Placental DNA methylation signatures of prenatal air pollution exposure and potential effects on birth outcomes: an analysis of three prospective cohorts.

BACKGROUND: Pregnancy air pollution exposure (PAPE) has been linked to a wide range of adverse birth and childhood outcomes, but there is a paucity of data on its influence on the placental epigenome, which can regulate the programming of physiological functions and affect child development. This study aimed to investigate the association between prenatal air pollutant exposure concentrations and changes in placental DNA methylation patterns, and to explore the potential windows of susceptibility and sex-specific alterations. METHODS: This multi-site study used three prospective population-based mother-child cohorts: EDEN, PELAGIE, and SEPAGES, originating from four French geographical regions (Nancy, Poitiers, Brittany, and Grenoble). Pregnant women were included between 2003 and 2006 for EDEN and PELAGIE, and between 2014 and 2017 for SEPAGES. The main eligibility criteria were: being older than 18 years, having a singleton pregnancy, and living and planning to deliver in one of the maternity clinics in one of the study areas. A total of 1539 mother-child pairs were analysed, measuring placental DNA methylation using Illumina BeadChips. We used validated spatiotemporally resolved models to estimate PM2·5, PM10, and NO2 exposure over each trimester of pregnancy at the maternal residential address. We conducted a pooled adjusted epigenome-wide association study to identify differentially methylated 5'-C-phosphate-G-3' (CpG) sites and regions (assessed using the Infinium HumanMethylationEPIC BeadChip array, n=871), including sex-specific and sex-linked alterations, and independently validated our results (assessed using the Infinium HumanMethylation450 BeadChip array, n=668). FINDINGS: We identified four CpGs and 28 regions associated with PAPE in the total population, 469 CpGs and 87 regions in male infants, and 150 CpGs and 66 regions in female infants. We validated 35% of the CpGs available. More than 30% of the identified CpGs were related to one (or more) birth outcome and most significant alterations were enriched for neural development, immunity, and metabolism related genes. The 28 regions identified for both sexes overlapped with imprinted genes (four genes), and were associated with neurodevelopment (nine genes), immune system (seven genes), and metabolism (five genes). Most associations were observed for the third trimester for female infants (134 of 150 CpGs), and throughout pregnancy (281 of 469 CpGs) and the first trimester (237 of 469 CpGs) for male infants. INTERPRETATION: These findings highlight the molecular pathways through which PAPE might affect child health in a widespread and sex-specific manner, identifying the genes involved in the major physiological functions of a developing child. Further studies are needed to elucidate whether these epigenetic changes persist and affect health later in life. FUNDING: French Agency for National Research, Fondation pour la Recherche Médicale, Fondation de France, and the Plan Cancer.

Meconium Concentrations of Pesticides and Risk of Hypospadias: A Case-Control Study in Brittany, France.

BACKGROUND: Hypospadias is a male genital tract defect for which an increase in prevalence has been documented over the last few decades. A role for environmental risk factors is suspected, including prenatal exposure to pesticides. OBJECTIVES: To study the risk of hypospadias in association with multiple pesticide measurements in meconium samples. METHODS: The Brittany Registry of Congenital Anomalies (France) conducted a case-control study between 2012 and 2018. Cases were hypospadias, ascertained by a pediatrician and a pediatric surgeon, excluding genetic conditions, following European Surveillance of Congenital Anomalies guidelines (N = 69). Controls (N = 135) were two male infants without congenital anomaly born after each case in the same maternity unit. Mothers in the maternity units completed a self-administered questionnaire, we collected medical data from hospital records, and medical staff collected meconium samples. We performed chemical analysis of 38 pesticides (parent compound and/or metabolite) by UHPLC/MS/MS following strict quality assurance/quality control criteria and blind to case-control status. We carried out logistic regression accounting for frequency-matching variables and major risk factors. RESULTS: Among the 38 pesticides measured, 16 (42%) were never detected in the meconium samples, 18 (47%) were in <5% of samples, and 4 (11%) in ≥5% of the samples. We observed an association between the detection of fenitrothion in meconium and the risk of hypospadias (OR = 2.6 [1.0-6.3] with n cases = 13, n controls = 21), but not the other pesticides. CONCLUSIONS: Our small study provides a robust assessment of fetal exposure. Fenitrothion's established antiandrogenic activities provide biologic plausibility for our observations. Further studies are needed to confirm this hypothesis.

Prenatal exposure to persistent organic pollutants and molar-incisor hypomineralization among 12-year-old children in the French mother-child cohort PELAGIE.

BACKGROUND: Exceptional episodes of exposure to high levels of persistent organic pollutants have already been associated with developmental defects of enamel among children, but knowledge is still scarce concerning the contribution of background levels of environmental contamination. METHODS: Children of the French PELAGIE mother-child cohort were followed from birth, with collection of medical data and cord blood samples that were used to measure polychlorinated biphenyls (PCBs), organochlorine pesticides (OCs), and perfluorinated alkyl substances (PFASs). At 12 years of age, molar-incisor hypomineralization (MIH) and other enamel defects (EDs) were recorded for 498 children. Associations were studied using logistic regression models adjusted for potential prenatal confounders. RESULTS: An increasing log-concentration of ß-HCH was associated with a reduced risk of MIH and EDs (OR = 0.55; 95% CI, 0.32-0.95, and OR = 0.65; 95% CI, 0.43-0.98, respectively). Among girls, intermediate levels of p,p'-DDE were associated with a reduced risk of MIH. Among boys, we observed an increased risk of EDs in association with intermediate levels of PCB 138, PCB 153, PCB 187, and an increased risk of MIH with intermediate levels of PFOA and PFOS. CONCLUSIONS: Two OCs were associated with a reduced risk of dental defects, whereas the associations between PCBs and PFASs and EDs or MIH were generally close to null or sex-specific, with an increased risk of dental defects in boys. These results suggest that POPs could impact amelogenesis. Replication of this study is required and the possible underlying mechanisms need to be explored.

Use and storage of pesticides at home in France (the Pesti'home survey 2014).

Some epidemiological studies have raised health concerns following the chronic exposure of pregnant women and children to pesticides in the domestic environment. In France very little is known about potential exposure to pesticides at home. An observational study called Pesti'home was carried out in continental France between July and November 2014. The residential use of pesticides was investigated and an inventory of pesticides and active ingredients used and stored at home was drawn up. Plant protection products, biocides, and human and animal external pest control products were listed during face-to-face interviews. A random sample of households including at least one adult (18-79 years old) was selected following a two-stage stratified random sampling method using the national census database. Within each household, an adult was appointed to answer survey questions. Data related to the interviewee's sociodemographic and housing characteristics, the reported use of pesticides at home, and a visual inventory of all stored pesticides were collected. Overall, 1507 households participated. The participation rate was between 36% and 57% according to the definition chosen. Over the previous 12 months, 75% of households declared that they had used at least one pesticide. Households who used and stored at least one product most frequently used an insecticide (84%). The active ingredients most frequently used by these households as insecticides were pyrethroids, namely tetramethrin and permethrin. The Pesti'home survey collected detailed data on the residential use of pesticides for risk assessment at national and European levels.

Prenatal exposure to organophosphate pesticides and autism spectrum disorders in 11-year-old children in the French PELAGIE cohort.

BACKGROUND: Organophosphate (OP) pesticides act by inhibiting acetylcholinesterase activity at synaptic junctions and have already been linked with deleterious effects on neurodevelopment, including autism spectrum disorders (ASD). OBJECTIVES: To investigate the association of prenatal exposure to OP pesticides with traits related to ASD in 11-year-old children. METHODS: The "Childhood Autism Spectrum Test" (CAST) parent questionnaire was used to screen for autistic traits in 792 children from the French PELAGIE cohort. Prenatal maternal urine samples were collected <19 weeks of gestation in which metabolites of organophosphate insecticides were assessed for 185 of them. Negative binomial regression models were performed to explore the association between the CAST score and 8 groups of urine components, adjusted for potential ASD risk factors. RESULTS: In these urine samples, dialkylphosphates (DAP) were detected most often (>80%), terbufos and its metabolites least often (<10%). No association with ASD was found for DAP, terbufos or its metabolites. Incidence rate ratios (IRRs) increased with maternal urinary diazinon concentrations, from 1.11 (95% CI: 0.87-1.42) to 1.17 (95% CI: 0.94-1.46). Higher CAST scores were statistically significantly associated with the maternal urine samples in which chlorpyrifos or two of its metabolites (chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol) were detected. The IRR for exposure to chlorpyrifos or chlorpyrifos-oxon was 1.27 (95%CI: 1.05-1.52) among all children, and 1.39 (95%CI: 1.07-1.82) among boys. CONCLUSION: These findings suggest an increase in autistic traits among 11-year-old children in association with prenatal maternal exposure to chlorpyrifos and possibly diazinon. These associations were previously suspected in the literature, in particular for chlorpyrifos. Further work establishing the causal mechanisms behind these risk association is needed.

Prenatal exposure to pesticides and risk of preeclampsia among pregnant women: Results from the ELFE cohort.

BACKGROUND: Preeclampsia is a pregnancy-specific syndrome caused by abnormal placentation. Although environmental chemicals, including some pesticides, are suspected of impairing placentation and promoting preeclampsia, its relationship with preeclampsia has been insufficiently explored. OBJECTIVES: We aimed to investigate the relation between non-occupational exposure to pesticides during pregnancy and the risk of preeclampsia. METHODS: The study cohort comprised 195 women with and 17,181 without preeclampsia from the ELFE birth cohort. We used toxicogenomic approaches to select 41 pesticides of interest for their possible influence on preeclampsia. We assessed household pesticide use (self-reported data), environmental exposure to agricultural pesticides (geographic information systems), and dietary exposure (food-frequency questionnaire with data from monitoring pesticide residues in food and water). Dietary exposures to pesticides were grouped into clusters of similar exposures to resolve collinearity issues. For each exposure source, pesticides were mutually adjusted, and odds ratios estimated with logistic regression models. RESULTS: The quantity of prochloraz applied within a kilometer of the women's homes was higher in women with than without preeclampsia (fourth quartile vs. others; adjusted odds ratio [aOR] = 1.54; 95%CI: 1.02, 2.35), especially when preeclampsia was diagnosed before 34 weeks of gestation (aOR = 2.25; 95%CI: 1.01, 5.06). The reverse was observed with nearby cypermethrin application (aOR = 0.59, 95%CI: 0.36, 0.96). In sensitivity analyses, women with preeclampsia receiving antihypertensive treatment had a significantly higher probability of using herbicides at home during pregnancy than women without preeclampsia (aOR = 2.20; 95%CI: 1.23, 3.93). No statistically significant association was found between dietary exposure to pesticide residues and preeclampsia. DISCUSSION: While the most of the associations examined remained statistically non-significant, our results suggest the possible influence on preeclampsia of residential exposures to prochloraz and some herbicides. These estimations are supported by toxicological and mechanistic data.

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

BACKGROUND: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. METHODS AND FINDINGS: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. CONCLUSIONS: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.

Multiple pesticides in mothers' hair samples and children's measurements at birth: Results from the French national birth cohort (ELFE).

BACKGROUND: A growing body of studies now suggests that the general population is continuously and ubiquitously exposed to numerous pesticides. However, studies investigating the possible role of environmental exposure to pesticides on fetal growth have focused on a limited set of substances, despite the hundreds of modern pesticides currently available. AIM: To explore the relation between maternal hair concentrations of 64 pesticides and metabolites and their newborns' measurements at birth, with data from the ELFE French nationwide birth cohort. METHODS: We measured 64 compounds (10-100% detection) in bundles of hair 9 cm long collected at birth from 311 women who gave birth in France in 2011. We assessed their associations with birth weight, length, and head circumference, adjusted for potential confounders, and used elastic net regularization to simultaneously select the strongest predictors of measurements at birth. Selected variables were multiply imputed for missing values, and unpenalized estimators were assessed by standard linear regression. RESULTS: We observed statistically significant associations between maternal hair concentrations of seven pesticides or pesticide metabolites and birth measurements (weight: fipronil sulfone; length: TCPy, bitertanol, DEP, and isoproturon; head circumference: tebuconazole and prochloraz). Analyses restricted to boys identified 12 additional compounds: 8 independently associated with birth weight (3Me4NP, DCPMU, DMST, fipronil, mecoprop, propoxur, fenhexamid, and thiabendazole), 2 with birth length (dieldrin and ß-endosulfan), and 6 with head circumference (ß-endosulfan, ß-HCH, fenuron, DCPMU, propoxur, and thiabendazole). CONCLUSION: Our results suggest that prenatal exposure to 19 pesticides or metabolites from various chemical families may influence measurements at birth. As with any exploratory research findings, results should be interpreted cautiously, until they are replicated or verified by further epidemiological or mechanistic studies.

Correction to: Occupational exposure to organic solvents during pregnancy and childhood behavior: findings from the PELAGIE birth cohort (France, 2002-2013).

Following publication of the original article [1], the author asked to replace Table 2 with the correct version.

Pesticides and Child's Health in France.

PURPOSE OF REVIEW: The use of pesticides is predominant in agriculture, inducing environmental contamination, and has been extended to the domestic sphere. In France, > 500 pesticides were authorized for use in 2009; given their various toxicological properties, there are legitimate concerns about the possible consequences for child health. This review summarizes the recent French studies of good quality dealing with pesticides and child health. RECENT FINDINGS: Three cohorts (mother-child, retrospective) and two case-control studies have been conducted in the last decade. Using various instruments for exposure assessment including biomarkers, they have suggested alterations of subclinical health parameters at birth, increased risk of otitis at age 2, and increased risk of several types of childhood cancer. However, there were no adverse neurodevelopmental outcomes at 6 years of age following prenatal exposure to pesticides. Both agricultural and domestic pesticides might be involved in such adverse health outcomes. Similar studies are lacking in Europe. Studies on fungicides and child health are scarce.

Occupational exposure to organic solvents during pregnancy and childhood behavior: findings from the PELAGIE birth cohort (France, 2002-2013).

BACKGROUND: Numerous industries use organic solvents, and many workers from various occupational sectors are exposed to these known neurotoxicants, including pregnant women. Our objective is to explore whether occupational exposure of pregnant women to solvents may impair the neurodevelopment of their babies and consequently affect their behavior in childhood. METHODS: Within the French birth cohort PELAGIE, parents assessed their children's internalizing and externalizing behaviors using items from the Child Behavior Checklist and the Preschool Social Behavior Questionnaire at age 2, and the Strength and Difficulties Questionnaire at age 6. The occupational exposure to solvents of the pregnant women was self-reported prospectively at the beginning of their pregnancy (N = 715). We applied structural equation modeling to capture the longitudinal association of prenatal exposure to solvents with children's behavioral traits at 2 and 6 years. RESULTS: Increased externalizing behavior score at age 2 was associated with prenatal exposure to solvents (standardized score: 0.34 (95% CI = 0.11, 0.57) for occasional exposure and 0.26 (0.05, 0.48) for regular exposure). This association was attenuated at age 6 (0.22 (- 0.02, 0.47) for occasional exposure and 0.07 (- 0.14, 0.28) for regular exposure). No association was observed for internalizing behavior. CONCLUSIONS: Pregnant women's occupational exposure to solvents may affect their children's behavior in early childhood. This effect may be attenuated with aging or diluted by the effects of other postnatal predictors.

Impairment of learning and memory performances induced by BPA: Evidences from the literature of a MoA mediated through an ED.

Many rodent studies and a few non-human primate data report impairments of spatial and non-spatial memory induced by exposure to bisphenol A (BPA), which are associated with neural modifications, particularly in processes involved in synaptic plasticity. BPA-induced alterations involve disruption of the estrogenic pathway as established by reversal of BPA-induced effects with estrogenic receptor antagonist or by interference of BPA with administered estradiol in ovariectomized animals. Sex differences in hormonal impregnation during critical periods of development and their influence on maturation of learning and memory processes may explain the sexual dimorphism observed in BPA-induced effects in some studies. Altogether, these data highly support the plausibility that alteration of learning and memory and synaptic plasticity by BPA is essentially mediated by disturbance of the estrogenic pathways. As memory function in humans involves similar signaling pathways, this mode of action of BPA has the potential to alter human cognitive abilities.

Prenatal exposure to endocrine disrupting chemicals and risk of being born small for gestational age: Pooled analysis of seven European birth cohorts.

BACKGROUND AND AIMS: There is evidence that endocrine disrupting chemicals (EDCs) have developmental effects at environmental concentrations. We investigated whether some EDCs are associated with the adverse birth outcome Small for Gestational Age (SGA). METHODS: We used PCB 153, p,p'-DDE, HCB, PFOS and PFOA measured in maternal, cord blood or breast milk samples of 5446 mother-child pairs (subset of 693 for the perfluorinated compounds) from seven European birth cohorts (1997-2012). SGA infants were those with birth weight below the 10th percentile for the norms defined by gestational age, country and infant's sex. We modelled the association between measured or estimated cord serum EDC concentrations and SGA using multiple logistic regression analyses. We explored effect modification by child's sex and maternal smoking during pregnancy. RESULTS: Among the 5446 newborns, 570 (10.5%) were SGA. An interquartile range (IQR) increase in PCB 153 was associated with a modestly increased risk of SGA (odds ratio (OR) of 1.05 [95% CI: 1.04-1.07]) that was stronger in girls (OR of 1.09 [95% CI: 1.04-1.14]) than in boys (OR of 1.03 [95% CI: 1.03-1.04]) (p-interaction = 0.025). For HCB, we found a modestly increased odds of SGA in girls (OR of 1.04 [95% CI: 1.01-1.07] per IQR increase), and an inverse association in boys (OR of 0.90 [95% CI: 0.85-0.95]) (p-interaction = 0.0003). Assessment of the HCB-sex-smoking interaction suggested that the increased odds of SGA associated with HCB exposure was only in girls of smoking mothers (OR of 1.18 [95% CI: 1.11-1.25]) (p-interaction = 0.055). Higher concentrations of PFOA were associated with greater risk of SGA (OR of 1.64 [95% CI: 0.97-2.76]). Elevated PFOS levels were associated with increased odds of SGA in newborns of mothers who smoked during pregnancy (OR of 1.63 [95% CI: 1.02-2.59]), while an inverse association was found in those of non-smoking mothers (OR of 0.66 [95% CI: 0.61-0.72]) (p-interaction = 0.0004). No significant associations were found for p,p'-DDE. CONCLUSIONS: Prenatal environmental exposure to organochlorine and perfluorinated compounds with endocrine disrupting properties may contribute to the prevalence of SGA. We found indication of effect modification by child's sex and smoking during pregnancy. The direction of the associations differed by chemical and these effect modifiers, suggesting diverse mechanisms of action and biological pathways.

Prenatal exposure to persistent organic pollutants and organophosphate pesticides, and markers of glucose metabolism at birth.

BACKGROUND: Experimental evidence suggests that developmental exposure to persistent organic pollutants (POP) and to some non persistent pesticides may disrupt metabolic regulation of glucose metabolism and insulin secretion, and thereby contribute to the current epidemic of obesity and metabolic disorders. Quasi-experimental situations of undernutrition in utero have provided some information. However, the evidence in humans concerning the role of the prenatal environment in these disorders is contradictory, and little is known about long-term outcomes, such as type 2 diabetes, of prenatal exposure. OBJECTIVES: Our aim was to evaluate the effects of prenatal exposure to POP and organophosphate pesticides on fetal markers of glucose metabolism in a sample of newborns from the Pelagie mother-child cohort in Brittany (France). METHODS: Dialkylphosphate (DAP) metabolites of organophosphate pesticides were measured in maternal urine collected at the beginning of pregnancy. Cord blood was assayed for polychlorinated biphenyl congener 153 (PCB153), p,p'-dichlorodiphenyl dichloroethene (DDE) and other POP. Insulin and adiponectin were determined in cord blood serum (n=268). RESULTS: A decrease in adiponectin and insulin levels was observed with increasing levels of DDE, but only in girls and not boys. Adiponectin levels were not related to the concentrations of other POP or DAP metabolites. Decreasing insulin levels were observed with increasing PCB153 concentrations. Insulin levels increased with DAP urinary levels. Additional adjustment for BMI z-score at birth modified some of these relations. CONCLUSIONS: Our observations bring support for a potential role of organophosphate pesticides and POP in alterations to glucose metabolism observable at birth.

Concentration and determinants of molds and allergens in indoor air and house dust of French dwellings.

Molds and allergens are common indoor biocontaminants. The aims of this study were to assess the concentrations of common molds in indoor air and floor dust and the concentrations of house dust mite, cat and dog allergens in mattress dust in French dwellings, and to assess predictors of these concentrations. A sample of 150 houses in Brittany (western France) was investigated. Airborne Cladosporium and Penicillium were detected in more than 90% of the dwellings, Aspergillus in 46% and Alternaria in only 6% of the housings. Regarding floor dust samples, Cladosporium and Penicillium were detected in 92 and 80% of the housings respectively, Aspergillus in 49% and Alternaria in 14%. House dust mite allergens Der p1 and Der f1 were detected in 90% and 77% of the mattress dust samples respectively and Can f1 and Fel d1 in 37% and 89% of the homes. Airborne and dustborne mold concentrations, although not statistically correlated (except for Aspergillus) shared most of their predictors. Multivariate linear models for mold levels, explaining up to 62% of the variability, showed an influence of the season, of the age of the dwelling, of aeration habits, presence of pets, smoking, signals of dampness, temperature and relative humidity. Allergens in the dust of the mattress were strongly related to the presence of pets and cleaning practices of bedsheets, these factors accounting for 60% of the variability. This study highlights ubiquitous contamination by molds and underlines complex interaction between outdoor and indoor sources and factors.

Prenatal exposure to PCB-153, p,p'-DDE and birth outcomes in 9000 mother-child pairs: exposure-response relationship and effect modifiers.

Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p'-DDE) can impair fetal growth; however, the exposure-response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure-response relationship between PCB-153 and p-p'-DDE and birth outcomes; to evaluate whether any no exposure-effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother-child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure-response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194g (95% CI -314, -74) per 1µg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure-response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association.

Can a deprivation index be used legitimately over both urban and rural areas?

BACKGROUND: Although widely used, area-based deprivation indices remain sensitive to urban-rural differences as such indices are usually standardised around typical urban values. There is, therefore, a need to determine to what extent available deprivation indices can be used legitimately over both urban and rural areas. METHODS: This study was carried out in Brittany, France, a relatively affluent region that contains deep rural areas. Among the 1,736 residential census block groups (IRIS) composing the Brittany region, 1,005 (57.9%) are rural. Four deprivation indices were calculated: two scores (Carstairs and Townsend) developed in the UK and two more recent French measures (Havard and Rey). Two standardisation levels were considered: all of the IRIS and only the urban IRIS of the region. Internal validity (Kappa coefficients and entropy values) and external validity (relationship with colorectal cancer screening [CCS] attendance) were investigated. RESULTS: Regardless of the deprivation measure used, wealthy areas are mostly clustered in the West and at the outskirts of major towns. Carstairs and Rey scores stand out by all evaluation criteria, capturing both urban and rural deprivation. High levels of agreements were found across standardisation levels (κ = 0.96). The distributions of deprivation scores were balanced across urban and rural areas, and high Shannon entropy values were observed in the capital city (≥0.93). Similar and significant negative trends were observed between CCS attendance and both deprivation indices, independent of the degree of urbanisation. CONCLUSIONS: These results provide support, despite potential sociological objections, for the use of a compromise index that would facilitate comparisons and interpretations across urban and rural locations in public health research.

Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent.

CONTEXT: Masculinization depends on the fetal testis. Exposure of the human fetus during pregnancy to paracetamol and/or to other mild analgesics is associated with an increased risk of cryptorchidism. OBJECTIVE: We aimed to determine whether mild analgesics disrupted the morphology and endocrine function of the human testis. DESIGN: We used an in vitro system based on the culture of human fetal testes exposed or not to paracetamol, its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404), aspirin, indomethacin, and ketoconazole at 10(-4) to 10(-7) M. SETTING: The study was conducted at the University of Rennes I. PATIENTS/PARTICIPANTS: Human fetal testes were from pregnant women after induced abortion, between 7 and 12 weeks of gestation (GW). MAIN OUTCOME MEASURES: Testosterone (RIA), anti-Müllerian hormone (ELISA), insulin-like factor 3 (RIA), and prostaglandin (PG) D2 and PGE2 (ELISA) were assayed in the medium. Testicular cells were counted using histology and image analysis. The possible nuclear receptor-mediated activities of the analgesics were investigated using reporter cell lines expressing estrogen, androgen, and peroxisome proliferator-activated γ receptors. RESULTS: Indomethacin and aspirin stimulated testosterone production, particularly by the younger testes (8-9 GW vs 10-12 GW). Paracetamol, AM404, and ketoconazole decreased insulin-like factor 3 levels. Aspirin stimulated whereas ketoconazole inhibited AMH production. PGE2 levels were inhibited by paracetamol and aspirin in the 7 to 12 GW testes and by indomethacin but only in 7 to 9.86 GW testes. The inhibitory trends seen for PGD2 were not statistically significant. CONCLUSIONS: Analgesics at concentrations relevant to human exposure cause endocrine disturbances in the fetal testis. We suggest that the fetal human testis displays slight critical age windows for sensitivity to direct exposure to aspirin, indomethacin, and paracetamol. The analgesic-induced inhibition of INSL3 may be the mechanism by which analgesics increase the risk of cryptorchidism. Greater caution is required concerning consumption of analgesics during pregnancy.

Urinary glycol ether metabolites in women and time to pregnancy: the PELAGIE cohort.

BACKGROUND: Glycol ethers are present in a wide range of occupational and domestic products. Animal studies have suggested that some of them may affect ovarian function. OBJECTIVE: We examined the relation between women's exposure to glycol ethers and time to pregnancy. METHODS: We used chromatography coupled to mass spectrometry to measure eight glycol ether metabolites in urine samples from randomly selected women in the PELAGIE mother-child cohort who had samples collected before 19 weeks of gestation. Using time to pregnancy information collected at the beginning of the pregnancy (women were asked how many months it took for them to conceive), we estimated associations between metabolite levels and time to pregnancy in 519 women with complete data using discrete-time Cox proportional hazards models to adjust for potential confounders. RESULTS: We detected glycol ether metabolites in 6% (for ethoxyacetic acid) to 93% (for phenoxyacetic and butoxyacetic acids) of urine samples. Phenoxyacetic acid was the only metabolite with a statistically significant association with longer time to pregnancy [fecundability OR = 0.82; 95% CI: 0.63, 1.06 for the second and third quartile combined; fecundability OR = 0.70; 95% CI: 0.52, 0.95 for a fourth-quartile (≥ 1.38 mg/L) vs. first-quartile concentration (< 0.14 mg/L)]. This association remained stable after multiple sensitivity analyses. CONCLUSION: Phenoxyacetic acid, which was present in most of the urine samples tested in our study, was associated with increased time to pregnancy. This metabolite and its main parent compound, 2-phenoxyethanol, are plausible causes of decreased fecundability, but they may also be surrogates for potential coexposures to compounds frequently present in cosmetics.

Folic acid supplementation use and the MTHFR C677T polymorphism in orofacial clefts etiology: An individual participant data pooled-analysis.

BACKGROUND: This study examines gene-environment interaction between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled-analytical approach on four studies that used similar methods. METHODS: We used logistic regression to analyze the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non-syndromic clefts lip or without cleft palate (CL(P)) and non-syndromic cleft palate (CP)] and control groups. RESULTS: There was a reduced risk of CL(P) with maternal folic acid use (p = 0.008; OR = 0.70, 95% CI: 0.65-0.94) and with supplements containing folic acid (p = 0.028, OR = 0.80, 95% CI: 0.65-0.94). Maternal smoking increased the risk of both CL(P) (p < 10 e-3; OR = 1.62, 95% CI: 1.35-1.95) and CP (p = 0.028; OR = 1.38, 95% CI: 1.04-1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes. CONCLUSION: This individual participant data (IPD) meta-analysis affords greater statistical power and can help alleviate the problems associated with aggregate-level data-sharing. The result of this IPD meta-analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes.