Abstract
Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0×, 0.5×, 10×, 100× and 500× the geometric mean of SELMA mothers’ concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.
Highlights
Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions
From the plethora of potentially implicated genes we favoured genes related to the Hypothalamic Pituitary Adrenal (HPA) axis function since it interferes with the aforementioned behaviors and because we[28,29,30] and others[31,32,33] have previously shown that it is impacted by early-life exposures to EDCs, such as bisphenol A (BPA), a chemical included in mixture N1
Emotionality and stress coping strategy is fine-tuned by the serotonin receptors HTR1a and 2a43, while the glutamate receptor subunit GRIN2b is implicated in EDC-mediated neurotoxicity and neurodevelopmental disorders in children including language, motor and learning deficits, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD)[44,45]
Summary
Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions. From the plethora of potentially implicated genes we favoured genes related to the Hypothalamic Pituitary Adrenal (HPA) axis function since it interferes with the aforementioned behaviors and because we[28,29,30] and others[31,32,33] have previously shown that it is impacted by early-life exposures to EDCs, such as BPA, a chemical included in mixture N1. Due to the plasticity of the limbic system to new experiences, the mixture effect on gene expression was examined in matched siblings a) under basal conditions and b) following the behavioral tests, in order to further investigate the potential impact of in utero exposure to mixture N1 on the new-experience-induced brain plasticity. Both sexes were included in our study in order to detect any sex-specific effects of mixture N1 exposure on behavior and brain gene expression
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