The estrogen-mimicking endocrine disrupter bisphenol A (BPA) which is used in the manufacture of plastic and epoxy resins, is one of the world's most heavily produced synthetic chemicals. BPA is detected in animal tissues, and its bio-accumulation has shown to be higher in the fetus than the mother. Exposure to doses below the daily safe limit has been reported to affect the sexual differentiation of the brain and modify the behavior of the exposed rodent offspring. The aim of the present study was to investigate in the rat the possible organizational effects of low BPA exposure on glucocorticoid-regulated responses. Female breeders were exposed to 40 microg/kg b.w. BPA daily throughout pregnancy and lactation. Plasma corticosterone levels and the two types of hippocampal corticosteroid receptors (GR and MR) were determined in mid-adolescent offspring under basal conditions and following a Y-maze task. BPA treated females had higher corticosterone levels than control females and BPA males and lower GR levels than BPA males, under basal conditions. Following the mildly stressful experience of Y-maze, corticosterone levels were increased in BPA-treated animals of both sexes, compared to the controls. GR levels were also increased in BPA-treated females compared to males. No effect of BPA was observed on MR levels, whereas the Y-maze experience significantly decreased receptors' levels in both female groups. The animals' performance in the task was also evaluated. BPA exposure significantly impaired the spatial recognition memory in both sexes, and modified the behavioural coping in a sex-dependent manner. Female BPA-treated offspring exhibited increased "anxiety-like" behaviour and dramatic loss of exploration attitude during the task, in comparison to males. This study provides for the first time evidence that corticosterone and its actions in the brain are sensitive to the programming effects of BPA at a dose below the currently acceptable daily intake.
"A number of reports have shown that BPA developmental exposure strongly affects anxiety-related behaviors in rodents, often blunting or reversing the normal dimorphic response in classical anxiety tests such as the elevated plus maze (Patisaul and Bateman 2008; Rubin et al. 2006) and the exploration in open-field (Gioiosa et al. 2007; Kubo et al. 2003). Notably, the increased anxiety shown by exposed females in exploratory tests goes in parallel to higher basal and stress-stimulated corticosterone levels (Poimenova et al. 2010). Taken as a whole, it appears from these and other behavioral evidences (see Wolstenholme et al. 2011 for references) that BPA might affect anxiety either interfering with the estrogen-induced sexual differentiation of the brain or via alteration of the HPA axis. "
[Show abstract][Hide abstract] ABSTRACT: Brain development is an organized, but constantly adaptive, process in which genetic and epigenetic signals allow neurons to differentiate, to migrate, and to develop correct connections. Gender specific prenatal sex hormone milieu participates in the dimorphic development of many neuronal networks. Environmental cues may interfere with these developmental programs, producing adverse outcomes. Bisphenol A (BPA), an estrogenic/antiandrogenic endocrine disruptor widely diffused in the environment, produces adverse effects at levels below the acceptable daily intake. This review analyzes the recent literature on the consequences of perinatal exposure to BPA environmental doses on the development of a dimorphic brain. The BPA interference with the development and function of the neuroendocrine hypothalamus and of the nuclei controlling energy balance, and with the hippocampal memory processing is also discussed. The detrimental action of BPA appears complex, involving different hormonal and epigenetic pathways activated, often in a dimorphic way, within clearcut susceptibility windows. To date, discrepancies in experimental approaches and in related outcomes make unfeasible to translate the available information into clear dose–response models for human risk assessment. Evaluation of BPA brain levels in relation to the appearance of adverse effects in future basic studies will certainly give better definition of the warning threshold for human health.
"This observation is supported epidemiologically, with parental loss, physical abuse, sexual abuse, and neglect having been shown to be important for determining developmental outcomes, including neuroendocrine stress response (Laurent et al., 2014). Other environmental factors known to modify affective or social behavior in maturity include perinatal exposure to toxic chemicals (Disney et al., 2008; Haijima et al., 2010; Xu et al., 2012; Hamilton et al., 2014; Kiryanova and Dyck, 2014), and some of these chemicalinduced behavioral abnormalities are associated with alterations in the stress response system (Glavas et al., 2007; Poimenova et al., 2010). It is hypothesized that early life environment, particularly one that affects the neuroendocrine stress response system, shapes the neural basis of social behavior, which in turn may contribute to the hierarchical status within a group later in life. "
[Show abstract][Hide abstract] ABSTRACT: Dominant and subordinate dispositions are not only determined genetically but also nurtured by environmental stimuli during neuroendocrine development. However, the relationship between early life environment and dominance behavior remains elusive. Using the IntelliCage-based competition task for group-housed mice, we have previously described two cases in which environmental insults during the developmental period altered the outcome of dominance behavior later in life. First, mice that were repeatedly isolated from their mother and their littermates (early deprivation; ED), and second, mice perinatally exposed to an environmental pollutant, dioxin, both exhibited subordinate phenotypes, defined by decreased occupancy of limited resource sites under highly competitive circumstances. Similar alterations found in the cortex and limbic area of these two models are suggestive of the presence of neural systems shared across generalized dominance behavior.
Frontiers in Neuroscience 03/2015; 9(91). DOI:10.3389/fnins.2015.00091 · 3.66 Impact Factor
"In addition to these " high dose " effects on survival and growth, other studies have shown a variety of effects induced by much lower doses of BPA, i.e. doses below the established NOAEL of 50 g/kg/day, which reproduce better the actual human exposure. The adverse effects induced by a " low dose " of BPA include neuronal and behavioral alterations: documented effects of prenatal exposure to BPA are abnormal development of the neocortex in terms of differentiation and neuronal migration  , aberrant positions and connections between thalamus and cortex , inhibition of the proliferation of neural progenitor cells , loss of sexual dimorphism in terms of brain structure and behavior , increased anxiety and cognitive deficits  . Part of these results are justified by the strong affinity of BPA to the dopamine receptor, the estrogen-like receptor-␤ type  and the estrogen-like receptor-␥ type present in hippocampal neurons . "
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