Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment

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.

GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms

“…Consistent with this idea, it is well-established that NMDAR expression and function are modulated by experience and various environmental factors, including developmental neurotoxins and some therapeutics (Neal et al, 2011;Wills et al, 2012;Alavian-Ghavanini et al, 2018;Repouskou et al, 2020;Engdahl et al, 2021a;Sheng et al, 2022). In addition, GRIN2B is a target for epigenetic control (Rodenas-Ruano et al, 2012;Gulchina et al, 2017;Alavian-Ghavanini et al, 2018;Loureiro et al, 2020;Engdahl et al, 2021a,b;Sheng et al, 2022). It is unclear the extent to which gene × environment interactions determine the symptomatic profile of this disease, but this will be an important avenue for future investigation.…”

Polluants in materials of everyday life and neurodevelopment in children

“…Dans la descendance des souris soumises pendant la gestation à une exposition aux perturbateurs endocriniens (BPA, phtalates, pesticides), équivalente à celle d'une cohorte de naissance suédoise, des altérations long terme dans les comportements sont observées avec modification de l'expression de gènes du cerveau. Des altérations similaires du comportement chez le male et la femelle peuvent avoir néanmoins des mécanismes moléculaires et biochimiques sousjacents différents (75).…”

Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

“…Benzyl butyl phthalate (BBP) was also reported to modulate the serotoninergic system in the brain of Fundulus heteroclitus (mummichog) [40]. Interestingly, a recent study that better mimics the real-life situation demonstrated that administration of a mixture of phthalates, pesticides, and BPA to mice throughout gestation modified serotonin receptor subtypes 1A and 2A expression in the limbic system of adult offspring animals [41]. These two serotonin receptor subtypes were known to be involved in emotionality and stress coping strategies [42].…”