Loss of Caenorhabditis elegans homologue of human MOB4 compromises life span, health life span and thermotolerance.

Mob1/phocein family proteins are conserved from yeast to mammals. Human has four MOB genes, MOB1, 2, 3 and 4. Human MOB1 protein, which is a component of the Hippo pathway, is involved in the inhibition of yes-associated protein (YAP1) through large tumor suppressor (LATS) kinases and plays a tumor suppressive role. In contrast, MOB4 activates YAP1. Caernorhabditis elegans (C. elegans) also has four MOB genes. Moreover, C. elegans has homologues of YAP1 (Ce_YAP-1) and LATS kinases (WTS-1). Nevertheless, our previous study revealed that the Hippo pathway is not conserved in C. elegans and that heat shock activates Ce_YAP-1. We also reported that Ce_YAP-1 is involved in the regulation of life span, healthy lifespan and thermotolerance. In this study, we raised a question whether and how C. elegans homologue of MOB4 (Ce_MOB-4) is involved in the regulation of Ce_YAP-1. Ce_MOB-4 is ubiquitously expressed in adult worms. This expression pattern is similar to that of Ce_YAP-1. mob-4 loss-of-function mutants show short life span, short health life span and compromise thermotolerance. However, heat shock activates Ce_YAP-1 in mob-4 mutant. In conclusion, the role of MOB4 in the activation of YAP1 is not conserved in C. elegans.

In vivo evaluation of arsenic-associated behavioral and biochemical alterations in F0 and F1 mice.

Groundwater contaminated with arsenic (As) is the biggest threat to public health in Bangladesh. The children of As-exposure parents are also exposing to As through drinking water. The effects of As on the children's health of As-exposure parents are poorly understood. An animal study was taken to evaluate the effects of As on behavioral and biochemical changes in F1 mice. Swiss albino mice were separated into three groups: a) control, b) As-treated F0 and c) As-treated F1. Elevated plus maze and Morris water maze tests were used for evaluating anxiety, spatial memory and learning, respectively. We found that the effect of As on anxiety like behavior, spatial memory and learning impairment in As-treated F1 mice was significantly higher than that of As-treated F0 mice and control group. Additionally, we also evaluated the effects of As on biochemical parameters by measuring ALT, AST, ALP, BChE, SOD activities and the level of creatinine in As-induced mice, where we found that all of the blood parameters were significantly changed in F1 generation. A significant portion of As accumulated in the brain, liver and kidney of F1 mice than F0 mice. Histological analysis revealed a significant change in tissue damage related to hepatic and renal dysfunctions that might be associated with As-induced biochemical alterations. In conclusion, arsenic plays an important role for the development of As-associated neurological disorders, hepatic toxicities, and renal dysfunctions in both F0 and F1 generations. Notably F1 mice were much more vulnerable to As-exposure than F0 mice.

Antimony-Induced Neurobehavioral and Biochemical Perturbations in Mice.

Groundwater used for drinking has been contaminated with naturally occurring inorganic arsenic and other metals, and metal-contaminated drinking water is the biggest threat to public health in Bangladesh. Toxic metals present in the drinking water have a strong relationship with chronic diseases in humans. Antimony (Sb), a naturally occurring metal, has been reported to be present in the drinking water along with other heavy metals in Bangladesh. Although Sb is present in the environment, very little attention has been given to the toxic effects of Sb. The present study was designed to investigate the in vivo effects of Sb on neurobehavioral changes like anxiety, learning and memory impairment, and blood indices related to organ dysfunction. Mice exposed to antimony potassium-tartrate hydrate (Sb) (10 mg/kg body weight) significantly (p < 0.05) decreased the time spent in open arms while increased the time spent in closed arms compared to the control mice in elevated plus maze. The mean latency time of control group to find the platform decreased (p < 0.05) significantly during 7 days learning as compared to Sb-treated group in Morris water maze test, and Sb-exposed group spent significantly (p < 0.05) less time in the desired quadrant as compared to the control group in probe trial. Sb treatment also significantly altered blood indices related to liver and kidney dysfunction. Additionally, Sb-induced biochemical alterations were associated with significant perturbations in histological architecture of liver and kidney of Sb-exposed mice. These data suggest that Sb has a toxic effect on neurobehavioral and biochemical changes in mice.

Individual and Combined Effects of Arsenic and Lead on Behavioral and Biochemical Changes in Mice.

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants.

Elevated concentrations of serum matrix metalloproteinase-2 and -9 and their associations with circulating markers of cardiovascular diseases in chronic arsenic-exposed individuals.

BACKGROUND: Cardiovascular diseases (CVDs) and cancers are the major causes of chronic arsenic exposure-related morbidity and mortality. Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) are deeply involved in the pathogenesis of CVDs and cancers. This study has been designed to evaluate the interactions of arsenic exposure with serum MMP-2 and MMP-9 concentrations especially in relation to the circulating biomarkers of CVDs. METHODS: A total of 373 human subjects, 265 from arsenic-endemic and 108 from non-endemic areas in Bangladesh were recruited for this study. Arsenic concentrations in the specimens were measured by inductively coupled plasma mass spectroscopy (ICP-MS) and serum MMPs were quantified by immunoassay kits. RESULTS: Serum MMP-2 and MMP-9 concentrations in arsenic-endemic population were significantly (p < 0.001) higher than those in non-endemic population. Both MMPs showed significant positive interactions with drinking water (r s = 0.208, p < 0.001 for MMP-2; r s = 0.163, p < 0.01 for MMP-9), hair (r s = 0.163, p < 0.01 for MMP-2; r s = 0.173, p < 0.01 for MMP-9) and nail (r s = 0.160, p < 0.01 for MMP-2; r s = 0.182, p < 0.001 for MMP-9) arsenic of the study subjects. MMP-2 concentrations were 1.02, 1.03 and 1.05 times, and MMP-9 concentrations were 1.03, 1.06 and 1.07 times greater for 1 unit increase in log-transformed water, hair and nail arsenic concentrations, respectively, after adjusting for covariates (age, sex, BMI, smoking habit and hypertension). Furthermore, both MMPs were increased dose-dependently when the study subjects were split into three (≤10, 10.1-50 and > 50 µg/L) groups based on the regulatory upper limit of water arsenic concentration set by WHO and Bangladesh Government. MMPs were also found to be significantly (p < 0.05) associated with each other. Finally, the concentrations of both MMPs were correlated with several circulating markers related to CVDs. CONCLUSIONS: This study showed the significant positive associations and dose-response relationships of arsenic exposure with serum MMP-2 and MMP-9 concentrations. This study also showed the interactions of MMP-2 and MMP-9 concentrations with the circulating markers of CVDs suggesting the MMP-2 and MMP-9 -mediated mechanism of arsenic-induced CVDs.