K.M. McCormack

Renal and hepatic microsomal enzyme stimulation and renal function following three months of dietary exposure to polybrominated biphenyls

Polybrominated biphenyls (PBB) stimulate microsomal enzyme activity and produce a variety of toxic manifestations, including renal and hepatic histopathological changes. Therefore, it was of interest to determine the effect of chronic exposure to PBB on renal and hepatic microsomal enzyme stimulation and renal function. Adult Sprague-Dawley rats were fed diets containing 0 or 100 ppm of PBB for 3 months. Treatment with PBB retarded weight gain and increased the liver to body weight ratio but did not alter kidney to body weight ratio. Biphenyl-4-hydroxylase (BP-4-OH) and biphenyl-2-hydroxylase (BP-2-OH) activities were elevated in the kidney and liver following treatment with PBB. Exposure to PBB increased aryl hydrocarbon hydroxylase (AHH) activity in the kidney and liver. Epoxide hydratase (EH) activity was increased in the liver but decreased in the kidney following exposure to PBB. A three-month exposure to PBB had no effect on blood urea nitrogen, the clearance of inulin, p-aminohippurate (PAH), or fractional sodium excretion. Similarly, the in vitro accumulation of PAH and N-methylnicotinamide (NMN) in thin renal cortical slices and ammoniagenesis and gluconeogenesis in renal cortical slices were not affected by PBB. In conclusion, chronic exposure to PBB resulted in significant alterations in renal and hepatic microsomal enzyme activities but had no detectable effect on renal function. These experiments suggest that alterations in microsomal enzyme activities following PBB do not lead to impairment of renal function; however, this compound may sensitize the kidney to toxicity produced by agents administered subsequent to PBB.

The effects of aluminum on microtubular integrity using in vitro and in vivo models

Since neuronal lesions produced by aluminum (Al) are morphologically similar to lesions produced by microtubule inhibitors, the effect of aluminum on microtubule integrity was investigated. Aluminum inhibited microtubule formation at concentrations as low as 0.1 mM. This approaches the aluminum concentrations found in brains of patients with several disorders which result in progressive dementia.

Biochemical and physiological sequelae to perinatal exposure to polybrominated biphenyls: A multigeneration study in rats

Abstract Polybrominated biphenyls (PBBs) cross the placenta and have been detected in milk. Since biologically stable PBBs are transferred readily from mother to offspring, addition of PBBs to the food supply of one generation may result in exposure of subsequent generations. Therefore, we identified physiological and biochemical sequelae to perinatal exposure to PBBs. Rats were fed diets containing 0, 10, or 100 ppm PBBs from Day 8 of pregnancy until 28 days postpartum at which time all offspring (F1-10 and F1-100) were weaned onto control diet, allowed to mature sexually, and bred with littermates to produce the F2 generation (F2-10 and F2-100). F2-100 littermates were bred to produce F3-100 animals. Experiments were conducted in offspring from each generation at 28 days of age. Results from this investigation demonstrate that survival can be reduced and growth and development retarded by perinatal exposure to PBBs. PBBs transferred from one generation to the next produced liver enlargement, hepatic histopathologic alterations, hepatic and renal microsomal enzyme stimulation, a reduction in the duration of anesthesia produced by pentobarbital or a large dose of progesterone, and a decrease in the concentration of vitamin A in liver. Therefore, the health hazard associated with exposure to PBBs may not be limited to a single generation.

Concomitant dietary exposure to polychlorinated biphenyls and polybrominated biphenyls: tissue distribution and arylhydrocarbon hydroxylase activity in lactating rats.

Abstract Polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) stimulate microsomal mixed function monooxygenases in liver and extrahepatic tissues. These compounds accumulate to high concentration in fatty tissues and are excreted into milk. Human populations that have been exposed to PBBs are also likely to have been exposed to PCBs. Therefore, to assess potential hazard of simultaneous exposure to PCBs and PBBs, it was of interest to determine the distribution of PCBs (Aroclor 1254) and PBBs (Firemaster BP6) in several tissues of lactating rats, to determine the concentrations of both agents in milk and to study the effects of these agents on hepatic and extrahepatic arylhydrocarbon hydroxylase (AHH) after concomitant dietary exposure. Sprague-Dawley rats were placed on diets containing PBBs and/or PCBs from the eighth day of pregnancy to 14 days postpartum. Treatment with the highest dose of PBBs (200 ppm) retarded both dam and pup body weight gain. Stimulation of AHH was greater after treatment with PBBs alone than PCBs alone. Extrahepatic tissue concentrations of PCBs and PBBs were similar regardless of whether these agents were administered together or alone. Liver and milk contained lower concentrations of PBBs after treatment with an equal mixture of PCBs and PBBs than when PBBs were administered alone. Milk contained higher concentrations of PCBs than PBBs indicating that this route of excretion may be more important for PCBs.

Liver and mammary arylhydrocarbon hydroxylase and epoxide hydratase in lactating rats fed polybrominated biphenyls

Abstract Female rats were fed polybrominated biphenyls (PBBs) (50 ppm) from day 8 of gestation through day 14 postpartum. Hepatic and mammary liver to body weight ratios, microsomal protein, arylhydrocarbon (benzo(a)pyrene) hydroxylase (AHH) activity and epoxide hydratase (EH) activities were measured. Exposure to PBBs significantly increased liver to body weight ratio, hepatic microsomal protein and hepatic AHH and EH activities. Mammary AHH activity was increased and EH activity was decreased after PBBs. These data demonstrate that AHH and EH are present in mammary tissue and can be altered by exposure to PBBs.

Postnatal morphology and functional capacity of the kidney following prenatal treatment with dinoseb in rats

Dinoseb has produced alterations that are suggestive of renal damage in mice and rats. Therefore it was of interest to determine the postnatal morphology and functional capacity of the kidney following prenatal treatment with dinoseb in rats. Fetal and neonatal rats treated with dinoseb on gestational d 10-12 had dilated renal pelves and ureters. Kidneys had dilated tubules and excessive mesenchymal tissue when examined perinatally. These pathological changes were reduced in incidence (kidney) or not detected (ureter) at 42 d postpartum and were not correlated with alterations in postnatal renal function. Livers from rats treated prenatally with dinoseb were vacuolated and necrotic even at 42 d postpartum. Rats treated prenatally with dinoseb had reduced body weights at 1 and 7 d postpartum. However, body weights of control and dinoseb-treated rats were not significantly different at 42 d of age. These results emphasize the need to determine the pesistence and functional consequences of anomalies detected in near-term fetuses for safety assessment of a chemical.

Effect of polybrominated biphenyls on hepatic microsomal metabolism of estrogens and uterotropic action of administered estrogen in rats

Perinatal exposure to polybrominated biphenyls (PBBs) increased the hepatic microsomal metabolism of estradiol, estrone, and ethynylestradiol in vitro. Pretreatment with PBBs decreased the effect of estradiol administered exogenously on uterine estrogen cytosolic receptor concentration. The effect of exogenous estradiol on uterine weight and uterine RNA content was also reduced by perinatal exposure to PBBs. Therefore, metabolism of estrogens is altered by PBBs.

Altered metabolism of progesterone by hepatic microsomes from rats following dietary exposure to polybrominated biphenyls

Abstract Polybrominated biphenyls (PBBs) have produced a variety of effects including alterations in the endocrine system and in activity of microsomal mixed function oxidases (MFOs). Since steroid sex hormones are substrates for MFOs, certain effects of PBBs on the endocrine system may be a consequence of enhanced steroid sex hormone catabolism. Therefore, the purpose of this investigation was to determine the effects of PBBs on hepatic microsomal metabolism of progesterone in vitro. Hepatic microsomes were prepared from rats exposed to 0 or 100 ppm PBBs from Day 8 of gestation until they were killed at 4 (male and female), 12 (male), or 21 (female) weeks of age. Progesterone and its metabolites were identified and quantified utilizing high-pressure liquid chromatography and/or thin-layer chromatography with liquid scintillation spectrometry. Steroid identification was confirmed with gas chromatography/mass spectrometry. Metabolism of progesterone to 16α- or 6β-hydroxyprogesterone was increased by pretreatment with PBBs. Effects of PBBs on progesterone metabolism were dependent on sex. Alterations in metabolism of progesterone by PBBs were compared to effects of phenobarbital or 3-methylcholanthrene. Stimulation of hepatic 16α- and 6β-progesterone hydroxylase following PBBs resembled that produced by phenobarbital. These results support the contention that effects of PBBs on the endocrine system may be due, at least in part, to accelerated metabolism of steroid sex hormones.

Effects of polybrominated biphenyls on kidney function and activity of renal microsomal enzymes.

Polybrominated biphenyls (PBBs) cause hepatic microsomal enzyme stimulation and histopathological alterations in several organs, including kidney. Concern about effects of PBBs on the health of newborns has increased after the discovery of PBBs in milk of nursing mothers. Therefore, it was of interest to investigate the effects of PBBs on kidney function and the activity of renal microsomal enzymes in adult and immature animals. Seven and eleven day old pups were treated with a single IP injection of either peanut oil or 150 mg/kg PBBs (FireMaster BP-6) in peanut oil. Adult virgin rats were fed diet containing 0 or 100 ppm PBBs for 30 or 90 days. Treatment with PBBs only retarded weight gain after 90 days exposure. Kidney-to-body weight ratio was not altered by PBBs. Arylhydrocarbon hydroxylase activity was increased while epoxide hydratase activity was decreased (adults) or not affected (immature rats) in kidney following treatment with PBBs. Administration of PBBs had no effect on blood urea nitrogen, the clearance of inulin, p-aminohippurate (PAH), or fractional sodium excretion. Similarly, the in vitro accumulation of PAH and N-methylnicotinamide (NMN) by thin renal cortical slices and ammoniagenesis and gluconeogenesis in renal cortical slices were not affected by PBBs. In conclusion, treatment with PBBs resulted in modification of the activity of renal microsomal enzyme activities but had no detectable effect on renal function. ImagesFIGURE 1.

Residual effects of polybrominated biphenyls following perinatal exposure in rats

Abstract Polybrominated biphenyls (PBBs) undergo transplacental movement and have been detected in milk. Since most PBBs are biologically stable and very slowly eliminated, exposed offspring may have significant body burdens of certain PBB congeners throughout their lifetime. Therefore, the persistence of effects of perinatal exposure to PBBs on liver and kidney morphology, microsomal enzyme activity and concentration of PBBs was determined. Rats were fed diet containing 0 or 100 ppm PBBs (Firemaster BP-6) from the eighth day of pregnancy through 28 days postpartum. All pups were then weaned onto a diet free of PBBs. Experiments were conducted in offspring at 28 days of age and during the residual phase, 150 and/or 328 days of age. PBBs were detected in liver, kidney, and fat even 300 days following treatment termination confirming the remarkable biological stability and slow elimination of at least several PBB congeners. Retention of PBBs in tissues was correlated with hepatic histopathological alterations, renal and hepatic microsomal enzyme stimulation, and a reduction in duration of anesthesia produced by pentobarbital throughout the 10-month residual phase. These results suggest that metabolism of certain exogenous and endogenous lipophilic compounds may be modified for an extended time following perinatal exposure to PBBs.