Biomedical subjects

Heldur Hakk

Publications and source records attributed to Heldur Hakk.

12 recordsLinked to original sources

PubMed2006

Fate and transport of 1278-TCDD, 1378-TCDD, and 1478-TCDD in soil-water systems.

The most toxic dioxin is 2,3,7,8-tetrachlorodibenzo-p-dioxin (2378-TCDD), and obtaining comprehensive experimental data for this compound is challenging. However, several nontoxic isomers of 2378-TCDD exist, and can provide significant experimental evidence about this highly toxic dioxin. The goal of this study was to obtain experimental evidence for the fate and transport of 2378-TCDD in natural soils using its nontoxic isomers, 1,2,7,8-tetrachlorodibenzo-p-dioxin (1278-TCDD), 1,3,7,8-tetrachlorodibenzo-p-dioxin (1378-TCDD), and 1,4,7,8-tetrachlorodibenzo-p-dioxin (1478-TCDD). Batch sorption and miscible-displacement experiments, in various soils, were done using [4-(14)C]-radiolabeled TCDDs, while metabolism of these compounds was monitored. The results from the batch experiments indicated a high sorption affinity of all the TCDD isomers to soils and a strong correlation to organic matter (OM) content. 1278-TCDD, 1378-TCDD and 1478-TCDD (TCDDs) were more tightly bound to the soil with high OM than to the soil with low OM; however, it took a longer contact time to approach sorption equilibrium of TCDDs in the soil with high OM. Miscible-displacement breakthrough curves indicated chemical nonequilibrium transport, where there was a rate-limited or kinetic sorption that was likely caused by OM. Combustion analyses of extracted soil from the soil columns showed that most TCDDs were adsorbed in the top 1-5 cm of the column. These column combustion results also showed that sorption was correlated to specific surface and soil depth, which suggested the possibility of colloidal transport.

Adsorption↗

PubMed2006

Toxicokinetics of polybrominated diphenyl ether congeners 47, 99, 100, and 153 in mice.

The congener profiles of polybrominated diphenyl ethers (PBDEs) in human and wildlife samples are dominated by brominated diphenyl ether (BDE) congeners 47, 99, 100, 153, and 154, all of which are components of the commercial pentaBDE mixtures commonly used in a variety of flammable consumer products. Very little information is available on the toxicokinetics of these congeners and no studies are available directly comparing these BDE congeners in mice. Therefore, the objective of this study was to compare the distribution, metabolism, and excretion of BDEs 47, 99, 100 and 153. Female C57BL/6 mice were administered a single dose of BDE (1 mg/kg: 2.1, 1.9, 1.9, and 1.8 mumol/kg, respectively) intravenously. Excretion was monitored daily, and terminal tissue disposition was examined 5 days following exposure. All BDE congeners in this study distribute with similar patterns into lipophilic tissues; however, tissue concentrations 5 days following exposure were much higher for BDE-153 than for 100, 99, and 47, respectively. Excretion rates were inversely related to tissue concentrations as BDE-47 was the most rapidly excreted congener, followed by BDE-99, -100, and -153. Differences in tissue concentrations were largely driven by congener-specific urinary elimination rates which were associated with protein binding in the urine. While the overall rate of metabolism appeared to be low, analysis of metabolites in daily feces samples revealed that BDE-99 was the most rapidly metabolized congener in this study. The results of this study demonstrate that congener substitution plays a role in the distribution, metabolism, and excretion of PBDEs in mice and it is therefore important to consider the differential toxicokinetic parameters associated with each congener when assessing the risk to human health from these PBDE congeners.

Animals↗

PubMed2006

Bioavailability and mass balance studies of a commercial pentabromodiphenyl ether mixture in male Sprague-Dawley rats.

Polybrominated diphenyl ethers (PBDE) are common flame retardants used in polyurethane foam, high impact polystyrene, and textiles which appear to be increasing in the environment and biota. Two PBDE congeners that are particularly prominent in environmental samples are 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99). These two congeners are major components in penta-BDE formulations which constitute a minor percentage of the commercial PBDE market. In order to determine the bioavailability and bioconcentration potential of these PBDEs, we have conducted a feeding experiment in rats, dosing with low amounts of a commercial penta-BDE mixture for 21 days to mimic an environmental exposure. The carcasses, livers, and feces from control and dosed rats were quantitated for PBDEs by a high resolution GC-MS isotope dilution method. Between 25% and 50% of each of the dosed congeners was retained in the rats with the liver being a minor depot (<1% of the dose). Fecal excretion accounted for 4-12% of the dosed congeners. A large percent of the dose (40-60%) was not recovered indicating that metabolic transformations may have occurred in the rats. Hydroxylated metabolites were qualitatively identified in the feces and carcass by GC-MS. The relative congener distribution in each tissue was nearly identical to the congener distribution of the commercial mixture. Conclusions from the study suggest that the tetra- to hexa-BDEs present in commercial penta-BDE formulations are largely bioavailable, that bioavailability in the rat is not dependent on the degree of bromination, and that metabolism may occur to a large extent during a chronic exposure.

Animals↗

PubMed2006

Cytosolic and localized inhibition of phosphodiesterase by atrazine in swine tissue homogenates.

Atrazine (ATR) significantly inhibited phosphodiesterase (PDE) in crude homogenates of swine heart, brain, and lung, but not liver or kidney tissues. Except for heart, PDE activities in the cytosolic fraction of the tissue homogenates were not affected by ATR. The inhibition of the PDE activity in the cytosol from heart homogenate was not significantly different between ATR and a non-specific PDE inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Dixon plots of the crude tissue homogenates showed that heart and brain were inhibited via two different mechanisms (competitive or mixed inhibition, and noncompetitive inhibition, respectively), suggesting that ATR may be a semi-specific PDE inhibitor. Furthermore, in crude tissue homogenates, ATR did not inhibit PDE as effectively as IBMX suggesting that there are ATR-susceptible and ATR-nonsusceptible forms of PDE. Association constants for ATR were 55 microM for heart and 310 microM for brain. The stability of the activity of PDE was affected by freezing, requiring the use of only freshly prepared tissue homogenates.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Sorption, mobility, and transformation of estrogenic hormones in natural soil.

Potent estrogenic hormones are consistently detected in the environment at low concentration, yet these chemicals are strongly sorbed to soil and are labile. The objective of this research was to improve the understanding of the processes of sorption, mobility, and transformation for estrogens in natural soils, and their interaction. Equilibrium and kinetic batch sorption experiments, and a long-term column study were used to study the fate and transport of 17beta-estradiol and its primary metabolite, estrone, in natural soil. Kinetic and equilibrium batch experiments were done using radiolabeled 17beta-estradiol and estrone. At the concentrations used, it appeared that equilibrium sorption for both estrogens was achieved between 5 and 24 h, and that the equilibrium sorption isotherms were linear. The log K(oc) values for 17beta-estradiol (2.94) and estrone (2.99) were consistent with previously reported values. Additionally, it was found that there was rate-limited sorption for both 17beta-estradiol (0.178 h(-1)) and estrone (0.210 h(-1)). An approximately 42 h long, steady-flow, saturated column experiment was used to study the transport of radiolabeled 17beta-estradiol, which was applied in a 5.00 mg L(-1) solution pulse for 44 pore volumes. 17beta-estradiol and estrone were the predominant compounds detected in the effluent. The effluent breakthrough curves were asymmetric and the transport modeling indicated that sorption was rate-limited. Sorption rates and distributions of the estrogens were in agreement between column and batch experiments. This research can provide a better link between the laboratory results and observations in the natural environment.

Adsorption↗

PubMed2005

Decrease in water-soluble 17beta-Estradiol and testosterone in composted poultry manure with time.

Little attention has been paid to the environmental fate of the hormones 17beta-estradiol and testosterone excreted in animal waste. Land application of manure has a considerable potential to affect the environment with these endocrine disrupting compounds (EDCs). Composting is known to decompose organic matter to a stable, humus-like material. The goal of the present study was to quantitatively assess levels of water-soluble 17beta-estradiol and testosterone in composting chicken manure with time. Chicken layer manure was mixed with hay, straw, decomposed leaves, and starter compost, adjusted to approximately 60% moisture, and placed into a windrow. A clay-amended windrow was also prepared. Windrows were turned weekly, and temperature, oxygen, and CO(2) in the composting mass were monitored for either 133 or 139 d. Commercial enzyme immunoassay kits were used to quantitate the levels of 17beta-estradiol and testosterone in aqueous sample extracts. Water-soluble quantities of both hormones diminished during composting. The decrease in 17beta-estradiol followed first-order kinetics, with a rate constant k = -0.010/d. Testosterone levels declined at a slightly higher rate than 17beta-estradiol (i.e., k = -0.015/d). Both hormones could still be measured in aqueous extracts of compost sampled at the conclusion of composting. The decline in water-soluble 17beta-estradiol and testosterone in extracts of clay-amended compost was not statistically different from normal compost. These data suggest that composting may be an environmentally friendly technology suitable for reducing, but not eliminating, the concentrations of these endocrine disrupting hormones at concentrated animal operation facilities.

Androgens↗

PubMed2004

Atrazine is a competitive inhibitor of phosphodiesterase but does not affect the estrogen receptor.

Atrazine (ATR), 2-chloro-4-ethylamino-6-isopropylamino-s-triazine, has been implicated in numerous studies to act as an endocrine disruptor, specifically by altering estradiol signaling via increased aromatase activity. Fluorescence polarization (FP) was used to show that the binding equilibria between estrogen receptor-alpha or estrogen receptor-beta, and estradiol were not affected by ATR and its metabolites: ATR-desethyl (ADE), ATR-desisopropyl (ADI), ATR-desethyldesisopropyl (ADD) and terbuthylazine (TBZ). Therefore, ATR and its degradation products were studied to determine their ability to inhibit phosphodiesterase (PDE), the enzyme responsible for hydrolyzing the second messenger cAMP to 5'-AMP. Using FP, it was found that ATR inhibited PDE with an IC50 value of 1.8 microM. This was lower than the known PDE inhibitor isobutyl methylxanthine (IBMX), which had an IC50 value of 4.6 microM. The ATR degradation products ADE, ADI, ADD and TBZ were less effective than ATR at inhibiting PDE when assayed using FP. Classical competitive binding assays, using radiolabeled 14C-cAMP in conjunction with thin layer chromatography (TLC), were used to determine that ATR was a competitive inhibitor of PDE with an association constant of 85 microM.

Atrazine↗

PubMed2004

Fate and transport of testosterone in agricultural soils.

Hormones excreted in animal waste have been measured in surface and groundwater associated with manure that is applied to the land surface. Limited studies have been done on the fate and transport of androgenic hormones in soils. In this study, batch and column experiments were used to identify the fate and transport of radiolabeled [14C] testosterone in agricultural soils. The batch results indicated that aqueous-phase concentrations decreased for the first 5 h and then appeared to increase through time. The first-order sorption kinetics ranged from 0.08 to 0.640 h(-1) for the first 5 h. Beyond 5 h the increase in aqueous 14C could have been caused by desorption of testosterone back into the aqueous phase. However, metabolites were also produced beyond 5 h and would have likely resulted in the increase in aqueous 14C by sorption site competition and/or by lower sorption affinity. There were weak correlations of sorption with soil particle size, organic matter, and specific surface area. Testosterone was the dominant compound present in the soil column effluents, and a fully kinetic-sorption, chemical nonequilibrium model was used to describe the data. Column experiment sorption estimates were lower than the batch, which resulted from rate-limiting sorption due to the advective transport. The column degradation coefficients (0.404-0.600 h(-1)) were generally higher than values reported in the literature for 17beta-estradiol. Although it was found that testosterone degraded more readily than 17beta-estradiol, it appeared to have a greater potential to migrate in the soil because it was not as strongly sorbed. This study underlined the importance of the simultaneous transformation and sorption processes in the transport of hormones through soils.

Agriculture↗

PubMed2004

Metabolism, tissue disposition, and excretion of 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) in male Sprague-Dawley rats.

A single oral dose of [14C] 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) was administered to conventional and bile-duct cannulated male Sprague-Dawley rats. Tissue disposition, excretion and metabolism was determined. BTBPE is a low-volume brominated flame retardant used in resins or plastics, and toxicity data in peer-reviewed journals is extremely limited. BTBPE was fairly insoluble in lipophilic solutions, which made dose preparation difficult. The great majority of 14C (>94%) was excreted in the feces of both groups of rats at 72 h, and tissue retention was minimal. Lipophilic tissues contained the highest concentrations of BTBPE, e.g. thymus, adipose tissue, adrenals, lung, and skin. Metabolites were excreted in the urine, bile and feces, but at a very low level. Fecal metabolites were characterized as monohydroxylated, monohydroxylated with debromination, dihydroxylated/debrominated on a single aromatic ring, monohydroxylated on each aromatic ring with accompanying debromination, and cleavage on either side of the ether linkage to yield tribromophenol and tribromophenoxyethanol. Despite a limited quantity of stable metabolites extractable in the feces, non-extractable 14C levels were relatively high (39% of the 0-24 h fecal 14C), which suggested that BTBPE could be metabolically activated in the rat and covalently bound to fecal proteins and/or lipids. It was concluded that limited absorption and metabolism of BTBPE would occur by ingestion in mammals.

Animals↗

PubMed2003

Fate and transport of 17beta-estradiol in soil-water systems.

Over the past several years, there has been an increase in concern regarding reproductive hormones in the environment To date, there exists limited research on the fate and transport of these chemicals in the environment. In this study, a series of laboratory batch sorption and miscible-displacement experiments were done using radiolabeled [14C]17beta-estradiol. The 17beta-estradiol concentrations that were used were similar to those found in manures that are applied to field soils. Equilibrium batch experiments indicated high sorption affinity with correlations to mineral particle size and organic matter content. The sorption affinity appeared to be associated with the surface area and/or the cation-exchange capacity of the soil. The miscible-displacement breakthrough curves indicated chemical nonequilibrium transport, and a single highly polar metabolite was present in the column effluent along with sporadic and trace detections of estriol. Sorbed to the soil within the column were found 17beta-estradiol, estrone, and trace and sporadic detections of estriol. Two chemical nonequilibrium, miscible-displacement models were used to describe the column breakthrough curves; one without transformations and the other with transformations. Both models resulted in excellent descriptions of the data, which indicated nonunique solutions and less confidence in the parameter estimates. Nonetheless, the modeling and experimental results implied that degradation/transformation occurred in the sorbed phase and was rapid. Also, both models indicated that sorption was fully kinetic.

Adsorption↗

PubMed2003

Metabolism in the toxicokinetics and fate of brominated flame retardants--a review.

Several classes of brominated flame retardants (BFRs), namely polybrominated biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCCD), bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tris(2,3-dibromopropyl)phosphate (Tris), have been identified as environmental contaminants. PBDEs, TBBPA, and HBCCD are of particular concern due to increasing environmental concentrations and their ubiquitous presence in the tissues of humans and wildlife from Europe, Japan, and North America. Regardless, the toxicokinetics, in particular metabolism, of BFRs has received little attention. The present review summarizes the current state of knowledge of BFR metabolism, which is an important factor in determining the bioaccumulation, fate, toxicokinetics, and potential toxicity of BFRs in exposed organisms. Of the minimal metabolism research done, BFRs have been shown to be susceptible to several metabolic processes including oxidative debromination, reductive debromination, oxidative CYP enzyme-mediated biotransformation, and/or Phase II conjugation (glucuronidation and sulfation).However, substantially more research on metabolism is necessary to fully assess BFR fate, uptake and elimination kinetics, metabolic pathways, inter-species differences, the influence of congener structure, and the potential health risks to exposed organisms.

Animals↗

PubMed2003

Decabromodiphenyl ether in the rat: absorption, distribution, metabolism, and excretion.

Among the group of polybrominated diphenyl ethers used as flame-retardants, the fully brominated diphenyl ether, decabromodiphenyl ether (decaBDE), is the most commonly used. Despite the large usage of decaBDE, neither the metabolic pathways nor the absorption have been addressed, and there are very few studies on its toxicology. In this work, it is shown that after a single oral dose of 14C-labeled decaBDE to rats, at least 10% of the decaBDE dose is absorbed. The major excretion route in conventional rats is via feces that contained 90% of the decaBDE dose. The excretion in bile was close to 10% of the dose and represented mainly metabolites. It cannot be excluded that greater than 10% of the oral dose had been absorbed since 65% of the radioactivity excreted in feces was metabolites. The highest concentrations on a lipid weight basis were found in plasma and blood-rich tissues, and the adipose tissue had the lowest concentration of decaBDE. After derivatization of a phenolic fraction, gas chromatography-mass spectrometry (GC/MS) analyses indicated that metabolites with five to seven bromine atoms had formed, and they possessed a guaiacol structure (a hydroxy and a methoxy group) in one of the rings. In addition, traces of nonabrominated diphenyl ethers and monohydroxylated metabolites were found by GC/MS. Metabolites, characterized by their chemical properties, were interpreted to be covalently bound to macromolecules, either proteins or lipids. In addition, water solubility was suggested. The metabolic pathway was indicated to include a reactive intermediate.

Absorption↗