for future EU-wide HBM surveys are discussed.

The association between cannabis use and testicular function in men: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between cannabis use and testicular function (as assessed through semen quality and serum hormone levels) in different populations. EVIDENCE REVIEW: Systematic review and meta-analysis of population-based retrospective cohort studies. PRISMA guidelines were used for abstracting data and assessing data quality and validity. Data were pooled using a fixed-effects or random-effects model depending on the heterogeneity of studies included. Pooled risk ratio (RR) of having any sperm abnormality and testosterone, FSH, and LH standardized mean differences among male cannabis users and non-users, and meta-regression analysis according to age and year of publication. RESULTS: Nine studies were evaluated which included 4014 men with semen data and 4787 with hormonal data. Overall among 1158 cannabis users, 44.9% had impaired semen parameters, compared with 24.5% of the 2856 non-users. The relative risk among cannabis users for any abnormal semen parameter was 1.159 (95% CI: 0.840; 1.599, P = 0.369). The standardized mean difference between user and non-user testosterone levels was -0.139 (95% CI: -0.413; 0.134, P = 0.318). For FSH, the standardized mean difference estimate was -0.142 (95% CI: -0.243; -0.0425, P = 0.005), while for LH the standardized mean difference estimate was -0.318 (95% CI: -0.810-0.175; P = 0.206). CONCLUSIONS: The current evidence does not suggest clinically significant associations between cannabis use and testicular function. However, we cannot exclude an effect of cannabis because of the limited and heterogeneous studies. Additionally, well-designed studies will be needed to define the association between cannabis use and the male reproductive system.

Impact of psychological stress measured in three different scales on testis function: A cross-sectional study of 1362 young men.

BACKGROUND: Studies have reported associations between psychological stress and semen quality, but most have been performed on selected populations using different stress measures. Thus, it is uncertain which stress scale best quantifies the effects of stress on testicular function. OBJECTIVE: To study the association between three different measures of stress and testicular function in young men. MATERIAL AND METHODS: In total, 1362 men (median age 19 years) delivered semen and blood samples. They also answered a questionnaire including information from three stress scales: Stress Symptoms, Stressful Life Events and Perceived Stress. Various statistical analyses for associations between stress and testicular function (semen quality and reproductive hormones) were performed. RESULTS: Perceived Stress was negatively associated with sperm concentration, total count and motility and positively associated with serum FSH. Men with the highest scores (>30 points) had 38% (95% CI 3-84%) lower sperm concentration, 42% (95% CI 5-91%) lower total count and 22% (95% CI 2-32%) lower proportion of motile spermatozoa than men with the lowest scores (0-10 points). For the stress symptoms score, men with highest scores (>95th percentile vs. lower) had lower sperm concentration, total sperm count, motility and serum Inhibin-B/FSH-ratio. Although men with highest stress levels were characterized by an unhealthier lifestyle, adjusting for lifestyle factors did not attenuate results suggesting that the associations between stress and testicular function were not mediated by lifestyle. Stressful Life Events were not associated with testicular function. DISCUSSION AND CONCLUSION: The linear association between Perceived Stress and semen parameters and lack of dose-response association for the other two stress scales indicated that perceived stress was the most sensitive marker of stress affecting semen quality in young men. The lack of associations between Stressful Life Events and testis function confirmed that the perception of stressful events rather than the stressful event per se matters.

Semen Quality as a Predictor of Subsequent Morbidity: A Danish Cohort Study of 4,712 Men With Long-Term Follow-up.

Semen quality has been suggested to be a biological marker of long-term morbidity and mortality; however, few studies have been conducted on this subject. We identified 5,370 men seen for infertility at Frederiksberg Hospital, Denmark, during 1977-2010, and 4,712 of these men were followed in the Danish National Patient Registry until first hospitalization, death, or the end of the study. We classified patients according to hospitalizations and the presence of cardiovascular disease, diabetes, testicular cancer, or prostate cancer. We found a clear association between sperm concentration below 15 million/mL and all-cause hospitalizations (hazard ratio = 1.5, 95% confidence interval: 1.4, 1.6) and cardiovascular disease (hazard ratio = 1.4, 95% confidence interval: 1.2, 1.6), compared with men with a concentration above 40 million/mL. The probabilities for hospitalizations were also higher with a low total sperm count and low motility. Men with a sperm concentration of 195-200 million/mL were, on average, hospitalized for the first time 7 years later than were men with a sperm concentration of 0-5 million/mL. Semen quality was associated with long-term morbidity, and a significantly higher risk of hospitalization was found, in particular for cardiovascular diseases and diabetes mellitus. Our study supports the suggestion that semen quality is a strong biomarker of general health.

Phthalate exposure through different pathways and allergic sensitization in preschool children with asthma, allergic rhinoconjunctivitis and atopic dermatitis.

Studies in rodents indicate that phthalates can function as adjuvants, increasing the potency of allergens. Meanwhile, epidemiological studies have produced inconsistent findings regarding relationships between phthalate exposures and allergic disease in humans. The present study examined phthalate exposure and allergic sensitization in a large group of 3-5 year old children: 300 random controls and 200 cases with asthma, rhinoconjunctivitis or atopic dermatitis as reported in questionnaires. The children were clinically examined to confirm their health status. Blood samples were analyzed for IgE sensitization to 20 allergens. Adjusted logistic regressions were used to look for associations between phthalate exposure indicators (mass fractions in dust from children's homes and daycares, metabolites in urine, and estimated daily indoor intakes from dust ingestion, inhalation and dermal absorption) and sensitization and allergic disease. No direct associations were found between phthalate exposures and asthma, rhinoconjunctivitis or atopic dermatitis. However, among children with these diseases, there were significant associations between non-dietary exposures to DnBP, BBzP and DEHP in the indoor environment (mass fractions in dust or daily indoor intakes from dust ingestion, inhalation and dermal absorption) and allergic sensitization. Some exposure pathways were more strongly associated with sensitization than others, although the results are not conclusive and require confirmation. A number of the associations depended on accounting for a child's exposure in more than one environment (i.e., daycare facility as well as home). Significant associations were not observed between phthalate metabolites in urine, which reflected exposure from diet as well as indoor pathways, and allergic sensitization.

Birth size and age at menarche: a twin perspective.

STUDY QUESTION: Do birthweight (BW) and co-twin sex influence the age at menarche in twins? SUMMARY ANSWER: BW, but not co-twin sex, was associated with age at menarche in twins. However, BW was not associated with age at menarche after controlling for genetics and shared rearing environment. WHAT IS KNOWN ALREADY: Nutritional deprivation during critical developmental periods can trigger long-term effects on health. A small size at birth has been associated with early age at menarche in singletons. However, the relative influence of genetics and environmental factors on this association remains unresolved. STUDY DESIGN, SIZE, DURATION: In total, 2505 twin pairs were included in this cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were recruited from the Danish Twin Register. Data on the age at menarche were collected by questionnaire and combined with data on BW, birth length (BL) and gestational age (GA) from the Danish Medical Birth register. The BW for GA standard deviation score (BW-SDS) was calculated. MAIN RESULTS AND THE ROLE OF CHANCE: BW-SDS [hazard ratio (HR) 0.96; 95% confidence interval (CI): 0.93-0.00], P = 0.04], but not BW, BL or GA (P ≥ 0.15), was positively associated with age at menarche in all twins after adjustment for zygosity and year of birth. However, BW-SDS was not associated with menarcheal age within twin pairs (HR 1.01; 95% CI: 0.91-1.12, P = 0.88). No differences were found in the age at menarche or birth size between twin girls from same sex and twin girls from opposite-sex pregnancies. Heritability of menarcheal age and BW were estimated to be 0.61 (95% CI: 0.38-0.84) and 0.27 (95% CI: 0.18-0.38), respectively. Both BW and menarcheal age were influenced by genetic and environmental factors. LIMITATIONS, REASONS FOR CAUTION: A limitation of this study is recall bias on the age at menarche. It is also not clear how these results should be extrapolated to the non-twin population. WIDER IMPLICATIONS OF THE FINDINGS: lower BW for GA is associated with earlier age at menarche in twin girls. However, the lack of within-pair differences in menarcheal age between even markedly BW-discordant twins indicates that this association is governed by environmental or genetic factors shared by both twins. Thus, within-pair differences in intrauterine nutritional factors leading to discordant growth do not seem to influence timing of menarche. STUDY FUNDING/COMPETING INTEREST(S): The authors have nothing to declare. Departmental funds were used to support all authors during the study period and preparation.

Maternal blood pressure in pregnancy, birth weight, and perinatal mortality in first births: prospective study.

OBJECTIVE: To investigate the relation of diastolic blood pressure in pregnancy with birth weight and perinatal mortality. DESIGN: Prospective study. SETTING: 15 maternity units in one London health region, 1988-2000. PARTICIPANTS: 210 814 first singleton births of babies weighing more than 200 g among mothers with no hypertension before 20 weeks' gestation and without proteinuria, delivering between 24 and 43 weeks' gestation. MAIN OUTCOME MEASURES: Birth weight and perinatal mortality. RESULTS: The mean (SD) birth weight of babies born to mothers with no hypertension before 20 weeks' gestation or proteinuria was 3282 g (545 g) and there were 1335 perinatal deaths, compared with 94 perinatal deaths among women with proteinuria or a history of hypertension. Diastolic blood pressure at booking for antenatal checks was progressively higher from weeks 34 to 40 of gestation. The birth weight of babies being delivered after 34 weeks was highest for highest recorded maternal diastolic blood pressures of between 70 and 80 mm Hg and lower for blood pressures outside this range. Both low and high diastolic blood pressures were associated with statistically significantly higher perinatal mortality. Using a linear quadratic model, 94 of 825 (11.4%) perinatal deaths could be attributed to mothers having blood pressure differing from the optimal blood pressure (82.7 mm Hg) predicted by the fitted model. Most of these excess deaths occurred with blood pressures below the optimal value. CONCLUSIONS: Both low and high diastolic blood pressures in women during pregnancy are associated with small babies and high perinatal mortality.

How would a decline in sperm concentration over time influence the probability of pregnancy?

BACKGROUND: Reports have suggested a decline in sperm concentration during the second half of the 20th century. The effect of this decline on fecundability (the monthly probability of pregnancy) could be detected in principle by a study of time to pregnancy. In practice, the amplitude of this expected effect is not well known and the statistical power of time-to-pregnancy studies to detect it has not been explored. METHODS: We developed a nonparametric model to describe a temporal decline in sperm concentration using data on French semen donors. We then applied this model to 419 Danish couples planning a first pregnancy in 1992, to predict their time to pregnancy as if the pregnancy attempt had begun during earlier decades with higher sperm concentrations. Finally, we used bootstrap simulations to estimate the statistical power of prospective or retrospective studies that compared fecundability (estimated from time to pregnancy) across these time periods. We express the change in fecundability over time as a fecundability ratio (FR), with values less than 1 indicating decreased fecundability. RESULTS: We estimate that the median sperm concentration decreased by 21% from 1977 to 1992 and by 47% from 1947 to 1992. The estimated decline in fecundability with those semen changes was 7% from 1977 to 1992 (FR = 0.93, adjusted) and 15% from 1947 to 1992 (FR = 0.85, adjusted). The total numbers of couples that would be needed in prospective studies of time to pregnancy to detect these changes in fecundability (with a power of 80%) were 12,000 when comparing 1977 to 1992, and 2000 when comparing 1947 to 1992. Retrospective studies of the same size that excluded childless couples had much lower statistical power and were biased toward the null. CONCLUSION: The effect of realistic declines in sperm concentration on time to pregnancy may be observed only with studies that include several thousand couples.

Oxidative DNA damage in human sperm influences time to pregnancy.

BACKGROUND: Oxidative stress and related DNA damage in human sperm may be important for fecundity and pregnancy outcome. METHODS: We studied the level of oxidative DNA damage in terms of 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in sperm DNA among 225 first-pregnancy planners. Over the six menstrual cycle follow-up time, after cessation of contraception, 135 pregnancies were conceived. RESULTS: The likelihood of pregnancy occurring in a single menstrual cycle was inversely associated with the 8-oxodG level (P < 0.01). The odds ratio of pregnancy in each of the first three or all six follow-up menstrual cycles was 0.42 (0.23-0.78; 95% CI) and 0.61 (0.36-0.91) per unit increase in the log 8-oxodG/100 000 dG ratio after adjustment for potential confounders, (including sperm concentration) respectively. The intra-individual coefficient of variation of 8-oxodG in 2-6 monthly repeated sperm samples from 116 men was 19% for the 8-oxodG/dG ratio, whereas the inter-individual coefficient of variation was 49%. The 8-oxodG level was not significantly associated with smoking, consumption of alcohol or caffeine, exposure to welding fumes or the plasma levels of sex hormones. CONCLUSIONS: The data suggest that oxidative damage to sperm DNA influences fecundity and the level of damage is relatively constant within an individual and not influenced by smoking.