Prabir K. Mandal

Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology

A highly persistent trace environmental contaminant and one of the most potent toxicants known is dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin or TCDD). TCDD induces a broad spectrum of biological responses, including induction of cytochrome P-450 1A1 (CYP1A1), disruption of normal hormone signaling pathways, reproductive and developmental defects, immunotoxicity, liver damage, wasting syndrome, and cancer. Its classification was upgraded from “possible human carcinogen” (group 2B) to “human carcinogen” (group 1) by the International Agency for Research on Cancer (IARC) in 1997. Exposure to TCDD may also cause changes in sex ratio, and tumor promotion in other animals. Because of the growing public and scientific concern, toxicological studies have been initiated to analyze the short- and long-term effects of dioxin. TCDD brings about a wide variety of toxic and biochemical effects via aryl hydrocarbon receptor (AhR)-mediated signaling pathways. Essential steps in this adaptive mechanism include AhR binding of ligand in the cytoplasm of cells associated with two molecules of chaperone heatshock protein (Hsp90) and AhR interactive protein, translocation of the receptor to the nucleus, dimerization with the Ah receptor nuclear translocator, and binding of this heterodimeric transcription factor (present in CYP1A) to dioxin-responsive elements upstream of promoters that regulate the expression of genes involved in xenobiotic metabolism.

Mechanisms of heavy-metal sequestration and detoxification in crustaceans: a review.

This review is an update of information recently obtained about the physiological, cellular, and molecular mechanisms used by crustacean organ systems to regulate and detoxify environmental heavy metals. It uses the American lobster, Homarus americanus, and other decapod crustaceans as model organisms whose cellular detoxification processes may be widespread among both invertebrates and vertebrates alike. The focus of this review is the decapod hepatopancreas and its complement of metallothioneins, membrane metal transport proteins, and vacuolar sequestration mechanisms, although comparative remarks about potential detoxifying roles of gills, integument, and kidneys are included. Information is presented about the individual roles of hepatopancreatic mitochondria, lysosomes, and endoplasmic reticula in metal sequestration and detoxification. Current working models for the involvement of mitochondrial and endoplasmic reticulum calcium-transport proteins in metal removal from the cytoplasm and the inhibitory interactions between the metals and calcium are included. In addition, copper transport proteins and V-ATPases associated with lysosomal membranes are suggested as possible sequestration processes in these organelles. Together with several possible cytoplasmic divalent and trivalent anions such as sulfate, oxalate, or phosphate, accumulations of metals in lysosomes and their complexation into detoxifying precipitation granules may be regulated by variations in lysosomal pH brought about by bafilomycin-sensitive proton ATPases. Efflux processes for metal transport from hepatopancreatic epithelial cells to the hemolymph are described, as are the possible roles of hemocytes as metal sinks. While some of the cellular processes for isolating heavy metals from general circulation occur in the hepatopancreas and are beginning to be understood, very little is currently known about the roles of the gills, integument, and kidneys in metal regulation. Therefore, much remains to be clarified about the organs and mechanisms involved in metal homeostasis in decapod crustaceans.

Heavy metal detoxification in crustacean epithelial lysosomes: role of anions in the compartmentalization process

SUMMARY Crustacean hepatopancreatic lysosomes are organelles of heavy metal sequestration and detoxification. Previous studies have shown that zinc uptake by lysosomal membrane vesicles (LMV) occurred by a vanadate- and thapsigargin-sensitive ATPase that was stimulated by a transmembrane proton gradient established by a co-localized V-ATPase associated with this organelle. In the present study, hepatopancreatic LMV from the American lobster Homarus americanus were prepared by standard centrifugation methods and 65Zn2+, 36Cl–, 35SO42– and 14C-oxalate2– were used to characterize the interactions between the metal and anions during vesicular detoxification events. Vesicles loaded with SO42– or PO43– led to a threefold greater steady-state accumulation of Zn2+ than similar vesicles loaded with mannitol, Cl– or oxalate2–. The stimulation of 65Zn2+ uptake by intravesicular sulfate was SO42– concentration dependent with a maximal enhancement at 500 μmol l–1. Zinc uptake in the presence of ATP was proton-gradient enhanced and electrogenic, exhibiting an apparent exchange stoichiometry of 1Zn+/3H+. 35SO42– and 14C-oxalate2– uptakes were both enhanced in vesicles loaded with intravesicular Cl– compared to vesicles containing mannitol, suggesting the presence of anion countertransport. 35SO42– influx was a sigmoidal function of external [SO42–] with 25 mmol l–1 internal [Cl–], or with several intravesicular pH values (e.g. 7.0, 8.0 and 9.0). In all instances Hill coefficients of approximately 2.0 were obtained, suggesting that 2 sulfate ions exchange with single Cl– or OH– ions. 36Cl– influx was a sigmoidal function of external [Cl–] with intravesicular pH of 7.0 and 9.0. A Hill coefficient of 2.0 was also obtained, suggesting the exchange of 2 Cl– for 1 OH–. 14C-oxalate influx was a hyperbolic function of external [oxalate2–] with 25 mmol l–1 internal [Cl–], suggesting a 1:1 exchange of oxalate2– for Cl–. As a group, these experiments suggest the presence of an anion exchange mechanism exchanging monovalent for polyvalent anions. Polyvalent inorganic anions (SO42– and PO43–) are known to associate with metals inside vesicles and a detoxification model is presented that suggests how these anions may contribute to concretion formation through precipitation with metals at appropriate vesicular pH.

Expression of Na+/d-glucose cotransport in Xenopus laevis oocytes by injection of poly(A)+ RNA isolated from lobster (Homarus americanus) hepatopancreas

Xenopus laevis oocytes were used for expression and characterization of lobster (Homarus americanus) hepatopancreas Na(+)-dependent D-glucose transport activity. Poly(A)(+) RNA from the whole hepatopancreatic tissue was injected and transport activity was assayed by alpha-D-[2-(3)H] glucose. Injection of lobster hepatopancreatic poly(A)(+) RNA resulted in a dose (1-20 ng) and time (1-5 days) dependent increase of Na(+)-dependent D-glucose uptake. Kinetics of Na(+)-dependent glucose transport was a hyperbolic function (K(m)=0.47+/-0.04 mM) of external D-glucose concentration and a sigmoidal function (K(Na)=68.32+/-1.57 mM; Hill coefficient=2.22+/-0.09) of external Na(+) concentration. In addition, Na(+)-dependent D-glucose uptake was significantly inhibited by both (0.1-0.5 mM) phloridzin and (0.1-0.5 mM) methyl-alpha-D-glucopyranoside. After size fractionation through a sucrose density gradient, poly(A)(+) RNA fractions with an average length of 2-4 kb induced a twofold increase in Na(+)-dependent phloridzin-inhibited D-glucose uptake as compared to total poly(A)(+) RNA-induced uptake. The results of this study provide the functional basis to screen lobster hepatopancreatic cDNA libraries for clones encoding putative and still not known crustacean SGLT-type Na(+)/glucose co-transporter(s).

Heavy Metal Transport and Detoxification by Crustacean Epithelial Lysosomes

Lysosomes are multi-functional organelles that aid in the disassembly of large organic molecules and store a variety of xenobiotics. Lysosomes, and vacuolar components of the endo-membrane system, play apparently ubiquitous sequestration and detoxification roles for heavy metals in cells of many organisms. X-ray microprobe analysis of metal-containing granules (concretions) in these organelles from many animal phyla suggest that monovalent, divalent, and trivalent metal cations can be stored in these compartments in conjunction with anionic elements such as phosphorus and sulfur. There is also evidence that thiol-containing compounds such as glutathione and metallothionein, which bind metals in the cytoplasm with high affinity, may also be translocated across lysosomal membranes for metal storage. Few studies have examined the nature of the sequestration and detoxification processes for heavy metals displayed by invertebrate lysosomes or other endo-membrane components. This review summarizes recent investigations focused on lysosomal function in crustacean hepatopancreatic absorptive epithelia. It describes the carrier-mediated transport processes that occur on lysosomal membranes for accumulating metals from the cytoplasm and how these metal transporters are linked with the uptake of multivalent anions that may precipitate concretions within the organelle at appropriate ion concentrations and pH conditions. In addition, preliminary data describing the potential role of the Organic Anion Transporter (OAT) in transporting glutathione with its associated metal load from cytoplasm to lysosomal interior are described. A model summarizing proposed coupling between cationic metal and polyvalent anion transports and how they might be linked with concretion formation and metal detoxification is presented.

Infant Mortality: A Leading Health Indicator

The purpose of this research was to study infant mortality and their rates in Duval County, Florida. Infant mortality rate is the estimate of infant deaths per 1,000 live births. The U.S. Infant Mortality Rate (IMR) currently ranks 27th among industrialized countries, with wide and persistent disparities by race, socioeconomic status, and geography. The objective of this research was to study infant mortality rates in each zip code in Duval County along with demographic information such as poverty, household income, prenatal care, and education. An analysis of the data collected was then used to establish whether there is a correlation between as poverty, household income, prenatal care, and education with infant mortality rates in zip codes with the highest and lowest infant mortality rates. The data for this research was gathered through the Florida Health department and nefloridacounts.org. The infant mortality rates and demographic information was sourced from the year 2014.

Community-Based Educational Approach to Reduce Health Disparity

Health disparities refer to differences between groups of people. These differences can affect how frequently a disease affects a group, how many people get sick, or how often the disease cause death. Racial and ethnic disparities in health and health care recently have received considerable attention. Racial and ethnic minorities tend to receive poorer quality care compared with non-minorities. The Institute of Medicine (IOM) defines disparities as “racial or ethnic differences in the quality of health care that are not due to access-related factors or clinical needs, preferences, and appropriateness of intervention [1]. While the World Health Organization (WHO), have adopted a different view of what constitutes a disparity, major stakeholders agree that such disparities are unjust and need to be addressed [2]. In order to decrease this differential, it is critical to understand the particular barriers to health and health care that underserved minorities face. The barriers have been identified as: inadequate access to and availability of health care services, lack of knowledge of disease prevention and screening recommendations, low literacy, mistrust of the health care system, fear, fatalism regarding cure, genetic and environmental risk factors.

Ion (Organic Acid and Base) Transporters and Homeostasis: A Review with Reference to its Usefulness as Biomarkers

Organisms are continuously exposed to a great variety of xenobiotics via food and environment. Evolution has equipped the body with a plethora of protecting systems to defend itself against the potentially harmful effects of these compounds. One of the important defense mechanisms include the active extrusion of xenobiotics by commonly shared transport proteins, mainly located in kidney, liver and intestine. An attempt has been made to understand the structural and functional properties of organic anion transporters (OAT1, OAT2, OAT3) and organic cation transporters (OCTN1, OCTN2, OCT1, OCT2, OCT3). These transporters share a predicted 12-transmembrane domain (TMD) structure with a large extracellular loop between TMD1 and TMD2, carrying potential N-glycosylation sites. Conserved amino acid motifs revealed a relationship to the sugar transporter family within the major facilitator superfamily. Following heterologous expression, most OATs transported the model anion p-aminohippurate (PAH). OAT1, but not OA...