A pilot study on polycystic ovarian syndrome caused by neonatal exposure to tributyltin and bisphenol A in rats.

The development of polycystic ovary syndrome (PCOS) could be caused by exposure to environmental endocrine disrupting chemicals (EDCs). In the current study, two commonly found EDCs, bisphenol A (BPA) and tributyltin (TBT), were investigated for their effects on PCOS occurrence in neonatal female rats. TBT (10 and 100 ng kg-1 d-1), BPA (50 µg kg-1 d-1), and a mixture of the two (TBT 100 ng kg-1 d-1 with BPA 50 µg kg-1 d-1) were administered to female rats from postnatal day 1-16. TBT, BPA, and TBT + BPA treatment resulted in an irregular estrus cycle and disturbed ovarian development, with less corpora lutea and antral follicles, but more atretic follicles and cysts. In addition, serum testosterone and luteinizing hormone levels were significantly elevated, whereas a reduced level of serum sex hormone-binding globulin was observed after TBT100, BPA50, and TBT + BPA treatments. Moreover, gene expression analyses identified significant differential expression of the genes involved in a variety of biological pathways, such as lipid transport and steroidogenesis. Moreover, the expression level of proteins regulating lipid and androgen biosynthesis was elevated after the treatments. In conclusion, this study demonstrated that exposure to TBT, BPA, and a mixture of the two in newborn rats could contribute to a PCOS-like syndrome. The mechanism of PCOS pathogenesis caused by exposure to TBT and BPA is likely to be mediated by the lipid metabolism and steroidogenesis pathways. Our results provide novel insight into female reproduction affected by EDCs, which may be helpful for revealing the pathogenesis of PCOS.

Exposure to environmental level phenanthrene induces a NASH-like phenotype in new born rat.

More and more evidence indicates that persistent organic pollutants (POPs) are a risk factor for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Phenanthrene (Phe) is a kind of POP which existed extensively in the environment, but whose toxicity on mammals has so far received less focus. Subcutaneously injection of Phe (0.5, 5, 50 µg/kg) for 21 days induced significant NAFLD/NASH symptoms in new born rats. Exposure to environmental levels of Phe decreased body weight and liver-somatic index; impaired histology of liver; influenced the peroxisome proliferator-activated receptor gamma (PPARγ) signaling and lipid metabolism in liver; stimulated oxidative stress in the rats' liver; induced the variation of NFκB pathway and liver inflammatory response; and caused liver fibrosis via transforming growth factor ß1 (tgfß1). We speculated that the subcutaneously injected Phe was transferred to the liver through blood circulation, which may have induced the elevation of PPARγ directly or indirectly, leading to liver steatosis. Excess lipid, acting as the first hit, stimulated the second hit factors - oxidative stress, inflammatory response and lipid peroxidation, and finally resulted in steatohepatitis and liver fibrosis.

Association of serum organochlorine pesticides concentrations with reproductive hormone levels and polycystic ovary syndrome in a Chinese population.

To investigate the serum concentrations of organochlorine pesticides (OCPs) in patients with polycystic ovary syndrome (PCOS), a total of 178 women were studied. The concentrations of hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT) in serum were determined using Gas Chromatography Mass-Mass Spectrometer. No differences with statistical significance in the mean HCH, p,p'-DDD, p,p'-DDE concentrations were observed between the patients with PCOS and the control group. Serum p,p'-DDT (P = 0.016) and o,p'-DDT (P = 0.000) levels were significantly higher in patients with PCOS compared with the control group. The results of the association between OCPs levels and hormone levels indicated that o,p'-DDT may play a role in the pathogenesis of PCOS by affecting hormones levels. Further trials should be investigated with the findings in this study to obtain new pathogenesis of PCOS.

Hexabromocyclododecane exposure induces cardiac hypertrophy and arrhythmia by inhibiting miR-1 expression via up-regulation of the homeobox gene Nkx2.5.

Hexabromocyclododecane (HBCD) is one of the most widely used brominated flame retardants. Although studies have reported that HBCD can cause a wide range of toxic effects on animals including humans, limited information can be found about its cardiac toxicity. In the present study, zebrafish embryos were exposed to HBCD at low concentrations of 0, 2, 20 and 200 nM. The results showed that HBCD exposure could induce cardiac hypertrophy and increased deposition of collagen. In addition, disordered calcium (Ca(2+)) handling was observed in H9C2 rat cardiomyocyte cells exposed to HBCD. Using small RNA sequencing and real-time quantitative PCR, HBCD exposure was shown to induce significant changes in the miRNA expression profile associated with the cardiovascular system. Further findings indicated that miR-1, which was depressed by Nkx2.5, might play a fundamental role in mediating cardiac hypertrophy and arrhythmia via its target genes Mef2a and Irx5 after HBCD treatment. HBCD exposure induced an arrhythmogenic disorder, which was triggered by the imbalance of Ryr2, Serca2a and Ncx1 expression, inducing Ca(2+) overload in the sarcoplasmic reticulum and high Ca(2+)-ATPase activities in the H9C2 cells.

Chronic Exposure to Aroclor 1254 Disrupts Glucose Homeostasis in Male Mice via Inhibition of the Insulin Receptor Signal Pathway.

Epidemiological studies demonstrate that polychlorinated biphenyls (PCBs) induce diabetes and insulin resistance. However, the development of diabetes caused by PCBs and its underlying mechanisms are still unclear. In the present study, male C57BL/6 mice were orally administered with Aroclor 1254 (0.5, 5, 50, and 500 µg/kg) once every 3 days for 60 days. The body weight and the fasting blood glucose levels were significantly elevated; the levels of serum insulin, resistin, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) increased, while glucagon levels decreased in the animals treated with Aroclor 1254. Pancreatic ß-cell mass significantly increased, while α-cell mass was reduced. Aroclor 1254 inhibited the expression of the insulin receptor signaling cascade, including insulin receptor, insulin receptor substrate, phosphatidylinositol 3-kinase-Akt, and protein kinase B and glucose transporter 4, both in the skeletal muscle and the liver. The results suggested that chronic exposure to Aroclor 1254 disrupted glucose homeostasis and induced hyperinsulinemia. The significant elevation of serum resistin, TNFα and IL-6 indicated that obesity caused by Aroclor 1254 is associated with insulin resistance. The elevation of blood glucose levels could have been mainly as a result of insulin receptor signals pathway suppression in skeletal muscle and liver, and a decrease in pancreatic α-cells, accompanied by a reduction of serum glucagon levels, may play an important role in the development of type 2 diabetes.

Decrease in prosaposin in spermatozoon is associated with polychlorinated biphenyl exposure.

Polychlorinated biphenyls (PCBs) are a class of ubiquitous persistent organic pollutants and they have been associated with declining male fertility. In the present study, we aimed to determine the responsiveness of prosaposin (Psap) expression to PCB exposure. Male C57 mice were exposed to PCB mixture (Aroclor 1254) of environmental related doses by oral gavage. After exposure for 50 days, the expression of Psap was significantly decreased by PCB exposure in epididymides and epydidymal spermatozoa, but not in testis. The Psap abundance in sperm was decreased in a dose-dependent manner. Benchmark dose modeling revealed the 95% lower confidence limit on the benchmark dose (BMDL) and Benchmark Dose (BMD) for Psap reduction were 1.25 and 8.89 µg/kg Aroclor 1254, and for sperm motility reduction were 11.85 and 61.9 µg/kg Aroclor 1254. The depressed Psap level also showed a significant correlation (P<0.01, r=-0.531) with PCB accumulation in liver. In men with detectable PCB exposure in semen, Psap expression in sperm was significantly decreased whereas the semen parameters were unaffected. Linear regression showed that a negative association between total PCB level in seminal plasma and Psap level in ejaculated spermatozoa (P<0.05, r=-0.396). In conclusion, our data suggested that the abundance of Psap in sperm sample may be a sensitive endpoint to predict PCB exposure.

Association of Serum Heavy Metals and Trace Element Concentrations with Reproductive Hormone Levels and Polycystic Ovary Syndrome in a Chinese Population.

To investigate the serum concentrations of 11 heavy metals and trace elements in patients with polycystic ovary syndrome (PCOS). A total of 369 women (including 96 patients with PCOS) were studied. No differences with statistical significance in the median barium, cadmium, lead, arsenic, chromium, gallium, strontium, and vanadium concentrations were observed between the patients with PCOS and the control group. Serum nickel (Ni) (P = 0.000) and copper (Cu) (P = 0.000) levels were significantly higher, but zinc (Zn) levels (P = 0.009) were significantly lower in patients with PCOS compared with the control group. The results of the association between metal levels and hormone levels indicated that Ni, Cu, and Zn may play a role in the pathogenesis of PCOS related with reproductive hormone levels. The findings in the present study should be investigated with further trials in order to obtain new insights into PCOS.

Levels of heavy metals and trace elements in umbilical cord blood and the risk of adverse pregnancy outcomes: a population-based study.

To better understand the relationship between prenatal exposure to heavy metals and trace elements and the risk of adverse pregnancy outcomes, we investigated the status of heavy metals and trace elements level in a Chinese population by collecting umbilical cord blood. Umbilical cord blood heavy metals and trace elements concentrations were determined by inductively coupled plasma-mass spectrometry. No differences with statistical significance in the median arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), strontium (Sr), thallium (Tl), vanadium (V), and zinc (Zn) concentrations were observed between the adverse pregnancy outcome group and the reference group. Titanium (Ti) and antimony (Sb) were found at higher levels with statistical significance in the cord blood samples with adverse pregnancy group when compared to the ones in the reference group. The association between Ti levels and the risk of adverse pregnancy outcomes remained significant after adjusting for potential confounding factors, including newborn weight. These results indicated that environmental exposure to Ti may increase the risk of adverse pregnancy outcomes in Chinese women without occupational exposure.