Victoria Linares

Human exposure to PBDE and critical evaluation of health hazards

Abstract Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardant additives in a number of commercial products. Biomonitoring data show that, in recent years, PBDE concentrations have increased rapidly in the bodies of wildlife and humans. Usually, PBDE levels in North America have been reported to be higher than those in Europe and Asia. Moreover, body burden of PBDEs is three- to ninefold higher in infants and toddlers than in adults, showing these last two age groups the highest levels of these compounds, due to exposure via maternal milk and through dust. Tetra-, Penta-, and Hexa-BDEs are the isomers most commonly found in humans. Based on studies on experimental animals, the toxicological endpoints of exposure to PBDEs are likely to be thyroid homeostasis disruption, neurodevelopmental deficits, reproductive changes, and even cancer. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or postnatal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly on motor activity and cognition. This paper is focused on reviewing the current status of PBDEs in the environment, as well as the critical adverse health effects based on the recent studies on the toxic effects of PBDEs.

Effects of BDE-99 on hormone homeostasis and biochemical parameters in adult male rats

In this study, we evaluated the effects of BDE-99 on hormone homeostasis, as well as in urinary and serum biochemical parameters of adult male rats. Animals (10 per group) received BDE-99 by gavage at single doses of 0, 0.6 and 1.2mg/kg. Forty-five days after BDE-99 exposure, urine and serum samples were collected for hormonal and biochemical analysis. Oxidative stress (OS) markers in erythrocytes, plasma and urine were also evaluated. Urinary excretion of total protein significantly increased following BDE-99 exposure, while lactate dehydrogenase (LDH), gamma-glutamil transferase (GGT), and N-acetylglucosaminidase (NAG) activities significantly decreased. Liver toxicity was evidenced by elevated serum activities of the enzymes glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and alkaline phosphatase (ALP). Following BDE-99 administration, OS markers in erythrocytes showed an increase in superoxide dismutase (SOD) activity, and a reduction in glutathione reductase (GR) activity. In urine, isoprostane levels increased after BDE-99 exposure. The hormonal analysis showed a significant decrease in testosterone and progesterone levels. These results support the hypothesis that BDE-99 interacts with hormonal response. Moreover, BDE-99 administration to adult male rats showed signs of renal and hepatic toxicity.

Sulfasalazine induced oxidative stress: A possible mechanism of male infertility

The mechanism of action of sulfasalazine (SASP) in male infertility is not well elucidated. For it, an oxidative stress-like mechanism inductor of infertility was hypothesized. Adult male Sprague-Dawley rats (20/group) were orally administered 0, 300, and 600mg SASP/kg body weight for 14 days. One-half of animals in each group remained an additional period of 14 days without treatment. SASP induced a significant decrease of superoxide dismutase (SOD) and glutathione reductase (GR) at the highest dose in both testis and epididymis. GR remained altered in these tissues within the recovery period. However, an increase in SOD was noted in epididymis. An increase in thiobarbituric acid-reactive substances (TBARS) was noted in all SASP-treated groups. In epididymis, catalase (CAT) significantly increased at 600mg/(kgday). These results suggest that SASP induces oxidative stress, which in turn might act as a possible mechanism of male-induced infertility.

Melatonin reduces uranium‐induced nephrotoxicity in rats

Abstract:  The protective role of exogenous melatonin on U‐induced nephrotoxicity was investigated in rats. Animals were given single doses of uranyl acetate dihydrate (UAD) at 5 mg/kg (subcutaneous), melatonin at 10 or 20 mg/kg (intraperitoneal), and UAD (5 mg/kg) plus melatonin (10 or 20 mg/kg), or vehicle (control group). In comparison with the UAD‐treated group only, significant beneficial changes were noted in some urinary and serum parameters of rats concurrently exposed to UAD and melatonin. The increase of U excretion after UAD administration was accompanied by a significant reduction in the renal content of U when melatonin was given at a dose of 20 mg/kg. Melatonin also reduced the severity of the U‐induced histological alterations in kidney. In renal tissue, the activity of the superoxide dismutase (SOD) and the thiobarbituric acid reactive substances (TBARS) levels increased significantly as a result of UAD exposure. Following UAD administration, oxidative stress markers in erythrocytes showed a reduction in SOD activity and an increase in TBARS levels, which were significantly restored by melatonin administration. In plasma, reduced glutathione (GSH) and its oxidized form (GSSG) were also altered in UAD‐exposed rats. However, only the GSSG/GSH ratio was restored to control levels after melatonin treatment. Oxidative damage was observed in kidneys. Melatonin administration partially restored these adverse effects. It is concluded that melatonin offers some benefit as a potential agent to treat acute U‐induced nephrotoxicity.

Oxidative Stress-Related Markers and Langerhans Cells in a Hairless Rat Model Exposed to UV Radiation

Biomarkers related to the oxidative stress in blood and epidermis and the number of Langerhans cells were determined in hairless rats after acute irradiation with 1.54, 1.93, or 2.41 J/cm2 of ultraviolet (UV) light and chronic exposure to 13 suberythemal UV doses of 1.1 J/cm2 for 2 mo. After acute UV irradiation, in epidermis, the thiobarbituric acid-reactive substances (TBARS) content increased at the highest UV dose, whereas the activities of glutathione S-transferase and catalase rose and the oxidized glutathione (GSSG) content diminished at all UV doses. In erythrocytes, glutathione S-transferase activity increased at the two lowest UV doses, glutathione peroxidase activity rose at all UV doses, and catalase activity increased after the highest UV dose. In plasma, the TBARS content and the reduced glutathione (GSH)/GSSG ratio increased at the highest UV dose; the number of Langerhans cells decreased at all UV doses. Linear Pearson correlation analysis revealed many relationships between different biomarkers, and multiple linear regression analysis indicated that the number of Langerhans cells was predicted by epidermal GSSG and catalase (R 2 = .64) and by erythrocytic glutathione peroxidase and GSSG (R 2 = .72). After suberythemal UV radiation, in epidermis, the GST activity and the content of GSH and GSSG increased; in erythrocytes, the GST activity decreased and the GSH/GSSG ratio increased. Thus, the hairless rat appears to be a useful model for studying the oxidative stress-related mechanisms after UV radiation, which are involved in the loss of the immune capacity mediated by Langerhans cells, even at suberythemal doses. This study was conducted at the School of Medicine, Rovira i Virgili University, Reus, Spain. This work was supported by a Research and Development grant (SAF-99-0048) from the Spanish Ministry of Health and Social Security and cosponsored by Novartis CH (Spain). We thank Prof. J. Fernández of the School of Medicine (Reus) for his help with the statistical analyses.

Lipid peroxidation and antioxidant status in kidney and liver of rats treated with sulfasalazine

Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD). In this study, the changes in endogenous antioxidant capacity and oxidative damage in liver and kidney of SASP-treated rats were investigated. Adult male Sprague-Dawley rats were orally given 0, 300, or 600 mg SASP/kg body weight for 14 days. One half of the animals in each group remained 14 additional days without SASP treatment. At the end of the experimental period, rats were euthanized and liver and kidney were removed. In both organs, the following stress markers were determined: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid-reactive substances (TBARS). Moreover, histological examination of kidneys showed phagolysosomes after 14 days of SASP withdrawal. A dropsical degeneration was also observed in renal tissue. Oral SASP administration induced a significant increase in TBARS levels in both liver and kidney. After 2 weeks without SASP administration, a recovery of these levels was noted. SOD activity was significantly reduced, while CAT activity significantly increased at 600 mg SASP/(kg day). In kidney, GPx activity significantly increased, while GST activity and GSH levels were significantly reduced at 600 mg SASP/(kg day). These results suggest that in male rats, oxidative damage can be a mechanism for nephro- and hepatotoxicity related with SASP treatment.

Dietary exposure to organochlorine compounds in Tarragona Province (Catalonia, Spain): health risks.

ABSTRACT The human health risks due to the dietary exposure to organochlorine compounds (OC) were assessed in the Catalan stretch of the Ebro River (Spain). The concentrations of various persistent organic pollutants (POPs): polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), pentachlorobenzene (PeCB), various hexachlorocyclohexanes (HCHs), as well as dichloro-diphenyl-trichloroethane (DDT) and derivatives, were determined in samples of fish and seafood, vegetables, fruits, and rice, acquired in localities of the zone under evaluation. In general terms, pollutant concentrations were similar to recent levels reported in the literature. With the exception of the consumption of fish and seafood by children, and due to the presence of PCBs (Aroclor 1254), food intake from local sources does not pose non-carcinogenic risks for all population groups examined. The presence of OC in foods of local origin in the Catalan basin of the Ebro River would not increase the health risks for the areas consumers.

Neurobehavioral effects of concurrent exposure to cesium-137 and paraquat during neonatal development in mice.

As a result of nuclear power plants accidents such as Chernobyl or Fukushima, some people were exposed to external and internal ionizing radiation (IR). Human brain is highly sensitive to IR during fetal and postnatal period when the molecular processes are not completely finished. Various studies have shown that exposure to low doses of IR causes a higher incidence of cognitive impairment. On the other hand, in industrialized countries, people are daily exposed to a number of toxicant pollutants. Exposure to environmental chemicals, such as paraquat (PQ), may potentiate the toxic effects induced by radiation on brain development. In this study, we evaluated the cognitive effects of concomitant exposure to low doses of internal radiation ((137)Cs) and PQ during neonatal brain development. At the postnatal day 10 (PND10), two groups of mice (C57BL/6J) were exposed to (137)Cs (4000 and 8000 Bq/kg) and/or PQ (7 mg/kg). To investigate the spontaneous behavior, learning, memory capacities and anxiety, behavioral tests were conducted in the offspring at two months of age. The results showed that cognitive functions were not significantly affected when (137)Cs or PQ were administered alone. However, alterations in the working memory and anxiety were detected in mice exposed to (137)Cs combined with PQ.

Behavioral effects in mice of postnatal exposure to low-doses of 137-cesium and bisphenol A

Bisphenol A (BPA) is the most important plasticizer used in many household products such as polycarbonate plastics or epoxy resins. Public and scientific concerns exist regarding the possibility that the neonatal exposure to BPA may contribute to neurobehavioral disorders. On the other hand, there is little information on the effects of low doses of ionizing radiation during critical phases of postnatal brain development, as well as the combination of radiation and environmental chemicals. In this study, C57BL/6J mice were exposed to low doses of internal radiation ((137)Cs), and/or BPA on postnatal day 10 (PND10). At the age of two months, animals were submitted to several tests to assess anxiety, activity, learning, and memory. Results showed that exposure to (137)Cs, alone or in combination with BPA, increased the anxiety-like of the animals without changing the activity levels. Animals exposed to (137)Cs showed impaired learning, and spatial memory, an impairment that was not observed in the groups co-exposed to BPA.

Environmental exposure to low-doses of ionizing radiation. Effects on early nephrotoxicity in mice

ABSTRACT Nuclear accidents of tremendous magnitude, such as those of Chernobyl (1986) and Fukushima (2011), mean that individuals living in the contaminated areas are potentially exposed to ionizing radiation (IR). However, the dose‐response relationship for effects of low doses of radiation is not still established. The present study was aimed at investigating in mice the early effects of low‐dose internal radiation exposure on the kidney. Adult male (C57BL/6 J) mice were divided into three groups. Two groups received a single subcutaneous (s.c.) doses of cesium (137Cs) with activities of 4000 and 8000 Bq/kg bw. A third group (control group) received a single s.c. injection of 0.9% saline. To evaluate acute and subacute effects, mice (one‐half of each group) were euthanized at 72 h and 10 days post‐exposure to 137Cs, respectively. Urine samples were collected for biochemical analysis, including the measurement of F2‐isoprostane (F2‐IsoP) and kidney injury molecule‐1 (KIM‐1) levels. Moreover, the concentrations of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), a sensitive marker of oxidative DNA damage, were measured in renal tissue. Urinary excretion of total protein significantly increased at 72 h in mice exposed to Cs4000. Uric acid and lactate dehydrogenase (LDH) decreased significantly at both times post‐exposure in animals exposed to Cs8000. After 72 h and 10 d of exposure to Cs4000, a significant increase in the &ggr;‐glutamil transferase (GGT) and N‐acetyl‐&bgr;‐D‐glucosaminidase (NAG) activities was observed. In turn, F2‐IsoP levels increased ‐mainly in the Cs4000 group‐ at 72 h post‐exposure. Following irradiation (137Cs), the highest level of KIM‐1 was corresponded to the Cs4000 group at 72 h. Likewise, the main DNA damage was detected in mice exposed to Cs4000, mainly at 10 d after irradiation. The alterations observed in several biomarkers suggest an immediate renal damage following exposure to low doses of IR (given as 137Cs). Further investigations are required to clarify the mechanisms involved in the internal IR‐induced nephrotoxicity. HighlightsVery low doses of internal ionizing radiation induced early renal histologic injury.Cs137 induced acute oxidative stress that contributes to radiation‐induced cytotoxicity.A single low dose internal radiation‐induced oxidative DNA damage in the kidney.