Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus.

Bisphenol A (BPA) is a widely used compound in the food packaging industry. Prenatal exposure to BPA induces histological abnormalities in the neocortex and hypothalamus in association with abnormal behaviors. Yet, the molecular and cellular neurodevelopmental toxicological mechanisms of BPA are incompletely characterized on neuroinflammatory-related endopoints. To evaluate the neurodevelopmental effects of BPA exposure in mouse embryos, we examined microglial numbers as well as the expression of microglial-related factors in the E15.5 embryonic brain. BPA-exposed embryos exhibited significant increases in Iba1-immunoreactive microglial numbers in the dorsal telencephalon and the hypothalamus compared to control embryos. Further, the expression levels of microglial markers (Iba1, CD16, iNOS, and CD206), inflammatory factors (TNFα and IL4), signal transducing molecules (Cx3Cr1 and Cx3Cl1), and neurotrophic factor (IGF1) were altered in BPA-exposed embryos. These findings suggest that BPA exposure increases microglial numbers in the brain and alters the neuroinflammatory status at a transcriptional level. Together, these changes may represent a novel target for neurodevelopmental toxicity assessment after BPA exposure.

Expression of Kisspeptin in Gonadotrope Precursors in the Mouse Pituitary during Embryonic and Postnatal Development and in Adulthood.

BACKGROUND: Kisspeptins are important regulators of the development and function of the hypothalamic-pituitary-gonadal axis. However, the importance of kisspeptin at the pituitary level is unclear. METHODS: We examined the expression profile of kisspeptin in the mouse pituitary during development and in adulthood using RT-PCR, quantitative PCR and immunohistochemistry. RESULTS: Kiss1 mRNA was detected in both embryonic and postnatal pituitaries. Kisspeptin-immunoreactive (+) cells were detected from embryonic day (E) 13.5 throughout adulthood, being localized to the rostroventral portion in the anterior pituitary (AP) in embryos, and also to the dorsocaudal AP postnatally. A large proportion of kisspeptin+ cells were double-labeled with gonadotrope markers including Foxl2, SF-1, and LHß, and the percentage of LHß+ cells in kisspeptin+ cells increased during development. No kisspeptin+ cells were positive for the proliferating cell marker MCM7 (minichromosome maintenance protein 7), but a few kisspeptin+ cells co-expressed the stem/progenitor cell marker Sox2. Kisspeptin expression was similar between sexes and between agonadal SF-1 knockout embryos and wild-type littermates. Kiss1 mRNA levels were not significantly different between sexes or during early postnatal development, but levels in females increased when puberty began and were significantly higher than in males at postpubertal ages. CONCLUSIONS: These results suggest that kisspeptin is expressed in gonadotrope precursors during gonadotrope differentiation, and that kisspeptin expression begins soon after the initiation of αGSU production and is extinguished soon after the initiation of LH production. Furthermore, pituitary kisspeptin expression may be regulated in a gonad-independent manner during development, but may be associated with gonadotrope function in adulthood.

Involvement of SF-1 in neurogenesis and neuronal migration in the developing neocortex.

The nuclear receptor steroidogenic factor-1 (SF-1) plays essential roles in the development and function of the endocrine and reproductive systems. During embryogenesis, SF-1 is expressed in the ventromedial hypothalamic nucleus (VMH) and regulates the migration and terminal differentiation of the VMH neurons. Additionally, in situ hybridization data indicated SF-1 expression in the dorsal telencephalon at embryonic day (E) 13.5. In this study, we investigated the neocortical development in SF-1 knockout (KO) mouse embryos. The number of neurons was increased in the intermediate/subventricular zones and decreased in the cortical plate in the SF-1 KO embryos. SF-1 KO embryos produced more neural stem/progenitor cells, especially apical progenitor cells, and showed abnormal radial glial fiber morphology. The increase in neural stem/progenitor cells was caused by an increased S-phase fraction in the proliferative cells and the inhibition of cell cycle exit in these cells. The mRNA expression of the estrogen receptor ESRα was up-regulated and that of the estrogen synthetase Cyp19a1 was down-regulated in the dorsal telencephalon of SF-1 KO embryos. We showed that SF-1 is expressed in the dorsal telencephalon at E15.5 and E18.5, but not in adult animals. Our data demonstrated that SF-1 is involved in cell cycle regulation, neurogenesis, and neuronal migration via controlling the estrogen signaling for proper neocortical development.