Effects of bisphenol A treatment during pregnancy on kidney development in mice: a stereological and histopathological study.

Bisphenol A (BPA) is a chemical found in plastics that resembles oestrogen in organisms. Developmental exposure to endocrine-disrupting chemicals, such as BPA, increases the susceptibility to type 2 diabetes (T2DM) and cardiovascular diseases. Animal studies have reported a nephron deficit in offspring exposed to maternal diabetes. The aim of this study was to investigate the prenatal BPA exposure effects on nephrogenesis in a mouse model that was predisposed to T2DM. This study quantitatively evaluated the renal structural changes using stereology and histomorphometry methods. The OF1 pregnant mice were treated with a vehicle or BPA (10 or 100 µg/kg/day) during days 9-16 of gestation (early nephrogenesis). The 30-day-old offspring were sacrificed, and tissue samples were collected and prepared for histopathological and stereology studies. Glomerular abnormalities and reduced glomerular formation were observed in the BPA offspring. The kidneys of the BPA10 and BPA100 female offspring had a significantly lower glomerular number and density than those of the CONTROL female offspring. The glomerular histomorphometry revealed a significant difference between the female and male CONTROL offspring for the analysed glomerular parameters that disappeared in the BPA10 and BPA100 offspring. In addition, the kidney histopathological examination showed typical male cuboidal epithelial cells of the Bowman capsule in the female BPA offspring. Exposure to environmentally relevant doses of BPA during embryonic development altered nephrogenesis. These structural changes could be associated with an increased risk of developing cardiometabolic diseases later in life.

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain.

This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERalpha and ERbeta1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERalpha expression was visible only in the hypothalamic area. Decline in ERbeta1 expression was slower than that of ERalpha, and ERalpha-negative, ERbeta1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5alpha-androstane-3beta, 17beta-diol (3betaAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3betaAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3betaAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3betaAdiol, is important in neuronal function in the postnatal brain.

Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis.

The link between endocrine disruptors and altered blood glucose homeostasis has been recently suggested. Epidemiological studies have correlated levels of phthalates, dioxins and persistent organic pollutants with alterations of blood glucose homeostasis in humans. Environmentally relevant doses of the ubiquitous endocrine disruptor bisphenol-A (BPA) have profound effects on mice endocrine pancreas--an essential tissue involved in glucose metabolism. BPA exerts rapid non-genomic effects on insulin releasing beta-cells and glucagon releasing alpha-cells within freshly isolated islets of Langerhans. In vivo, a single BPA injection of 10 microg/kg rapidly increases plasma insulin and concomitantly decreases glycaemia. When mice were treated with BPA 100 microg/kg/day for 4 days, the environmental oestrogen produced an increase in beta-cell insulin content along with a post-prandial hyperinsulinaemia and insulin resistance. The results reviewed here demonstrate that doses well below the current lowest observed adverse effect level considered by the US-EPA, disrupt pancreatic beta-cell function producing insulin resistance in male mice. Therefore, this altered blood glucose homeostasis by BPA exposure may enhance the risk of developing type II diabetes.

Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner.

The soy isoflavone genistein targets adipose tissue and elicits physiological effects that may vary based on dietary intake. We hypothesized that the adipose effects of genistein are dose and gender dependent. Four-week-old C57BL/6 male and female mice received daily oral doses of genistein (50-200,000 microg/kg.d) or 17beta-estradiol (E2) (5 microg/kg.d) for 15 d or a diet containing 800 ppm genistein. Genistein increased epididymal and renal fat pad and adipocyte size at doses up to 50,000 microg/kg.d or at 800 ppm in the diet in males but not in females. The alteration in adipocity correlated with changes in peripheral insulin resistance. These treatments increased genistein serum concentrations from 35+/-6 to 103+/-26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 microg/kg.d genistein dose decreased adipose tissue weight similarly to E2. This genistein dose down-regulated estrogen receptor (beta more than alpha) and progesterone receptor expression and induced estrogen-dependent adipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tK-LUC mice, which was positively modulated in other tissues (e.g. the lung). E2 down-regulated almost all examined adipogenic factors. Gene microarray analysis identified factors in fat metabolism and obesity-related phenotypes differentially regulated by low and high doses of genistein, uncovering its adipogenic and antiadipogenic actions. The lower dose induced the phospholipase A2 group 7 and the phospholipid transfer protein genes; the 200,000 microg/kg.d dose inhibited them. The antiadipogenic action of genistein and down-regulation of adipogenic genes required the expression of ERbeta. In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition.

Quantitative histochemical assessment of oxidative metabolism in the subfornical organ after partial aortic ligature in rats.

Circumventricular organs are considered to be involved in hydromineral homeostatic responses. In this study we used quantitative histochemistry of cytochrome oxidase to evaluate the oxidative metabolic activity of the subfornical organ of rats with a partial aortic occlusion. These rats showed a significant increase in water intake from the second day after the ligature, while natriophilia was already significant on the first day. Greater levels of cytochrome oxidase activity were found in subfornical organs of partial aortic ligated rats when compared with control, providing further evidence for the involvement of this circumventricular structure in fluid homeostasis at least in this hyperdipsic, hypernatriophilic, hyperreninemic and hypertensive experimental model.