Lack of Effect of 3,3′4,4′,5-Pentachlorobiphenyl (PCB 126) Throughout Gestation and Lactation on Multiple Fixed Interval–Fixed Ratio and DRL Performance in Rats

There is evidence that polychlorinated biphenyl (PCB) congeners have differential effects on endpoints of neurotoxicity depending on their chemical structure: specifically, that ortho-substituted congeners are neurotoxic while coplanar (dioxin-like) congeners are relatively inactive in producing neurotoxic effects. This study extends research on the effects of developmental exposure to the coplanar congener 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) in Long–Evans rats. Dams were dosed with 0, 0.25, or 1 μg/kg/day Monday to Friday beginning 5 weeks before and continuing through gestation and lactation. The first 2-week breeding period produced 10, 7, and 13 litters in the three dose groups, respectively, used in behavioral assessment. Breeding females from the control and low-dose group that did not conceive were rebred after 76 days of dosing, producing 6 and 6 litters used in behavioral testing. One female and male from each litter were tested on a multiple fixed interval–fixed ratio schedule of reinforcement beginning at about 200 days of age, followed immediately by performance on a DRL schedule. There were no compelling indications of a treatment-related effect on either schedule. These same rats failed to exhibit PCB-induced impairment on a spatial delayed alternation task performed prior to the current experiments. This regimen of PCB exposure produced reduced weight gain between birth and weaning in Cohort 1, and decreased thyroxine levels and changes in hematology and serum biochemistry parameters in both cohorts. These data provide further evidence for absence of behavioral toxicity as a result of gestational and lactational exposure to a dioxin-like PCB congener. Published by Elsevier Science Inc.     

Effects of dietary PCB exposure on adrenocortical function in captive American kestrels (Falco sparverius)

We experimentally examined the effects of dietary exposure to polychlorinated biphenyls (PCBs) on adrenocortical function in American kestrels (Falco sparverius). Nine captive male American kestrels previously exposed to a PCB mixture (Aroclor1248:1254:1260; 1:1:1) in their diet were subjected to a standardized capture, handling and restraint protocol designed to produce an increase in circulating corticosterone. A similar protocol has been applied to a wide range of avian species and was used here to evaluate the response of PCB-exposed and control kestrels to a defined physical stressor. Both baseline and stress-induced corticosterone levels were significantly lower in PCB-exposed birds when compared with control birds of the same age. PCB-exposed birds exhibited significantly lower corticosterone levels during the corticosterone response when compared with control birds, independent of body condition. Furthermore, baseline corticosterone concentrations exhibited a hormetic response characterized by an inverted U-shaped dose response in relation to total PCB liver burden. These results support several recent studies which report decreased levels of circulating corticosterone in PCB-exposed wild birds. The results presented here provide the first evidence that exposure to an environmentally relevant level of PCBs (approximately 10 mg/kg body weight) can impair the corticosterone stress response in kestrels, potentially increasing the susceptibility of birds to environmental stressors such as severe weather and predatory and human disturbance.     

Behavioral Effects of Pre-and Postnatal Exposure to a Mixture of Low Chlorinated PCBs in Rats

Behavioral Effects of Pre- and Postnatal Exposure to a Mixtureof Low Chlorinated PCBs in Rats. LILIENTHAL, H., NEUF, M., MUNOZ,C, AND WINNEKE, G. (1990). Fundam. Appl. Toxicol. 15, 457–467.Polychlorinated biphenyl (PCB)-treated Wistar rats were testedon three different behavioral paradigms. Animals were pre- andpostnatally exposed to a technical mixture of PCBs with a chlorinecontent of 42%. Exposure levels were 0, 5, or 30 mg/kg diet.These conditions did not affect the health of the dams, thelitter size or weight, or the physical development of the offspring.Relative liver weights in the offspring, however, were elevatedin a dose-dependent manner. Open-field ambulation, active avoidancelearning, and operant conditioning on a fixed interval 30-secschedule (FI-30-sec) were used to evaluate PCB-induced behavioralalterations. Ambulation was increased in 30-mg-treated ratsat Day 22, but not at Day 120. There were more avoidance responsesand intertrial responses in the 30-mg group than in both othergroups. On the FI-30-sec schedule slightly more reactions wereemitted by the 30-mg group during the first 10 sec of the intervalthan by the other animals. More pronounced, however, were thedifferences between groups in the temporal pattern of responseswithin the 30-sec interval. It is concluded that in rats PCBexposure causes consistent alterations in all of the testedactivity-dependent behaviors.     

Fetal adrenal development: Comparing effects of combined exposures to PCB 118 and PCB 153 in a sheep model

This study investigated the effects of exposure to the ubiquitous contaminants polychlorinated biphenyls (PCBs) on the fetal adrenal cortex and on plasma cortisol using the domestic sheep (Ovis aries) as a model. Pregnant ewes were intendedly subjected to oral treatment with PCB 153 (98 μg/kg bw/day), PCB 118 (49 μg/kg bw/day) or the vehicle corn oil from mating until euthanasia on gestation day 134 (±0.25 SE). However, because of accidental cross‐contamination occurring twice causing a mixed exposure scenario in all three groups, the focus of this paper is to compare three distinct groups of fetuses with different adipose tissue PCB levels (PCB 153high, PCB 118high and low, combined groups) rather than comparing animals exposed to single PCB congeners to those of a control group. When comparing endocrine and anatomical parameters from fetuses in the PCB 153high (n = 13) or PCB 118high (n = 14) groups with the low, combined group (n = 14), there was a significant decrease in fetal body weight (P < 0.05), plasma cortisol concentration (P < 0.001) and adrenal cortex thickness (P < 0.001). Furthermore, adrenal weight was decreased and plasma ACTH was increased only in the PCB 118high group. Expression of several genes encoding enzymes and receptors related to steroid hormone synthesis was also affected and mostly down‐regulated in fetuses with high PCB tissue levels. In conclusion, we suggest that mono‐and di‐ortho PCBs were able to interfere with growth, adrenal development and cortisol production in the fetal sheep model. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.     

Alterations in geometry,biomechanics, and mineral composition of juvenile rat femur induced by nonplanar PCB‐155 and/or planar PCB‐169

Exposure to widespread lipophilic and bioaccumulative polychlorinated biphenyls (PCBs) induces diverse biochemical and toxicological responses in various organs, including the bone. The aim of this study was to evaluate the changes in growth rate, geometry, serum, and bone biochemical parameters and biomechanics of juvenile rat femur induced by lactational exposure to nonplanar PCB‐155 and planar PCB‐169 individually and in combination. Fifteen lactating Wistar rats were divided into four groups (PCB‐169, PCB‐155, PCB‐155+169, and control), and PCBs were administered intraperitoneally at different time points after delivery. Femurs from 22‐day‐old offspring were analyzed by microCT, three‐point bending test and inductively coupled plasma‐mass spectrometry (ICP‐MS) to obtain data on bone geometry, biomechanics and mineral composition. The serum levels of calcium, phosphate and alkaline phosphatase were also determined. Lactational exposure to planar PCB‐169 resulted in shorter and thinner femurs, reduced endosteal and periosteal perimeters, smaller total cross‐sectional and medullary areas, and lowered serum bone marker levels and calcium levels in the bone, while femur mechanical properties were not significantly altered. The changes observed in the combination exposure (PCB‐155+169) group were similar to those observed in the PCB‐169 group but were less pronounced. In summary, our results demonstrate that alterations in lactationally exposed offspring were primarily induced by planar PCB‐169. The milder outcome in the combined group suggested that the PCB‐169‐mediated toxic effects on the bone might be reduced by a nonplanar PCB‐155 congener. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1135–1146, 2017.     

The effects of ortho chloro substituents on the retention of PCB isomers in rat,rabbit, japanese quail,guinea pig and trout

A mixture of 2,2',4,4',6,6'-, 2,2',4,4',5',6-, 2,2',4,4',5,5'-, 2',3,4,4',5,5'- and 3,3',4,4',5,5'-hexachlorobiphenyls (HCBP) was administered by gastric lavage to rats, guinea pigs, rabbits, Japanese quail and trout, and the concentrations in the fat or whole carcass were determined after 29 days. The total HCBP levels in rat, rabbit and guinea pig fatty tissue were 8.27, 6.84 and 4.74 ppm, respectively: whereas 3.02 and 2.15 ppm of the HCBPs were detected in the trout and Japanese quail carcasses. The extent of ortho chloro substitution markedly affected the levels of the individual HCBP isomers retained in the test animals; the rabbit and guinea pig preferentially retained the HCBPs with 0,1 and 2 ortho chloro substituents, the Japanese quail retained only the 3,3',4,4',5,5'-HCBP isomer, whereas no striking preferences in HCBP isomer retention in the rat and trout were observed. The marked differences in the retention of HCBP isomers with 0, 1, 2, 3 and 4 ortho chloro substitution by different animal species should be considered in chronic toxicity studies since the most toxic polychlorinated biphenyls have minimal (1 or 0) ortho chloro substituents.     

Combined Exposure to Multiple Mycotoxins: An Example of Using a Tiered Approach in a Mixture Risk Assessment

Humans are exposed to mycotoxins on a regular basis. Exposure to a mixture of mycotoxins may, therefore, result in a combination of adverse effects, or trigger the same effects. This should be accounted for when assessing the combined risk of multiple mycotoxins. Here, we show the outcome of using different approaches in assessing the risks related to the combined exposure to mycotoxins. We performed a tiered approach using assessment groups with a common target organ (kidney, liver and haematologic system), or a common adverse effect (phenomenon) (reduced white blood cell count), to combine the exposure to mycotoxins. The combined exposure was calculated for the individuals in this assessment, using the Monte Carlo Risk Assessment (MCRA) tool. The risk related to this combined exposure was assessed using toxicological reference values, e.g., health based guidance values. We show that estimating the combined risk by adding the single compounds’ risk distributions slightly overestimates the combined risk in the 95th percentile, as compared to combining the exposures at an individual level. We also show that relative potency factors can be used to refine the mixture risk assessment, as compared to ratios of toxicological reference values with different effect sizes and assessment factors.     

Sublethal effects of chronic exposure to an organochlorine compound on northern leopard frog (Rana pipiens) tadpoles

Global contamination with organochlorine compounds (OCs) has posed developmental and reproductive problems in wildlife worldwide. However, little is known about the impact of OCs or other pollutants on amphibians, despite mounting concerns about amphibian population declines and developmental deformities in the wild. Wildlife populations may be affected critically by sublethal impacts of anthropogenic disturbances, yet little research has focused on such effects in amphibians. In the current study, northern leopard frog (Rana pipiens) tadpoles were chronically exposed to a polychlorinated biphenyl (PCB) congener, 77-TCB, and effects on behavior, morphology, competitive performance, and corticosterone content were determined. R. pipiens activity levels and feeding rates were decreased by 77-TCB exposure, but morphology of mouthparts and body proportions were unaffected. 77-TCB enhanced growth and altered competitive interactions between R. pipiens and wood frog (Rana sylvatica) tadpoles. R. pipiens tadpoles exposed to 77-TCB showed decreased whole-body corticosterone content compared to controls both before and after injection with adrenocorticotropic hormone (ACTH). All of the factors examined in the current study play critical roles in tadpole development, growth, survivorship, and eventual reproductive success, suggesting negative population-level consequences for amphibians in PCB-contaminated habitats.     

Induction of CYP1A1 in primary rat hepatocytes by 3,3',4,4',5-pentachlorobiphenyl: evidence for a switch circuit element.

In vivo induction of CYP1A1 in hepatocytes by aryl hydrocarbon receptor agonists is heterogeneous. Using immunohistochemistry, cells appear to be either induced or not induced as if the response of an individual cell is better represented as a switch. We have examined induction of CYP1A1 in vitro in primary rat hepatocytes to distinguish the responses of populations of cells and responses of individual cells. Cells were treated with various concentrations of the aryl hydrocarbon receptor agonist, 3,3',4,4',5-pentachlorobiphenyl. Concentration-response and time-course responses were determined for the population of cells by Western blotting for CYP1A1 protein and by real-time RT-PCR for CYP1A1 mRNA. Individual cell responses were visualized by immunocytochemistry (ICC) for protein and by in situ hybridization (ISH) for mRNA. CYP1A1 mRNA was quantified by frequency distribution analysis of grains observed on the ISH slides. Population responses showed time- and concentration-related increases in induction. Single cell responses appeared as all-or-none in the field, with cells appearing to be induced and others appearing to be not induced. Even at the highest concentrations (2.5 x 10(-7) M), some hepatocytes remained unresponsive. Distribution frequencies of single cell induction were more consistent with a switch with variable levels of induction in cells depending on treatment concentration. Combined with the reports from in vivo studies, our results support a switch with rheostat behavior for individual hepatocytes. Mechanistic studies in liver cell lines that are confirmed to exhibit switch-like induction of single cells will be necessary to assess the molecular pathways of this circuit element.     

Kanechlor 500‐mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin‐unrelated manner

The effects of Kanechlor‐500 (KC500) on the levels of serum total thyroxine (T₄) and hepatic T₄ in wild‐type C57BL/6 (WT) and its transthyretin (TTR)‐deficient (TTR‐null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100 mg/kg body weight), serum total T₄ levels were significantly decreased in both WT and TTR‐null mice. The KC500 pretreatment also promoted serum [¹²⁵I]T₄ clearance in both strains of mice administrated with [¹²⁵I]T₄, and the promotion of serum [¹²⁵I]T₄ clearance in WT mice occurred without inhibition of the [¹²⁵I]T₄‐TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady‐state distribution volume of [¹²⁵I]T₄, hepatic accumulation level of [¹²⁵I]T₄, and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500‐mediated decrease in serum T₄ level occurs in a TTR‐unrelated manner and further suggest that KC500‐promoted T₄ accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T₄ transportation from serum to liver.     

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology,Behavior, and Dopamine System Development

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP_ND), an index of tracer-specific binding, and amphetamine-induced changes in BP_ND of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.     

Reduced levels of 1,25-dihydroxyvitamin D(3) in rat dams and offspring after exposure to a reconstituted PCB mixture.

Previous studies revealed effects of polychlorinated biphenyls (PCBs) and other polyhalogenated hydrocarbons on steroid hormone levels and hormone-dependent functions including behavior. In the present study serum concentrations of the vitamin D(3) metabolites 25-hydroxycholecalciferol (25-D) and 1,25-dihydroxycholecalciferol (1,25-D) were determined in rat dams and offspring after exposure to a PCB mixture that was reconstituted according to the congener pattern found in human breast milk. Unmated females were exposed to diets adulterated with 0; 5; 20; or 40 mg PCBs/kg diet. Exposure started 50 days prior to mating and was terminated at birth. Gestational exposure reduced serum concentrations of 1,25-D in dams in a dose-dependent manner. Concentration of 25-D was also decreased at the time of delivery, but not at weaning. Determination of 1,25-D in offspring at weaning revealed reductions in both high-exposure groups. Levels of 25-D were diminished only at the highest exposure level. Internal PCB concentrations in adipose tissue and brains exhibited a linear relation to dosages in diet. Concentrations of PCBs in brains were similar in dams and offspring at birth, but decreased at the end of lactation in dams. In offspring, values increased during this period because of continued exposure via the milk. In the adipose tissue, PCB levels were much lower in offspring than in dams. To our knowledge, this is the first report of PCB-induced effects on vitamin D(3) metabolites. In dams, reductions were seen even at the lowest exposure level used. Further studies are needed to evaluate the biological significance of these reductions in pregnant dams and possible consequences for the developing offspring.     

Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on long-term potentiation and [3H]MK-801 binding in occipital cortex and hippocampus.

The central nervous system is one of the target organs for polychlorinated biphenyls (PCBs). We measured the effects of maternal exposure of Long-Evans rats to a mixture of PCB congeners reconstituted according to the pattern found in human breast milk (reconstituted mixture, RM) on long-term potentiation (LTP) in two brain regions. Exposure of the dams via food started 50 days prior to mating and was terminated at birth. In the first experiment, adult male and female offspring were exposed maternally to 40 mg/kg of the RM or the commercial mixture Aroclor 1254 (A1254). LTP and paired-pulse inhibition were measured in slices of the visual cortex. In addition, the binding of [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor-ion channel as well as the [3H]muscimol binding to the GABA-A receptor in membrane preparations from the occipital cortex and hippocampus were determined. LTP as well as [3H]MK-801 binding were significantly reduced in the cortex following PCB exposure, while [3H]MK-801 binding in the hippocampus was not affected. In a succeeding experiment, LTP was determined in cortical and hippocampal slices from rats at postnatal days 10 to 20, following exposure to 0, 5, or 40 mg/kg of the RM. Cortical LTP was significantly affected by the RM while no effects were seen in hippocampal LTP. Taking the two experiments together, PCB exposure significantly reduced LTP, as well as [3H]MK-801 binding, in the cortex and had no effect in the hippocampus. The LTP deficits can only partly be related to the reduction of binding sites to the NMDA receptor; other PCB-induced neurochemical changes have to be assumed.     

The Effect of N–acetyJated DL–penicillamine and DL–homocysteine Thiolactone on the Mercury Distribution in Adult Rats,Rat Foetuses and Macaca Monkeys after Exposure to Methyl Mercuric Chloride

Abstract The distribution and excretion of mercury was studied in pregnant rats, given a single intravenous dose of 2 μmol/kg of CH₃²⁰³HgCl on the 13th day of pregnancy. Oral treatment for one week with N–acetyl–DL–penicillamine (4 mmol/kg per day) increased the mercury excretion in faeces (from 45 to 120 nmol) and urine (from 9 to 160 nmol). Such treatment mobilized mercury from all the organs tested, and the foetal and maternal brain levels of mercury were decreased to 1/5 and 1/3 of the controls, respectively. A four–day period of treatment with N–acetyl–DL–penicillamine started three days after the injection of methyl mercury reduced the foetal and maternal brain levels to 1/2 and 2/3 of the controls, respectively. The rapid removal of metal deposits following treatment with N–acetyl–DL–penicillamine is attributed to a free penetration of the complexing thiol into the tissue cells in question. No signs of toxicity were detected in monkeys given an effective daily dose of the agent (4 mmol/kg) for 6 days. In contrast N–acetyl–DL–homocysteine thiolactone was found to be toxic in the monkeys. In addition, the latter agent was ineffective in increasing the mercury elimination from the brains of monkeys, rats and rat foetuses.     

Effect of an LTB4 Aerosol Exposure on Pulmonary Function,Cell Populations,and Mediators in the Lungs of Rhesus Monkeys

Abstract

Six adult rhesus monkeys (5–7 kg) were anesthetized with sodium pentobarbital, 30 mg/kg iv, intubated, and exposed for 4 h, once per week, to air (baseline), normal saline, an inactive isomer of leukotriene B₄ (LTB₄), and LTB₄. Anesthesia was maintained with sodium pentobarbital, S mg/kg/h iv. Pulmonary function was monitored for a 30-min baseline period and during the 4-h exposure. After each exposure, the upper and lower airways were lavaged. The upper airway lavage was performed by inclining the animal head down, inserting a small catheter through the endotracheal (ET) tube to the carina, then instilling 15 ml normal saline through the catheter and collecting the fluid as it came out the ET tube. The lower airway lavage was performed with a fiberoptic bronchoscope placed at the level of generation 5–7 of a lower lobe. Two 10-ml aliquots of saline were instilled and gently suctioned via syringe. Cell counts and differentials were performed. Supernatant was analyzed for levels of LTB₄, LTC₄ and TxB₂. After the LTB₄ exposure, the animals were killed and the lungs were removed for histopathology. There were no significant changes in pulmonary function or cell populations from the upper airways after any treatment. LTB₄ levels were significantly increased over baseline only in the upper air-ways after the LTB₄ aerosol exposure. The lower airways showed a significant increase in total white cells due to a dramatic (1100%) increase in neutrophils after LTB₄ treatment only. The pulmonary tissue response was characterized by a multifocal accumulation of neutrophils in alveoli, neutrophilic infiltration of bronchiolar wall smooth muscle, and a slight accumulation of cell and mucous debris within small bronchi. It was concluded that, in these monkeys, an LTB₄ aerosol causes neutrophils to accumulate in the lungs without evidence of inflammation or altered pulmonary function.The LTB₄ and the 12-epi,6-trans-LTB₄ were synthesized and kindly supplied by D. R. Dobson and Dr. S. R. Baker, respectively, Eli Lilly and Company.     

Effect of a mercurial ayurvedic drug (kajyoli) on the ion concentration and respiratory activity in brain,liver and kidney of the albino rat

The effect of a mercurial ayurvedic drug (kajyoli), on the concentration of Na⁺, K⁺ and Ca²⁺ in rat liver, kidney and brain, and on the respiratory activity of these tissues is reported. The doses used were 20 mg and 40 mg. day^?1. kg^?1 body wt. daily for 30 days, the lower level being equivalent to the human dose. A marked dose-dependent decrease in respiratory activity occurred in the three tissues. The only significant changes seen in the ion concentration were a decrease in Na⁺ at the higher dose level in the kidney and a dose-dependent decrease in Ca²⁺in the liver.     

Loss of Pre-B and Igm + B Cells in the Bone Marrow After Exposure to a Mixture of Herbicides

This study determined alterations to bone marrow B-cell populations after in vivo exposure to a mixture containing the herbicides 3,4-dichloropropionanilide (propanil) and 2,4-dichlorophenoxyacetic acid (2,4-D) and compared them to the effects of exposure to the individual herbicides. Propanil and 2,4-D are postemergent herbicides that are sold commercially as a mixture. The individual herbicides or the mixture containing propanil and 2,4-D were administered intraperitoneally to C57Bl/6 female mice at doses from 50 to 200 mg herbicide/kg body weight. The mixtures were given in a 1:1 ratio. Flow cytometric analysis was performed to quantitate bone marrow B-cell populations at 1, 2, 7, and 14d posttreatment. Mixture treatment decreased pre-B and immunoglobulin (Ig) M + B-cell populations at all doses by 2 d postexposure. The cell populations were still decreased at 7d posttreatment. In contrast, exposure to the individual herbicides only caused decreases in the pre-B and IgM + B-cell populations 7d after exposure to the high doses. Previous studies have demonstrated that corticosterone levels are increased by exposure to propanil. Therefore, the glucocorticoid hormone, corticosterone, was investigated as a possible mediator of cell loss in the bone marrow. Treatment with the glucocorticoid receptor antagonist, RU 486, however, did not prevent cell loss in the bone marrow of mice exposed to the mixture of propanil and 2,4-D. This study demonstrates that pre-B and IgM + B-cell populations are decreased after exposure to propanil, 2,4-D, or the mixture containing propanil and 2,4-D. Exposure to the mixture had greater toxic effects than the individual herbicides on bone marrow pre-B and IgM + B-cell populations, emphasizing the need to study mixture interactions.     

Effect of typical inducers of microsomal drug-metabolizing enzymes on phospholipid metabolism in rat liver.

The effect of administration of phenobarbital (PB), polychlorinated biphenyls(PCBs) or 3-methyl-cholanthrene (3-MC) on the metabolism of phospholipids in rat liver was studied by the i.p. injection of [³²P]orthophosphate or [Me-¹⁴C]choline chloride. The inducers were given to animals for 2 successive days PB had no significant effect on the incorporation rate of ³²Pi into liver microsomal phospholipid classes 48 hr after the first administration. The rate of incorporation of [¹⁴C]choline into phosphatidylcholine (PC) in both subcellular components of the liver and blood plasma decreased slightly at this experimental period. In addition, the ratio of [¹⁴C] sp. act. of phosphorylcholinc to that of microsomal phosphulipid was considerably higher on PB-trcated rats as compared with the ratio in control rats. These and previous findings strongly suggest that proliferation of liver endoplasmic reticulum (ER) membranes induced by PB would be accompanied by the stimulation of phospholipid synthesis at the early process of induction and subsequently followed by the decrease in turnover rate of microsomal phospholipids. The administration of PCBs, on the other hand, caused strong inhibition of both ³²Pi and ¹⁴C incorporation into PC in liver subcellular fractions. The secretion of PC from liver cells to blood plasma was also strongly depressed. In addition, phospholipid catabolizing activity was found to be depressed in the liver. These results indicate that hypertrophy of ER membranes in the liver after PCBs administration could be due to a depression of both secretion of lipoprotein from liver cells to plasma and catabolic activity toward membranous phospholipids in liver cells. The decrease in ³²Pi incorporation into liver microsomal PC was also observed in rats treated with 3-MC. There occurred a considerable accumulation of ¹⁴C activity in phosphorylcholine in the liver of rats treated with either PCBs or 3-MC, suggesting strongly that these drugs caused an inhibition of PC synthesis at the site of CDP-choline formation, namely the inhibition of the reaction catalyzed by cholinephosphate cytidylyltransferase.