Maternal imprinting and determinants of neonates’ immune function in the SEPAGES mother-child cohort

IntroductionImmune function in pregnancy is influenced by host-specific and environmental factors. This may impact fetal immune development, but the link between maternal and neonatal immune function is still poorly characterized. Here, we investigate the relationship between maternal and neonatal immune function, and identify factors affecting the association between maternal and child cytokine secretion.MethodsIn the French prospective cohort SEPAGES, blood samples were obtained from pregnant women (n=322) at gestational week 20 ± 4 and from their child at birth (n=156). Maternal and cord blood cytokine and chemokine (CK) levels were measured at baseline in all subjects and after T cell or dendritic cell activation with phytohemagglutinin or R848 (in total 29 and 27 measures in maternal and cord blood samples, respectively). Associations between environmental, individual factors and CK level were estimated by linear regression modeling. The maternal-cord blood CK relations were assessed by Pearson correlation and regression models.ResultsWe observed that pregnant women and neonates displayed specific CK secretion profiles in the innate and adaptive compartments at baseline and upon activation. Activation of T cells in cord blood induced high levels of IL-2, but low levels of IFNγ, IL-13 or IL-10, in comparison to maternal blood samples. Elsewhere, neonatal innate immune responses were characterized by low production of IFNα, while productions of IL-1β, IL-6, IL-8, IL-10 and TNFα were higher than maternal responses. Strong correlations were observed between most CK after activation in maternal and cord blood samples. Strikingly, a statistical association between global mother and child cytokine profiles was evidenced. Correlations were observed between some individual CK of pregnant women and their children, both at baseline (MCP1, RANTES) and after activation with R848 (IL-6, IL-8 and IL-10). We looked for factors which could influence cytokine secretion in maternal or cord blood, and found that leucocyte counts, maternal age, pre-conception BMI, smoking and season were associated with the levels of several CK in mothers or children. DiscussionOur study reveals in utero immune imprinting influencing immune responses in infants, opening the way to investigate the mechanisms responsible for this imprinting. Whether such influences have long lasting effects on children health warrants further investigation

Within-Day, Between-Day, and Between-Week Variability of Urinary Concentrations of Phenol Biomarkers in Pregnant Women

International audienceBackground: Toxicology studies have shown adverse effects of developmental exposure to industrial phenols. Evaluation in humans is challenged by potentially marked within-subject variability of phenol biomarkers in pregnant women, which is poorly characterized.Objectives: We aimed to characterize within-day, between-day, and between-week variability of phenol urinary biomarker concentrations during pregnancy.Methods: In eight French pregnant women, we collected all urine voids over a 1-wk period (average, 60 samples per week per woman) at three occasions (15±2, 24±2, and 32±1 gestational weeks) in 2012-2013. Aliquots of each day and of the whole week were pooled within-subject. We assayed concentrations of 10 phenols in these pools, and, for two women, in all spot (unpooled) samples collected during a 1-wk period. We characterized variability using intraclass correlation coefficients (ICCs) with spot samples (within-day variability), daily pools (between-day variability), and weekly pools (between-week variability).Results: For most biomarkers, the within-day variability was high (ICCs between 0.03 and 0.50). The between-day variability, based on samples pooled within each day, was much lower, with ICCs >0.60 except for bisphenol S (0.14, 95% confidence interval [CI]: 0.00, 0.39). The between-week variability differed between compounds, with triclosan and bisphenol S having the lowest ICCs (0.9).Conclusion: During pregnancy, phenol biomarkers showed a strong within-day variability, while the variability between days of a given week was more limited. One biospecimen is not enough to efficiently characterize exposure; collecting biospecimens during a single week may be enough to represent well the whole pregnancy exposure for some but not all phenols. https://doi-org.proxy.insermbiblio.inist.fr/10.1289/EHP1994

Pre- and early post-natal exposure to phthalates and DINCH in a new type of mother-child cohort relying on within-subject pools of repeated urine samples

International audienceFor non-persistent chemicals such as phthalates, a single spot urine sample only reflects exposure in the past few hours. Collecting repeated urine samples for each participant over windows of sensitivity is expected to improve exposure characterization but has rarely been done. We aimed to rely on within-subject pools of repeated urine samples to assess phthalate exposure during pregnancy and infancy. Women of the French SEPAGES mother-child cohort were asked to collect three urine samples per day over seven consecutive days, twice during their pregnancy (approximatively second (T2) and third (T3) trimesters). For their infants they also collected one sample per day during a week at two (M2) and twelve months (M12). Samples were pooled (within-subject, within-period) prior to phthalate and DINCH metabolite concentrations assessment. Number of pooled samples assayed was 477, 456, 152 and 100 for T2, T3, M2 and M12, respectively. All metabolites were detected in more than 95% of the pooled samples except for the two DINCH metabolites (oh- and oxo-MINCH), MMCHP and oh-MPHP at M2 for which detection frequencies ranged between 64% and 88%. Maternal concentrations of MiBP, MBzP, DEHP metabolites and oxo-MiNP decreased between 2014 and 2017, whereas concentrations of oh-MiNP and the two DINCH metabolites increased (Mann-Kendall p-values < 0.05). While improved compared to studies that relied on spot samples, Intraclass Correlation Coefficients for the pregnancy were below 0.40 for most metabolites. Spearman correlation coefficients between pooled samples collected in infancy were lower than those observed during pregnancy, and were all below 0.30. Exposure to emerging phthalate substitutes such as DINCH and DPHP seems widespread among pregnant women and infants. Collecting repeated urine samples in pregnant women and infants is feasible. The relatively low correlation across trimesters and between maternal and infant samples highlights the need to collect biospecimens in the assumed sensitive time window

Exposure to phenols during pregnancy and the first year of life in a new type of couple-child cohort relying on repeated urine biospecimens

International audienceBackground: Parabens, bisphenol A and triclosan have been forbidden or restricted in specific types of consumer goods in Europe and France. Limited biomonitoring data are available in France since the implementation of these regulations, and exposure data on infants is scarce worldwide. Understanding the predictors of phenol urinary concentrations will help identify potential targets for prevention.Aim: We described levels, variability and predictors of exposure to 12 phenols in pregnant women and infants recruited between 2014 and 2017 in a French couple-child cohort.Methods: Among 479 pregnant women and 150 of their infants, we studied phenol urinary concentrations in within-subject, within-period pools of repeated urine samples collected during the second and third trimesters of pregnancy (up to 42 samples per woman), at 2 months and 12 months (up to 14 samples per infant). Time trends and associations with demographic, protocol, occupational and behavioral factors were studied using interval censored models to accommodate for undetected and unquantified urine concentrations.Results: Detection rates were above 90% for bisphenol A, ethylparaben, methylparaben, benzophenone-3 and triclosan and below 5% for bisphenol AF, B, F and triclocarban. Median levels of bisphenol A, bisphenol S, methylparaben, ethylparaben and propylparaben at 12 months were similar or higher than during pregnancy. For pregnant women all phenols but benzophenone-3 and bisphenol S showed a linear decrease between 2014 and 2017 (p-values < 0.02). Women with the shortest education (primary and secondary school) had higher urinary concentrations of triclosan (β = 0.58 (95% confidence interval (CI), −0.04; 1.20)), ethyl (β = 0.43 (95%CI, 0.03; 0.84)) and propyl paraben (β = 1.39 (95%CI, 0.55; 2.24)) than those with the longest education. Cashiers had higher conccentrations of bisphenol S (β = 0.99 (95%CI, −0.11; 2.09)) but not of bisphenol A (β = −0.04 (95%CI, −0.26; 0.19)) than unemployed women.Conclusions: Despite recent regulations, bisphenol A, triclosan and paraben detection rates were high in women and young infants. High bisphenol and paraben median levels at 12 months require further investigation as early infancy is a sensitive period for exposure to environmental contaminants

Effects of early exposure to phthalates on cognitive development and visual behavior at 24 months

International audienceBackground and objectives: Studies focusing on the neurodevelopmental effects of phthalates seldom consider exposure during infancy, a critical period for brain development. Most rely on parent-completed questionnaires to assess child neurodevelopment, which may be subject to reporting error. We studied the associations between prenatal and infancy exposure to phthalates and objective measures of neurodevelopment at the age of two. Methods: We relied on 151 mother-child pairs from the SEPAGES mother-child cohort. Women were asked to collect three spot urine samples per day over seven consecutive days during the second (median: 18.0 gestational weeks) and third (median: 34.2 gestational weeks) trimesters of pregnancy. They then collected one urine sample per day over seven consecutive days from their infants around the age of 12 months. Metabolites of phthalates and non-phthalate plasticizers were measured in within-subject and within-period pools of repeated urine samples. Eye tracking tasks were performed at two years allowing to compute four indicators linked with cognitive development and visual behavior: mean fixation duration, novelty preference, percent time spent looking at the eyes and mean reaction time. Results: Pre-natal exposure to monobenzyl phthalate at the second and third trimesters was associated with shorter fixation durations. In models allowing for interaction with child sex, these associations were only observed among girls. Exposure to di(2-ethylhexyl) phthalate at the third but not the second trimester was associated with increased time spent looking at a novel face and eyes. We observed faster reaction times and decreased time spent looking at the eyes in a face recognition task, with increased post-natal exposure to monoethyl, mono-iso-butyl and mono-n-butyl phthalates. Discussion: Relying on improved exposure assessment, we highlighted associations of pre-and post-natal exposure to phthalates with indicators derived from eye tracking tasks, mainly in girls. Some of these indicators have been affected in individuals with neurodevelopmental disorders

Intra-breath changes in respiratory mechanics are sensitive to history of respiratory illness in preschool children: the SEPAGES cohort

Abstract Background Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children. Methods History of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R7), frequency-dependence of resistance (R7 − 19), reactance at 7 Hz (X7), area of the reactance curve (AX), end-inspiratory and end-expiratory R (ReI, ReE) and X (XeI, XeE), and volume-dependence of resistance (ΔR = ReE-ReI) was estimated by linear regression adjusted on confounders. Results Among the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher ReI, ReE, ΔR and R7 and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R7 and AX and lower XeI and bronchitis with higher ReI. No statistically significant association was observed for hospitalisation. Conclusions Our findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts

Effects of early exposure to phthalates on cognitive development and visual behavior at 24 months

International audienceBackground and objectives: Studies focusing on the neurodevelopmental effects of phthalates seldom consider exposure during infancy, a critical period for brain development. Most rely on parent-completed questionnaires to assess child neurodevelopment, which may be subject to reporting error. We studied the associations between prenatal and infancy exposure to phthalates and objective measures of neurodevelopment at the age of two. Methods: We relied on 151 mother-child pairs from the SEPAGES mother-child cohort. Women were asked to collect three spot urine samples per day over seven consecutive days during the second (median: 18.0 gestational weeks) and third (median: 34.2 gestational weeks) trimesters of pregnancy. They then collected one urine sample per day over seven consecutive days from their infants around the age of 12 months. Metabolites of phthalates and non-phthalate plasticizers were measured in within-subject and within-period pools of repeated urine samples. Eye tracking tasks were performed at two years allowing to compute four indicators linked with cognitive development and visual behavior: mean fixation duration, novelty preference, percent time spent looking at the eyes and mean reaction time. Results: Pre-natal exposure to monobenzyl phthalate at the second and third trimesters was associated with shorter fixation durations. In models allowing for interaction with child sex, these associations were only observed among girls. Exposure to di(2-ethylhexyl) phthalate at the third but not the second trimester was associated with increased time spent looking at a novel face and eyes. We observed faster reaction times and decreased time spent looking at the eyes in a face recognition task, with increased post-natal exposure to monoethyl, mono-iso-butyl and mono-n-butyl phthalates. Discussion: Relying on improved exposure assessment, we highlighted associations of pre-and post-natal exposure to phthalates with indicators derived from eye tracking tasks, mainly in girls. Some of these indicators have been affected in individuals with neurodevelopmental disorders

Pre-natal exposure to NO2 and PM2.5 and newborn lung function: An approach based on repeated personal exposure measurements

International audienceContext: While strong evidence supports adverse effects of pre-natal air pollution on child’s lung function, previous studies rarely considered fine particulate matter (PM2.5) or the potential role of offspring sex and no study examined the effects of pre-natal PM2.5 on the lung function of the newborn. Aim: We examined overall and sex-specific associations of personal pre-natal exposure to PM2.5 and nitrogen (NO2) with newborn lung function measurements. Methods: This study relied on 391 mother-child pairs from the French SEPAGES cohort. PM2.5 and NO2 exposure was estimated by the average concentration of pollutants measured by sensors carried by the pregnant women during repeated periods of one week. Lung function was assessed with tidal breathing analysis (TBFVL) and nitrogen multiple breath washout (N2MBW) test, performed at 7 weeks. Associations between pre-natal exposure to air pollutants and lung function indicators were estimated by linear regression models adjusted for potential confounders, and then stratified by sex.Results: Mean exposure to NO2 and PM2.5 during pregnancy was 20.2 μg/m3 and 14.3 μg/m3, respectively. A 10 μg/m3 increase in PM2.5 maternal personal exposure during pregnancy was associated with an adjusted 2.5 ml (2.3%) decrease in the functional residual capacity of the newborn (p-value=0.11). In females, functional residual capacity was decreased by 5.2 ml (5.0%) (p=0.02) and tidal volume by 1.6 mL (p=0.08) for each 10 μg/m3 increase in PM2.5. No association was found between maternal NO2 exposure and newborns lung function. Conclusions: Personal pre-natal PM2.5 exposure was associated with lower lung volumes in female newborns, but not in males. Our results provide evidence that pulmonary effects of air pollution exposure can be initiated in utero. These findings have long term implications for respiratory health and may provide insights into the underlying mechanisms of PM2.5 effects

An Empirical Validation of the Within-subject Biospecimens Pooling Approach to Minimize Exposure Misclassification in Biomarker-based Studies

International audienceBackground: Within-subject biospecimens pooling can theoretically reduce bias in dose-response functions from biomarker-based studies when exposure assessment suffers from classical-type error. However, collecting many urine voids each day is cumbersome. We evaluated the empirical validity of a within-subject pooling approach and compared several options to avoid sampling each void.Methods: In 16 pregnant women who collected a spot of each urine void over several nonconsecutive weeks, we compared concentrations of 10 phenols in daily, weekly, and pregnancy within-subject pools. We pooled either three or all daily samples. In a simulation study using these data, we quantified bias in dose-response functions when using one to 20 urine samples per subject to assess methylparaben (a compound with moderate within-subject variability) and bisphenol A (high variability) exposures.Results: Correlations between exposure estimates from pools of all and of only three voids per day were above 0.80 for all time windows and compounds, except for benzophenone-3 and triclosan in the daily time window (correlations, 0.57-0.68). With one spot sample to assess pregnancy exposure, correlations were all below 0.74. Using only one biospecimen led to attenuation bias in the dose-response functions of 29% (methylparaben) and 69% (bisphenol A); four samples for methylparaben and 18 for bisphenol A decreased bias to 10%.Conclusions: For nonpersistent chemicals, collecting and pooling three samples per day instead of all daily samples efficiently estimates exposures over a week or more. Collecting around 20 biospecimens can strongly limit attenuation bias for nonpersistent chemicals such as bisphenol A

Early delivery following chronic and acute ambient temperature exposure: a comprehensive survival approach

International audienceBACKGROUND: Ambient temperature, particularly heat, is increasingly acknowledged as a trigger of preterm delivery, but study designs have been limited and results mixed. We aimed to comprehensively evaluate the association between ambient temperature throughout pregnancy and preterm delivery.METHODS: We estimated daily temperature throughout pregnancy using a cutting-edge spatiotemporal model for 5,347 live singleton births from three prospective cohorts in France, 2002-2018. We performed Cox regression (survival analysis) with forward (weekly from conception) and backward (30 days before delivery) distributed lags to evaluate time-varying associations with preterm birth. We examined weekly mean, daytime, night-time, and variability of temperature, and heatwaves accounting for adaptation to location and season.RESULTS: Preterm birth risk was higher following cold (5th vs 50th percentile of mean temperature) 7-9 weeks after conception [relative risk (RR) 1.3, 95% confidence interval (CI) 1.0-1.6 for 2°C vs 11.6°C] and 10-4 days before delivery (1.6 [1.1-2.1] for 1.2°C vs 12.1°C). Night-time heat (95th vs 50th percentile of minimum temperature; 15.7°C vs 7.4°C) increased risk when exposure occurred within five weeks of conception (2.0 [1.05-3.8]) or 20-26 weeks after conception (2.9 [1.2-6.8]). Overall and daytime heat (high mean and maximum temperature) showed consistent effects. We found no clear associations with temperature variability or heatwave indicators, suggesting they may be less relevant for preterm birth. CONCLUSION: In a temperate climate, night-time heat and chronic and acute cold exposures were associated with increased risk of preterm birth. These results suggest nighttime heat as a relevant indicator. In the context of rising temperatures and more frequent weather hazards, these results should inform public health policies to reduce the growing burden of preterm births