Nrf2 Activation Attenuates Acrylamide-Induced Neuropathy in Mice.

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.

Late-life Cardiac Injury in Rats following Early Life Exposure to Lead: Reversal Effect of Nutrient Metal Mixture.

Early-life exposure to lead (Pb) can lead to health effects in later life. The neurotoxic effects of Pb have been well documented but its effects on the heart are poorly elucidated. We examined the late life cardiac impairments resulting from developmental exposure to Pb. Further, we investigated the protective effect of the nutrient metal mixture containing calcium (Ca), zinc (Zn) and iron (Fe) against Pb-induced long-term effects on cardiac functions.Male albino rats were lactationally exposed to 0.2% Pb-acetate or 0.2% Pb-acetate together nutrient metal mixture as 0.02% in drinking water of the mother from PND 1 to PND 21. The results showed increased levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDLs) and lactate dehydrogenase (LDH) activity at postnatal day (PND) 28 [young], 4 months [adult] and 18 months [old] age group rats. Most notably, exposure to Pb decreased the activities of mitochondrial superoxide dismutase (SOD), thioredoxin reductase (TrxR), aconitase (Acon), isocitrate dehydrogenase (ICDH), xanthine oxidase (XO) and total antioxidant status while the MDA levels increased in all selected age groups of rats. The histological findings showed an age-dependent response to Pb exposure evidenced by extensive degeneration and necrosis in cardiac muscle, disruption in muscle connectivity, hemorrhage, and mononuclear cell infiltration. Co-administration of nutrient metal mixture reversed the Pb-induced cardiac impairments as reflected in the recovery of the chosen sensitive markers of oxidative stress, reduced Pb levels and cardiac tissue changes. In conclusion, the data demonstrate that early-life exposure to Pb continuously influence the cardiac mitochondrial functions from early life to older age and further suggesting that adequate intake of nutrient metals may be potential therapeutic treatment for Pb intoxication.

MicroRNAs and their role in environmental chemical carcinogenesis.

MicroRNAs (miRNAs) are a class of small, noncoding RNA species that play crucial roles across many biological processes and in the pathogenesis of major diseases, including cancer. Recent studies suggest that the expression of miRNA is altered by certain environmental chemicals, including metals, organic pollutants, cigarette smoke, pesticides and carcinogenic drugs. In addition, extensive studies have indicated the existence and importance of miRNA in different cancers, suggesting that cancer-related miRNAs could serve as potential markers for chemically induced cancers. The altered expression of miRNA was considered to be a vital pathogenic role in xenobiotic-induced cancer development. However, the significance of miRNA in the etiology of cancer and the exact mechanisms by which environmental factors alter miRNA expression remain relatively unexplored. Hence, understanding the interaction of miRNAs with environmental chemicals will provide important information on mechanisms underlying the pathogenesis of chemically induced cancers, and effectively diagnose and treat human cancers resulting from chronic or acute carcinogen exposure. This study presents the current evidence that the miRNA deregulation induced by various chemical carcinogens, different cancers caused by environmental carcinogens and the potentially related genes in the onset or progression of cancer. For each carcinogen, the specifically expressed miRNA may be considered as the early biomarkers of the cancer process. In this review, we also summarize various target genes of the altered miRNA, oncogenes or anti-oncogenes, and the existing evidence regarding the gene regulation mechanisms of cancer caused by environmentally induced miRNA alteration. The future perspective of miRNA may become attractive targets for the diagnosis and treatment of carcinogen-induced cancer.

Effects of combined arsenic and lead exposure on the brain monoaminergic system and behavioral functions in rats: Reversal effect of MiADMSA.

In this study, we evaluated the therapeutic efficacy of monoisoamyldimercaptosuccinic acid (MiADMSA) against individual and combined effects of arsenic (As) and lead (Pb) on the monoaminergic system and behavioral functions in rats. Pregnant rats were exposed to sodium metaarsenite (50 ppm) and lead acetate (0.2%) individually and in combination (As = 25 ppm + Pb = 0.1%) via drinking water from gestation day (GD) 6 to postnatal day (PND) 21. MiADMSA (50 mg/kg body weight) was given orally through gavage for 3 consecutive days to pups from PND 18 to PND 20. The results showed increases in synaptosomal epinephrine, dopamine, and norepinephrine levels with individual metal exposures and decreases with combined exposure to As and Pb in the cortex, cerebellum, and hippocampus in PND 21, PND 28, and 3 months age-group rats. We found decreased activity of mitochondrial monoamine oxidase in the selected brain regions following individual and combined exposures to Pb and As. In addition, rats treated with Pb and As alone or in combination showed significant deficits in open-field behavior, grip strength, locomotor activity, and exploratory behavior at PND 28 and 3 months of age. However, MiADMSA administration showed reversal effects against the As- and/or Pb-induced impairments in the monoaminergic system as well as in behavioral functions of rats. Our data demonstrated that the mixture of Pb and As induced synergistic toxicity to developing brain leading to impairments in neurobehavioral functions and also suggest therapeutic efficacy of MiADMSA against Pb- and/or As-induced developmental neurotoxicity.

Maternal urinary cadmium levels during pregnancy associated with risk of sex-dependent birth outcomes from an e-waste pollution site in China.

This study was to investigate whether exposure to cadmium (Cd) during pregnancy is associated with an increased risk of adverse birth outcomes in a sex-dependent manner. Cd concentrations in maternal urine (U-Cd) samples were measured in 237 subjects from Guiyu (e-waste area) and 212 subjects from Haojiang. A significance level of p <0.05 was used for all analyses. The maternal U-Cd levels in Guiyu residents were significantly higher than Haojiang. We found significant inverse associations between U-Cd concentrations and birth anthropometry (birth weight, birth length, Head Circumference and Apgar scores with 1min and 5 mins) in female neonates, but no significant associations were observed in male neonates except Apgar (1min) score after adjustment. The association was more pronounced among female neonates than male neonates, suggesting an association between Cd and adverse birth outcomes may be sex-specific.

Perinatal exposure to lead: reduction in alterations of brain mitochondrial antioxidant system with calcium supplement.

Lead (Pb) is a potent neurotoxicant that causes several neurochemical and behavioral alterations. Previous studies showed that the gestational and lactational exposure to Pb reduces the cholinergic and aminergic systems, and behavior of rats. The present study was designed to examine the protective effects of calcium supplementation against Pb-induced oxidative stress in cerebellum and hippocampus of brain at postnatal day (PND) 21, PND 28, PND 35, and PND 60. Pregnant rats were exposed to 0.2 % Pb (Pb acetate in drinking water) from gestational day 6 (GD 6) and pups were exposed through maternal milk till weaning (PND 21). We found that the activity of serum ceruloplasmin oxidase (Cp), mitochondrial manganese superoxide dismutase (Mn-SOD), copper zinc superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GPx), catalase (CAT), and xanthine oxidase (XO) enzyme activities were decreased, whereas the malondialdehyde (MDA) levels increased in the cerebellum and hippocampus of Pb-exposed rats. These changes were more prominent at PND 35 and greater in hippocampus compared to cerebellum. Among the enzyme activities, Mn-SOD and Cu/Zn-SOD showed maximum decrease compared to GPx, CAT, XO, and Cp. Furthermore, 0.02 % calcium supplementation together with 0.2 % Pb significantly reversed the Pb-induced alterations in the enzyme activities, and MDA levels. In conclusion, these data suggest that early life exposure to Pb induce alterations in the mitochondrial antioxidant system of brain regions which remain for long even after Pb exposure has stopped. Calcium supplementation may potentially be beneficial in treating Pb toxicity in the developing rat brain.