Exposure to Endocrine Disruptors during early life and child Neurodevelopment: the role of the hypothalamic–pituitary–adrenal axis – EDeN

We will rely on the SEPAGES mother-child cohort that enrolled 484 pregnant women between 2014 and 2017 from ultrasound practices located in Grenoble. We assessed exposure to 12 phenols and 14 phthalates by measuring their biomarkers in urine samples collected during pregnancy (1st and 3rd trimester) and the first year of life (6 weeks and 1 year). We rely on repeated urine samples (42 per participants during pregnancy and 14 during the 1st year of life) to precisely assess exposure, strongly limit measurement error and increase power (for a given sample size) compared to former studies using only one spot sample. The panel of chemicals assessed will include a non-phthalate plasticizer (1,2-Cyclohexane dicarboxylic acid, diisononyl ester, DICNH®), along with bisphenol S, AF, B, F. These compounds are used as substitute of several phthalates and bisphenol A and, to date, no data document levels of exposure in France nor allow to test their potential effects on child neurodevelopment. Child neurodevelopment is evaluated by validated questionnaires and clinical assessments performed by trained clinicians. Eye-tracking tasks are also performed allowing to objectively and precisely assess visual attention, infant’s reaction time and oculomotor control development. Maternal cortisol, the glucocorticoids end-product of the HPA axis, will be assessed in maternal hair collected at delivery. We will perform mediation analysis to examine whether the associations observed between prenatal exposure to phenols, phthalates and child neurodevelopment scores could be partly explained by changes in the chronic cortisol secretion during pregnancy.

The project is ongoing. Only one paper aiming at comparing different designs to pool repeated urine samples has been published so far.

This original project based on a well-defined cohort and validated tools will provide innovative results on the sensitivity to emerging environmental factors of a set of subclinical scores related to child neurodevelopment and on underlying biological pathways. Results of the EDeN project could lead to stricter regulation of phthalate and phenol usages in consumer products and to reduced exposure to these compounds in the general population.

Comparison of strategies to efficiently combine repeated urine samples in biomarker-based studies. Philippat C, Calafat AM.Environ Res. 2021 Jan;192:110275. doi: 10.1016/j.envres.2020.110275.

Child neurodevelopmental disorders usually emerge during childhood, persist into adulthood and are associated with lifelong functional impairments. Annual cost of child neurodevelopment disorders has been evaluated at 21€ billion in Europe, making the identification of modifiable risk factors a priority target for public health. In addition to genetic factors known to be important risk factors, exposure to pollutants during critical periods for brain development might be involved. Objectives of the EDeN (Endrocrine Disruptors and Neurodevelopment) project are to test whether early exposure to endocrine disruptors with widespread exposure in the general population (phenols and phthalates) is associated with child neurodevelopment (cognition and dysregulated behaviour) and maternal cortisol (a marker of the hypothalamic–pituitary–adrenal (HPA) functioning). Another aim is to characterize whether disruption of HPA axis can partly explain (i.e., mediate) the associations observed with neurodevelopment. We will rely on the SEPAGES mother-child cohort that enrolled 484 pregnant women between 2014 and 2017 from ultrasound practices located in Grenoble. We assess exposure to 12 phenols and 14 phthalates by measuring their biomarkers in urine samples collected during pregnancy (1st and 3rd trimester) and the first year of life (6 weeks and 1 year). We rely on repeated urine samples (42 per participants during pregnancy and 14 during the 1st year of life) to precisely assess exposure, strongly limit measurement error and increase power (for a given sample size) compared to former studies using only one spot sample. The panel of chemicals assessed include a non-phthalate plasticizer (1,2-Cyclohexane dicarboxylic acid, diisononyl ester, DICNH), along with bisphenol S, AF, B, F. These compounds are used as substitute of several phthalates and bisphenol A and, to date, no data document levels of exposure in France nor allow to test their potential effects on child neurodevelopment. Child neurodevelopment is evaluated by validated questionnaires and clinical assessments performed by trained clinicians. Eye-tracking tasks are also performed allowing to objectively and precisely assess visual attention, infant’s reaction time and oculomotor control development. Maternal cortisol, the glucocorticoids end-product of the HPA axis, will be assessed in maternal hair collected at delivery. We will perform mediation analyses to examine whether the associations observed between prenatal exposure to phenols, phthalates and child neurodevelopment scores could be partly explained by changes in the chronic cortisol secretion during pregnancy. Risks for this project are limited. Biological material needed to assess cortisol, phenols and phthalates has been already collected. Assessments of child neurodevelopment at 2 and 3 years are ongoing. These follow-ups will end in 2020. At 3 years participation rate is 80% and our sample size lead to a power of 0.89 to detect a variation of 2 points on the total IQ score for the chemicals studied. Strengths of the project are exposure assessment (relying on repeat urine samples and thus limiting measurement error) during critical periods for brain development (pregnancy and first year of life), the good characterization of child neurodevelopment (clinical exams, eye tracking) and the assessment of up to 25 endocrine disruptors, allowing to study cocktail effects. We will be the first providing data on the potential effect of bisphenol A and di-2-ethylhexyl phthalate substitutes. This original project based on a well-defined cohort and validated tools will provide innovative results on the sensitivity to emerging environmental factors of a set of subclinical scores related to child neurodevelopment and on underlying biological pathways. Results of the project could lead to stricter regulation of phthalate and phenol usages in consumer products and to reduced exposure to these compounds in the general population.