In utero exposure to endocrine-disrupting chemicals, maternal factors and alterations in the epigenetic landscape underlying later-life health effects.

Widespread persistence of endocrine-disrupting chemicals (EDCs) in the environment has mandated the need to study their potential effects on an individual's long-term health after both acute and chronic exposure periods. In this review article a particular focus is given on in utero exposure to EDCs in rodent models which resulted in altered epigenetic programming and transgenerational effects in the offspring causing disrupted reproductive and metabolic phenotypes. The literature to date establishes the impact of transgenerational effects of EDCs potentially associated with epigenetic mediated mechanisms. Therefore, this review aims to provide a comprehensive overview of epigenetic programming and it's regulation in mammals, primarily focusing on the epigenetic plasticity and susceptibility to exogenous hormone active chemicals during the early developmental period. Further, we have also in depth discussed the epigenetic alterations associated with the exposure to selected EDCs such as Bisphenol A (BPA), di-2-ethylhexyl phthalate (DEHP) and vinclozlin upon in utero exposure especially in rodent models.

In utero exposure to endocrine disruptors and developmental neurotoxicity: Implications for behavioural and neurological disorders in adult life.

Endocrine disrupting chemicals (EDCs) are a class of environmental toxicants that interfere with the endocrine system, resulting in developmental malformations, reproductive disorders, and alterations to immune and nervous system function. The emergence of screening studies identifying these chemicals in fetal developmental matrices such as maternal blood, placenta and amniotic fluid has steered research focus towards elucidation of in utero effects of exposure to these chemicals, as their capacity to cross the placenta and reach the fetus was established. The presence of EDCs, a majority of which are estrogen mimics, in the fetal environment during early development could potentially affect neurodevelopment, with implications for behavioural and neurological disorders in adult life. This review summarizes studies in animal models and human cohorts that aim to elucidate mechanisms of action of EDCs in the context of neurodevelopment and disease risk in adult life. This is a significant area of study as early brain development is heavily mediated by estrogen and could be particularly sensitive to EDC exposure. A network analysis presented using genes summarized in this review, further show a significant association with disorders such as major depressive disorder, alcoholic disorder, psychotic disorders and autism spectrum disorder. Functional outcomes such as alterations in memory, behaviour, cognition, learning memory, feeding behaviour and regulation of ion transport are also highlighted. Interactions between genes, receptors and signaling pathways like NMDA glutamate receptor activity, 5-hydroxytryptamine receptor activity, Ras-activated Ca2+ influx and Grin2A interactions, provide further potential mechanisms of action of EDCs in mediating brain function. Taken together with the growing pool of human and animal studies, this review summarizes current status of EDC neurotoxicity research, limitations and future directions of study for researchers.

Prenatal bisphenol-A exposure altered exploratory and anxiety-like behaviour and induced non-monotonic, sex-specific changes in the cortical expression of CYP19A1, BDNF and intracellular signaling proteins in F1 rats.

Bisphenol-A (BPA) is one of the extensively studied estrogenic endocrine disrupting chemicals (EDC) with ubiquitous exposure among humans and wildlife. While there are literature reporting the association of dysregulated Brain-derived neurotrophic factor (BDNF) expression levels with altered cognitive and emotional behaviour such as anxiety-like and stress behaviour in animal models, there are no studies in BPA that investigate these altered neurobehavioural outcomes in parallel with the expression of intracellular proteins involved in BDNF signaling pathway. In this study, pregnant Wistar rats were exposed to BPA through water (25 µg/L, 250 µg/L, and 2.5 mg/L) during gestation day (GD) 9-21. Prenatal BPA exposure, increased anxiety-like behaviour in males and decreased exploratory behaviour in both male and female offspring. Downregulation of both BDNF and CYP19A1 genes were observed in male BPA-exposed offspring, whereas in females, the expression was upregulated. The expression of p-AKT, p-MEK and p-ERK proteins were increased in males, while in females, it decreased. Both the male and the female BPA-exposed offspring exhibited elevated levels of DNMT1 protein. The sex-specific alteration in the expression of CYP19A1 and DNA methyltransferase 1 (DNMT1) suggests that both hormonal and epigenetic dysregulation could underlie the long-term BPA-induced effect on anxiety-like behaviour in the offspring.