Prenatal exposure to bisphenol A interferes with the development of cerebellar granule neurons in mice and chicken

Abstract

In mice, prenatal exposure to low doses of bisphenol A has been shown to affect neurogenesis and neuronal migration in cortex, resulting in disturbance of both neuronal positioning and the network formation between thalamus and cortex in the offspring brain. In the present study we investigated whether prenatal exposure to bisphenol A disturbs the neurodevelopment of the cerebellum. Two different model systems were used; offspring from two strains of mice from mothers receiving bisphenol A in the drinking water before mating, during gestation and lactation, and chicken embryos exposed to bisphenol A (in the egg) on embryonic day 16 for 24h before preparation of cerebellar granule cell cultures. In the cerebellum, tight regulation of the level of transcription factor Pax6 is critical for correct development of granule neurons. During the development, the Pax6 level in granule neurons is high when these cells are located in the external granule layer and during their migration to the internal granule layer, and it is then reduced. We report that bisphenol A induced an increase in the thickness of the external granule layer and also an increase in the total cerebellar Pax6 level in 11 days old mice offspring. In cultured chicken cerebellar granule neurons from bisphenol A injected eggs the Pax6 level was increased day 6 in vitro. Together, these findings indicate that bisphenol A may affect the granule neurons in the developing cerebellum and thereby may disturb the correct development of the cerebellum.

Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture

“…Since the cellular effects of hormones are mostly mediated by their cognate receptors, this observation can explain why the biological effects of BPA-exposure could have remained masked or even unrecognised for a long time in spite of the dramatically increased transcriptional activity. Several studies suggested that exposure to EDs early in life leads to altered CNS development and functional deficiencies later in adulthood (Mathisen et al, 2013). The present results suggest that the final, al-tered outcome of hormonal signalling during ED exposure may only partly account for those anomalies, since the increased material and energy consumption by CNS cells in the process of enhanced transcription could also lead to energydeficient intracellular conditions that could be, at least in part, responsible for developmental deficiencies.…”

Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

“…In the human embryo, the external granule layer reaches its peak thickness by gestational week 25, and the process of migration continues well into the first postnatal year. In the chicken cerebellum, the migration of cerebellar granule neurons occurs prenatally (Aden et al, 2008(Aden et al, , 2011Volpe, 2009;Mathisen et al, 2013), in contrast to the situation in the rodent cerebellum where the external granule layer is formed postnatally, and granule neurons migrate between postnatal days 4 and 15 (Fujita, 1967). In fish, the migration of granule neurons follows yet a different pattern from that of mammals and chicken or is absent altogether (Butts et al, 2014).…”

“…It is of particular benefit that the only endocrine influence the embryo receives from its mother is through the egg yolk. This facilitates external manipulation of the endocrine system and the study of whether pharmaceuticals and environmental chemicals cause endocrine disruption (Mathisen et al, 2013). Tight regulation of the endocrine system is crucial for correct development of the CNS.…”

“…This has been used to assess the neurodevelopmental effects of glucocorticoids (Aden et al, 2008(Aden et al, , 2011, a clinically relevant neonatal issue (Roberts and Dalziel, 2006;Brownfoot et al, 2013). The same model has been used to address developmental disruption caused by bisphenol A, with results in concordance with those reported in a mouse model (Mathisen et al, 2013). Histopathology remains the gold standard (Sasseville et al, 2014) for assessing detrimental effects on the developing CNS in chickens (Table 1).…”

“…The transcription factor PAX6 is important for cerebellar development and migration (Engelkamp et al, 1999), and perturbations of PAX6 expression have been linked to autism (Umeda et al, 2010). Also, the role of PAX6 has been studied and found to be important for brain development in the chicken embryo (Mathisen et al, 2013). Other markers that have been suggested and partly implemented in studies of neurotoxicity are Calbindin D28k and microtubule-associated protein-2 (Haworth et al, 2006).…”