Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) and its interaction with other polybrominated diphenyl ethers (PBDEs) in rodents

The disposition of the ¹⁴C-labelled polybrominated diphenyl ether (PBDE) 2,2′,4,4′,5,5′-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabelled 2,2′,4,4′-tetraBDE (BDE47) and 2,2′,4,4′,5-pentaBDE (BDE99). In single exposure studies there was little or no effect of dose on BDE153 disposition in male rats in the range 1–100?µmol?kg^?1. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was absorbed in rats or mice following gavage by approximately 70%; retained in tissues; and poorly metabolized and slowly excreted. Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in the liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in the liver due to minimal metabolism and elimination after ‘first-pass’ distribution to the tissue following gavage.     

Developmental exposure to methylmercury and 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) affects cerebral dopamine D1-like and D2-like receptors of weanling and pubertal rats

MeHg (0.5 mg/kg/day) and/or PCB153 (5 mg/kg/day) effects, administered orally to rat dams (GD7-PND21), were explored in PND21 and PND36 offspring brain in terms of density (Bmax) and affinity (Kd) of dopamine D1-like (D1-Rs) and D2-like receptors (D2-Rs), by saturation binding studies. D1-Rs decreased density in both cortex and striatum (15–30%) by MeHg and PCB153, either alone or combined, without additivity in PND21 males. Changes disappeared by PND36. In females, only MeHg caused a 15% Bmax decrease in striatum. D2-Rs enhanced density (23–50%) and reduced affinity in cortex to a similar extent by all treatments in both weanling and pubertal males. Affinity was also decreased in females by all types of exposure at both ages, while density was enhanced by PCB153 only in a delayed manner (PND36). No changes were detected in striatum. In MeHg and MeHg + PCB153 pup cortex, Hg concentrations ranged, on PND21, between 0.25 and 0.89 and 0.94–1.40 μg/g tissue, respectively, and were 5- to sixfold lower 2 weeks later. PCB153 levels, in PCB153 ± MeHg treated rats, were about 15 μg/g tissue (PND21) and 4–8 μg/g tissue (PND36). In striatum, the Hg and PCB153 concentrations were similar to those in cortex. Brain kinetics trend also applied to blood PCB153 or Hg levels. Perinatal exposure to MeHg and/or PCB153 affects D1- and D2-Rs in a gender-, time-, and brain area-dependent manner. Combined treatment does not exacerbate the neurochemical effects of the individual compounds.     

Absorption,distribution, metabolism and excretion (ADME) study with 2,2′,4,4′,5,6′-hexabromodiphenyl ether (BDE-154) in male Sprague–Dawley rats

1. A metabolism study of orally administered 2,2′,4,4′,5,6′-hexabromodiphenyl ether (BDE-154; 11.3 μmoles kg^?1) was conducted in conventional and bile duct-cannulated male Sprague–Dawley rats.

2. In conventional rats, approximately 31% of the radiolabelled dose was retained at 72 h, and lipophilic tissues were the preferred sites for disposition.

3. Urinary excretion of BDE-154 was very low (1.0%), and parent compound was detected.

4. Cumulative biliary excretion was 1.3%, and glutathione conjugates were suggested.

5. Over 62% of the dose in conventional male rats was excreted in faeces, and was composed of parent compound (7.3%), free metabolites (13.1%), and covalently bound residues (41.4%). Faecal metabolites characterized by gas chromatography/mass spectrometry included multiple isomers of monohydroxylated hexa-/penta-/tetrabromodiphenyl ethers, and di-hydroxylated hexa/pentabromodiphenyl ethers.

6. The adipose tissue ¹⁴C was extractable BDE-154, but 40% of liver ¹⁴C was bound to macromolecules.

7. The study demonstrated the importance of performing individual polybrominated diphenyl ether (PBDE) metabolism studies to understand fully PBDE pharmacokinetics.

     

2,2′,4,4′-Tetrabromodiphenyl ether disrupts spermatogenesis,impairs mitochondrial function and induces apoptosis of early leptotene spermatocytes in rats

Our objective was to explore molecular markers and mechanism of BDE47 on spermatogenesis in mammals. Adult male SD rats were gavaged daily with corn oil containing 0, 0.001, 0.03, 1 or 20 mg BDE47/kg bw for eight weeks. Testes morphology was analyzed using electron microscopy, TUNEL, immunohistochemistry and morphometry. Differential proteome profile and western blotting were applied to determine molecular markers and protein expression. GC1-spg cells (mouse spermatogonial cells) were used to verify mechanism of BDE47. Data showed BDE47 reduced tubular epithelial thickness, impaired mitochondrial function and induced apoptosis in early leptotene spermatocytes. Proteomic study identified 70 differential spots corresponding to 64 proteins. 20 proteins related to apoptosis, 15 located in mitochondria. Exposure of GC1-spg cells showed BDE47 induced apoptosis, impaired mitochondria and decreased Bcl-2 in cells. Data indicate that BDE47 disrupts spermatogenesis, impairs mitochondrial function and induces apoptosis of early leptotene spermatocytes in rats probably via mitochondrial pathway.     

Tissue disposition,excretion and metabolism of 2,2′,4,4′,6-pentabromodiphenyl ether (BDE-100) in male Sprague–Dawley rats

The absorption, disposition, metabolism and excretion study of orally administered 2,2′,4,4′,6-pentabromodiphenyl ether (BDE-100) was studied in conventional and bile-duct cannulated male rats. In conventional rats, >70% of the radiolabelled oral dose was retained at 72?h, and lipophilic tissues were the preferred sites for disposition, i.e. adipose tissue, gastrointestinal tract, skin, liver and lungs. Urinary excretion of BDE-100 was very low (0.1% of the dose). Biliary excretion of BDE-100 was slightly greater than that observed in urine, i.e. 1.7% at 72?h, and glucuronidation of phenolic metabolites was suggested. Thiol metabolites were not observed in the bile as had been reported in other PBDE metabolism studies. Almost 20% of the dose in conventional male rats and over 26% in bile-duct cannulated rats was excreted in the faeces, mainly as the unmetabolized parent, although large amounts of non-extractable radiolabel were also observed. Extractable metabolites in faeces were characterized by mass spectrometry. Monohydroxylated pentabromodiphenyl ether metabolites were detected; mono- and di-hydroxylated metabolites with accompanying oxidative debromination were also observed as faecal metabolites. Tissue residues of [¹⁴C]BDE-100 in liver, gastrointestinal tract and adipose tissue contained only parent material. The majority of the 0–72-h biliary radioactivity was associated with an unidentified 79-kDa protein or to albumin.     

Metabolism of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent

Abstract

1. Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized.

2. The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups.

3. In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male?>?female and PB?>?DEX?>?CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected.

4. Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs.     

Distribution and excretion of 2,3,6,2′,3′,6′- and 2,4,5,2′,4′,5′-hexachlorobiphenyl in senescent rats

The disposition of two symmetrical [¹⁴C]hexachlorobiphenyls (HCBs), 2,3,6,2′,3′,6′-HCB (236) and 2,4,5,2′,4′,5′-HCB (245), was studied in 24-month-old male Sprague-Dawley rats after iv treatment. Because body composition changes with age, complete dissections were performed on all rats to determine the size of the skin and adipose tissue depots. More than 50% of 236 was metabolized and excreted via the bile into the feces within 2 days. In contrast, 245 redistributed from the liver, muscle, and skin to adipose tissue where it accumulated without being metabolized. Only 2% of the total dose of 245 was excreted primarily in the feces within 21 days. The data obtained in this study were compared to results previously obtained from 2- to 3-month-old rats in this laboratory (Matthews and Tuey, 1980, Toxicol. Appl. Pharmacol.53, 377–388). Although the general pattern of HCB disposition did not change with age, i.e., metabolism and excretion of 236 versus persistence of 245, there were differences in the rates of elimination and in the tissue levels. There was enhanced metabolite retention in the muscle, skin, and adipose tissue of older animals which suggested an age-related decrease in tissue clearance. The large volume of adipose tissue in these older Sprague-Dawley rats could in part explain this observation. In general, there were few changes in decay rates from tissues or in biliary excretion. Age had a greater effect on the disposition of the persistent 245 than on the metabolizable 236. Thus, changes in body composition seemed to play a major role in age-related changes in the distribution and excretion of polychlorinated biphenyls.     

In vitro metabolism of 2,2′,3,4′,5,5′,6-heptachlorobiphenyl (CB187) by liver microsomes from rats,hamsters and guinea pigs

The metabolism of 2,2′,3,4′,5,5′,6-heptachlorobiphenyl (heptaCB) (CB187) was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 (CYP) inducers, phenobarbital (PB) and 3-methylcholanthrene (MC), was also investigated. In untreated animals, guinea pig liver microsomes formed three metabolites which were deduced to be 4′-hydroxy-2,2′,3,5,5′,6-hexachlorobiphenyl (M-1), 4′-hydroxy-2,2′,3,3′,5,5′,6-heptaCB (M-2) and 4-OH-CB187 (M-3) from the comparison of GC/MS data with some synthetic authentic samples. The formation rate of M-1, M-2 and M-3 was 18.1, 36.6, 14.7?pmol?h^?1?mg protein^?1, respectively. Liver microsomes of untreated rats and hamsters did not form CB187 metabolites. In guinea pigs, PB-treatment increased M-1 and M-2 significantly to 1.9- and 3.4-fold of untreated animals but did not affect the formation of M-3. In rats, PB-treatment resulted in the appearance of M-2 and M-3 with formation rates of 87.1 and 13.7?pmol?h^?1?mg protein^?1, respectively, but M-1 was not observed. In hamsters, PB-treatment formed only M-2 at a rate of 29.4?pmol?h^?1?mg protein^?1. On the other hand, MC-treatment of guinea pigs decreased the formation of M-1 and M-2 to less than 50% of untreated animals. MC-microsomes of rats and hamsters produced no metabolites. Preincubation of antiserum (300?µl) against guinea pig CYP2B18 with liver microsomes of PB-treated guinea pigs produced 80% inhibition of M-1 and the complete inhibition of M-2 and M-3. These results suggest that PB-inducible CYP forms, especially guinea pig CYP2B18, rat CYP2B1 and hamster CYP2B, are important in CB187 metabolism and that CB187 metabolism in guinea pigs may proceed via the formation of 3,4- or 3′,4′-oxide and subsequent NIH-shift or dechlorination.     

Transfer of 2,4,5,2′,4′,5′-hexachlorobiphenyl and 2,2-bis-(p-chlorophenyl),1,1,1-trichloroethane (p,p′-DDT) from maternal to newborn and suckling rats

Pregnant rats were given a small dose of ¹⁴C-2,4,5,2,4,5-hexachloro-biphenyl (HCB) and ³H-DDT intraperitoneally. The transfer of HCB and DDT through the placenta and milk was then investigated. Transfer through the placenta was 2.7 and 1.5% (respectively) of the initial doses; transfer through milk was 39.2 and 21.5%. HCB is obviously more transferable than DDT through the placenta and milk, the ratio of the amount of HCB transferred through milk to the amount transferred through the placenta agrees with that for DDT.Concentrations of HCB and DDT in the whole suckling rat increases rapidly and is similar to the sigmoidal growth curve and change in lipid concentration. Therefore, the concentrations of the chemicals in the maternal tissue generally decrease in comparison with those of nonpregnant rats.     

Roles of endoplasmic reticulum stress,apoptosis and autophagy in 2,2′,4,4′-tetrabromodiphenyl ether-induced rat ovarian injury

Endocrine disruptor 2,2′,4,4′-tetrabromodiphenylether (PBDE-47) can harm the female reproductive system. Recent studies showed that PBDE-47 neurotoxicity is associated with endoplasmic reticulum stress (ERS); however, the role of ERS in PBDE-47-induced ovarian injury is unclear. New-born female Sprague-Dawley rats were orally exposed to PBDE-47 (1, 5, or 10 mg/kg bw) on postnatal day 10. An additional 10 mg/kg bw PBDE-47 group was given the ERS inhibitor 4-PBA intraperitoneally for three weeks beginning on postnatal day 8. At 2 months of age, PBDE-47 exposure significantly reduced the ovarian coefficients, increased the expression of ERS and autophagy markers, including GRP78, IRE1, Caspase-12, Beclin1, LC3 and P62. In the 10 mg/kg bw PBDE-47 group, PARP and Caspase-3 were markedly activated, indicative of apoptosis. These were accompanied by histopathological damage. Intriguingly, 4-PBA attenuated all these effects. Thus, these results suggest that ERS plays a vital role in PBDE-47-induced ovarian injury by regulating autophagy and apoptosis.     

Cytotoxicity and apoptosis induction on RTG-2 cells of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and decabrominated diphenyl ether (BDE-209)

Recently, the environmental residues of polybrominated diphenyl ethers (PBDEs) have markedly increased. In particular, the levels of certain PBDE congeners in fish have raised concern regarding potential risks associated with dietary PBDEs exposures. However, little is known regarding PBDE-mediated cell injury in relevant in vitro fish cell models. In this study, the cytotoxic effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and decabrominated diphenyl ether (BDE-209) on RTG-2 cells were investigated. RTG-2 cells were incubated with different concentrations of BDE-47 and BDE-209 (1–100 μM) for 72 h, and a set of bioassays were conducted to measure: cell viability (evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and neutral red (NR) uptake), lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation and cell apoptosis. The results showed that BDE-47 and BDE-209 inhibited the cells viability, increased LDH leakage, and induced cell apoptosis in time and concentration-dependent manner. All significant effects were observed at concentrations of 12.5 μM and above for BDE-47 and 25 μM and above for BDE-209 (P < 0.05). At the concentration of 100 μM BDE-47 and BDE-209, the cell viability of the exposed cells dropped to about 40% and 50% of the control, and the apoptotic rates were 52.6% and 34.6%, respectively. After 12 h exposure, a concentration-dependent increases of BDE-47 and BDE-209 (12.5–100 μM) in ROS formation were observed. Collectively, the results of cell viability, LDH leakage, cell apoptosis and ROS formation demonstrated that the toxic mechanism of PBDEs on RTG-2 might be mediated by oxidative stress.     

Tissue disposition,excretion and metabolism of 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99) in the male Sprague-Dawley rat

1. A disposition, metabolism and excretion study of orally administered 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) was conducted in the conventional and bile duct-cannulated male rat. 2. In the conventional rat, >50% of the radiolabelled dose was retained at 72 h, and lipophilic tissues were the preferred sites for disposition, i.e. adipose tissue, adrenals, gastrointestinal tract and skin. 3. Urinary excretion of BDE-99 was very low (<1% of dose), and glucuronidation of phenolic metabolites was suggested. 4. Biliary excretion of BDE-99 was slightly greater than observed in urine, i.e. 3.6% at 72h. 5. Over 43% of the dose in the conventional male rat and 86% in the bile duct-cannulated rat was excreted in the faeces, mainly as the unmetabolized parent compound. 6. Metabolites in bile and faeces were not conjugated. Mono- and di-hydroxylated pentabromodiphenyl ether metabolites were characterized by mass spectrometry. Two thiol metabolites were characterized in the bile. Oxidative debromination was also observed in the faecal metabolites. 7. Tissue BDE-99 was readily extractable, except for in the liver. The tissue ¹⁴C was not associated with lipids and was mainly the unmetabolized parent compound. 8. Total thyroxine (T4) plasma levels were elevated at 3 and 6 days, and returned to control levels by day 12.     

The effect of 3,4,3′,4′-tetrachlorobiphenyl on plasma retinol and hepatic retinyl palmitate hydrolase activity in female Sprague-Dawley rats

A single ip dose of 1, 5, or 15 mg/kg 3,4,3′,4′-tetrachlorobiphenyl (TCB) caused a dose-dependent depression of plasma retinol levels 24 hr after treatment of female Sprague-Dawley rats. The loss of plasma retinol appeared to be a function of depressed levels of the retinol-retinol-binding protein (RBP)-transthyretin ternary complex. No free retinol-RBP was observed in plasma from treated animals. Hepatic retinyl palmitate hydrolase (RPH) activity was also depressed and highly and positively correlated to the plasma retinol levels. TCB was determined to be a noncompetitive inhibitor of partially purified RPH with a K_I of 91 μm. Incubation of TCB with liver microsomes and NADPH decreased the inhibition of RPH. Doses of either 2,4,5,2′,4′,5′-hexachlorobiphenyl (HCB) or 3,4,5,3′,4′,5′-HCB equimolar to the 15 mg/kg TCB dose failed to cause a similar depression of plasma retinol in treated female rats. We conclude that, unlike other polychlorinated biphenyl congeners, TCB causes a depression of plasma retinol by inhibition of hepatic RPH.     

Metabolism of 2,4,5,2′,4′,5′-hexachlorobiphenyl (PCB153) in guinea pig

1. The in vitro and in vivo metabolism of 2,4,5,2′,4′,5′-hexachlorobiphenyl (PCB153) in guinea pig has been studied. 2. Seven metabolites were detected in the faeces of PCB153-treated animals and three were identical to those produced by dog liver microsomes. The detection of a metabolite where a chlorine atom was shifted from the 2- to 3-position strongly suggested the involvement of 2,3-arene oxide intermediate, and evidence for the concomitant formation of a 3,4-arene oxide intermediate was provided by identifying other two minor metabolites which were dechlorinated at the 4-position. 3. In vitro studies using liver microsomes from guinea pigs revealed that the 2,3-arene oxide and 3-hydroxylation pathways are the predominant metabolic routes compared with the 3,4-arene oxide pathway. Although the guinea pig is an another species that can metabolize PCB153 mainly to the 2,3-arene oxide intermediate, the rate of formation was only about one-tenth of the dog. 4. These results indicate that the ability to form this unusual 2,3-arene oxide intermediate may not be responsible for high excretion rate of this congener. Our data also suggest that the cytochrome P450-catalysed metabolism of PCB153 in the guinea pig and dog are similar, whereas for post-cytochrome P450 metabolism, the guinea pig resembles the rabbit.     

Unlabeled hemoglobin adducts of 4,4′-methylenebis (2-chloroaniline) in rats and guinea pigs

The capacity of N-oxidized metabolites of 4,4-methylenebis(2-chloroaniline) (MBOCA) to form hemoglobin (Hb) adducts was determined in vitro, and the formation of Hb adducts following in vivo administration of MBOCA was assessed with or without prior induction of cytochrome P-450 enzymes with phenobarbital or -naphthoflavone. Hb adduct formation was determined by electron-capture GLC of MBOCA as the heptafluorobutyryl derivative following mild acid hydrolysis of protein-bound MBOCA. The method was confirmed by gas chromatography-mass spectrometry with selected ion monitoring. N-hydroxy- and mononitroso-MBOCA, but not MBOCA itself, formed adducts to rat and human Hb in vitro in a dose-related manner. Binding was inhibited by cysteine and glutathione but not oxidized glutathione or methionine. Intravenous administration of as little as 0.04 mol/kg N-hydroxy-MBOCA to rats resulted in measurable formation of MBOCA-Hb adducts (0.9 ng/50 mg Hb). Intraperitoneal administration of 0.5–50 mg/kg MBOCA to rats, and subcutaneous administration of 5–500 mg/kg MBOCA to rats and 4–100 mg/kg to guinea pigs resulted in dose-related formation of Hb adducts. MBOCA-Hb remained elevated in blood for greater than 10 weeks following a single subcutaneous dose in guinea pigs. Pretreatment of rats with phenobarbital induced microsomal benzphetamine N-demethylase (BND) activity and resulted in a small increase in in vitro N- andortho- hydroxylation of MBOCA, but did not increase in vivo Hb adducts. Pretreatment of rats with -naphthoflavone induced microsomal aryl hydrocarbon hydroxylase as well as ethoxyresorufin-O-deethylase, and increased in vitro N- but notortho-hydroxylation of MBOCA. -Naphthoflavone pretreatment increased the formation of MBOCA-Hb adducts when rats were dosed with MBOCA at 100 and 500 mg/kg, but not 20 mg/kg subcutaneously.     

β-Naphthoflavone- and self-induced metabolism of 3,3′,4,4′-tetrachlorobiphenyl in hepatic microsomes of the male,pregnant female and foetal rat

1. The in vitro metabolism of 3,3′,4,4′-tetrachloro-[¹⁴C]-biphenyl ([¹⁴C]-TCB) by hepatic microsomes from the Wistar rat was investigated with liver microsomes from the male, pregnant female and foetus.

2. Three hydroxylated metabolites (4-OH-3,3′,4,5′-tetrachlorobiphenyl, 5-OH-3,3′,4,4′-tetrachlorobiphenyl, and 6-OH-3,3′,4,4′-tetrachlorobiphenyl) were identified by hplc and gc-ms after incubations of liver microsomes from the β-naphthoflavone-pretreated male rat and TCB-treated pregnant rat. No metabolites of [¹⁴C]-TCB were found after incubation with foetal liver microsomes from dams pretreated with [¹⁴C]-TCB. The results indicate that the in vivo accumulation of 4-OH-tetraCB in the foetal compartment is probably due to transplacental transport rather than the formation of this metabolite in the foetus.

3. Pretreatment of the male rat with β-naphthoflavone substantially induced the formation of hydroxylated metabolites, but pretreatment with phenobarbital and dexamethasone was without effect. Based on in vitro incubations of liver microsomes from the β-naphthoflavone pretreated male rat, an apparent K_m and V_max of 4·5 μM and 240 pmol/mg protein/min respectively was determined for the metabolism of [¹⁴C]-TCB. The formation of phenolic metabolites of [¹⁴C]-TCB was most likely dependent on P4501A induction.     

Effects of arecoline and cholinesterase inhibitors on cyclic guanosine 3′,5′-monophosphate and adenosine 3′,5′-monophosphate in mouse brain

Summary In mice, Arecoline in vivo dose-dependently increased the cGMP concentrations of the cerebellum and the cerebrum (= parts of cortex, hippocampus, hypothalamus, thalamus, striatum and midbrain) without influencing the cAMP levels. The cholinesterase inhibitors paraoxon and physostigmine caused an elevation only in cerebrum, whereas the cGMP content of the cerebellum even decreased.Pretreatment with atropine prevented the rise in cGMP levels as well as the symptoms of cholinergic stimulation elicited by arecoline or paraoxon. Diazepam reduced cGMP levels below control values and blocked the effect of arecoline, while typical symptoms due to arecoline, e.g., tremor and salivation remained unaffected. The tripeptide prolyl-leucyl-glycinamide (MIF) had no effect on either cGMP values or the peripheral signs of cholinergic stimulation elicited by arecoline.The results show that elevation of cGMP in the central nervous system caused by cholinomimetic agents can be prevented not only by cholinolytics, blocking muscarinic receptors but also by influencing other mechanisms to be discussed.     

Different action of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and its hydroxylated metabolites on ERα and ERβ gene and protein expression

In our previously published data we showed that PBDEs act as endocrine disruptors in ovarian follicles by altering steroid secretion.     

Mammalian toxicology and human exposures to the flame retardant 2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol (TBBPA): implications for risk assessment

The compound 2,2′,6,6′-Tetrabromo-4,4′-isopropylidenediphenol (tetrabromobisphenol A, TBBPA) is used as a reactive and additive flame retardant. This review evaluates the mammalian toxicology of TBBPA and summarizes recent human exposure and risk assessments. TBBPA has a low potential for systemic or reproductive toxicity, and no-observed-adverse-effect-levels were greater than 1,000 mg/kg body weight (bw)/day in a 90-day oral toxicity study, a developmental toxicity study and a two-generation reproductive and developmental toxicity study. Some interactions of TBBPA with hormone-mediated pathways were noted in vitro; however, when studied in vivo, TBBPA did not produce adverse effects that might be considered to be related to disturbances in the endocrine system. Therefore, in accordance with internationally accepted definitions, TBBPA should not be considered an “endocrine disruptor.” Furthermore, TBBPA is rapidly excreted in mammals and therefore does not have a potential for bioaccumulation. Measured concentrations of TBBPA in house dust, human diet and human serum samples are very low. Daily intakes of TBBPA in humans were estimated to not exceed a few ng/kg bw/day. Due to the low exposures and the low potential for toxicity, margins of exposures for TBBPA in the human population were between 6 × 10⁴ (infants) to 6 × 10⁷ (adults). Exposures of the general population are also well below the derived-no-effect-levels derived for endpoints of potential concern in REACH.     

Effects of trophic 2,2′, 4,4′-tetrabromodiphenyl ether (BDE-47) exposure in Oreochromis niloticus: A multiple biomarkers analysis

Polybrominated diphenyl esters are emerging environmental contaminants with few toxicological data, being a concern for the scientific community. This study evaluated the effects of BDE-47 on the health of Oreochromis niloticus fish. The animals were exposed to three doses of BDE-47 (0, 0.253, 2.53, 25.3 ng g⁻¹) every 10 days, for 80 days. The BDE-47 affected the hepatosomatic and gonadosomatic index in female and the condition factor by intermediate dose in both sexes. The levels of estradiol decreased and the T4 are increased, but the vitellogenin production was not modulated in male individuals. Changes in AChE, GST, LPO and histopathology were observed while the integrated biomarker response index suggests that the lowest dose of BDE-47 compromised the activity of antioxidant enzymes. The oral exposure to BDE-47 in environmental concentrations is toxic to O. niloticus and the use of multiple biomarkers is an attribution in ecotoxicology studies and biomonitoring programs.