Viscoelasticity of dilute solutions of semiflexible polymers.

We show using Brownian dynamics simulations and theory how the shear relaxation modulus G(t) of dilute solutions of relatively stiff semiflexible polymers differs qualitatively from that of rigid rods. For chains shorter than their persistence length, G(t) exhibits three time regimes: At very early times, when the longitudinal deformation is affine, G(t) approximately t(-3/4). Over a broad intermediate regime, during which the chain length relaxes, G(t) approximately t(-5/4). At long times, G(t) mimics that of rigid rods. A model of the polymer as an effectively extensible rod with a frequency dependent elastic modulus B(omega) approximately ((i)omega)(3/4) quantitatively describes G(t) throughout the first two regimes.

Tube diameter in tightly entangled solutions of semiflexible polymers.

A statistical mechanical treatment is given of the confinement of a wormlike polymer in an entangled solution to a tube, yielding quantitative predictions for the average tube diameter D(e) and macroscopic plateau modulus G, in the tightly entangled regime in which D(e) is much less than the persistence length L(p). Three approaches are pursued. A self-consistent binary collision approximation, which explicitly describes the topological constraints imposed by neighboring chains, yields predictions consistent with the scaling laws D(e)proportional to rho(-3/5) and G proportional to rho(7/5) proposed previously, where rho is the contour length per unit volume. An effective medium approximation, which treats the network as a continuum with a modulus G, instead yields D(e) proportional to rho(-1/3) and G proportional to rho(4/3), which is found to be the correct scaling in the limit rhoL(2)(p)>>1. An elastic network approximation treats the displacement of a test chain as the sum of a collective displacement of the network, which is treated as a continuum, plus a local displacement, which is treated in a binary collision approximation. Predictions are compared to measurements of both D(e) and G in actin protein filament (F-actin) solutions.

Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain.

Cytochromes P450 1A1 and 1A2 are involved in the oxidation of a wide spectrum of endogenous compounds and xenobiotics. Although their presence has been repeatedly confirmed in brain tissue, reports regarding their distribution in the brain are often contradictory. In the present study the possibility was examined that CYP1A1 and CYP1A2 are localized and inducible in the brain-CSF barrier and regions with a leaky blood brain barrier, where they may serve as a protective metabolic barrier. CYP1A1 and CYP1A2 levels were determined in subcellular fractions of multiple brain regions, as well as tissue homogenates of circumventricular organs, and the meninges by Western blotting and catalytic activity in control male rats and rats treated with the inducer beta-naphthoflavone (BNF). In control animals CYP1A1 immunoreactive protein was undetectable in regional brain microsomes or whole tissue homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, median eminence, and pituitary. However, low levels of ethoxyresorufin O-deethylase (EROD) activity were observed in homogenates of the arachnoid, dura mater, choroid plexus, pineal gland, and pituitary. Western blotting revealed only low levels of CYP1A2 immunoreactive protein in brain microsomes from the cortex, cerebellum, brainstem, thalamus, hippocampus, and striatum from control animals. Following BNF treatment, EROD activity was induced 12-42-fold in the arachnoid, choroid plexus, dura mater, pineal gland, pituitary, and median eminence. Western blot analysis revealed CYP1A1 to be induced in the arachnoid, dura mater, choroid plexus, pineal gland, and pituitary, while CYP1A2 was undetectable. No induction of CYP1A1 or CYP1A2 protein was observed in brain microsomes from the olfactory bulb, cortex, striatum, hippocampus, cerebellum, or brainstem following BNF treatment, providing that the arachnoid membranes and choroid plexus had been carefully removed prior to brain dissection. Neither CYP1A1, 1A2 protein, nor EROD activity were detected in purified brain mitochondria, regardless of treatment or region. In conclusion, catalytically active CYP1A1 is located in the meninges as well as certain circumventricular organs, is inducible by BNF, and appears to be absent or expressed constitutively at very low levels in the majority of the brain parenchyma. The localization of CYP1A1 in the blood-CSF barrier and circumventricular tissues likely plays a role in protecting the brain from xenobiotics.

Interactions of persistent environmental organohalogens with the thyroid hormone system: mechanisms and possible consequences for animal and human health.

Several classes of environmental contaminants have been claimed or suggested to possess endocrine-disrupting potency, which may result in reproductive problems and developmental disorders. In this paper the focus is on the multiple and interactive mechanisms of interference of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites with the thyroid hormone system. Evidence suggests that pure congeners or mixtures of PHAHs directly interfere with the thyroid gland; with thyroid hormone metabolizing enzymes, such as uridine-diphosphate-glucuronyl transferases (UGTs), iodothyronine deiodinases (IDs), and sulfotransferases (SULTs) in liver and brain; and with the plasma transport system of thyroid hormones in experimental animals and their offspring. Changes in thyroid hormone levels in conjunction with high PHAH exposure was also observed in captive as well as free ranging wildlife species and in humans. Maternal exposure to PHAHs during pregnancy resulted in a considerable fetal transfer of hydroxylated PHAHs, which are known to compete with thyroxine (T4) for plasma transthyretin (TTR) binding sites, and thus may be transported to the fetus with those carrier proteins that normally mediate the delivery of T4 to the fetus. Concomitant changes in thyroid hormone concentrations in plasma and in brain tissue were observed in fetal and neonatal stages of development, when sufficient thyroid hormone levels are essential for normal brain development. Alterations in structural and functional neurochemical parameters, such as glial fibrillary acidic protein (GFAP), synaptophysin, calcineurin, and serotonergic neurotransmitters, were observed in the same offspring up to postnatal day 90. In addition, some changes in locomotor and cognitive indices of behavior were observed in rat offspring, following in utero and lactational exposure to PHAHs. Alterations in thyroid hormone levels and subtle changes in neurobehavioral performance were also observed in human infants exposed in utero and through lactation to relatively high levels of PHAHs. Overall these studies indicate that persistent PHAHs can disrupt the thyroid hormone system at a multitude of interaction sites, which may have a profound impact on normal brain development in experimental animals, wildlife species, and human infants.

Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD.

While the immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established, the effects of complex environmental mixtures of polyhalogenated aromatic hydrocarbons (PHAHs) are poorly understood. Many PHAHs, including the polychlorinated-biphenyls (PCBs), -dibenzofurans (PCDFs), and dibenzo-p-dioxins (PCDDs), possess 'dioxin-like' activities, and accumulate in the aquatic food chain. Organisms occupying high trophic levels may therefore be exposed to concentrations which may present an immunotoxic risk. In this study, pregnant PVG rats were administered a daily oral dose of 1 ml of the following during pregnancy and lactation: (1) oil extracted from herring caught in the relatively uncontaminated Atlantic Ocean; (2) oil extracted from herring caught in the contaminated Blastic Sea; or (3) the Atlantic herring oil extract spiked with 2,3,7,8-TCDD. The daily intakes of aryl hydrocarbon (Ah)-receptor dependent toxic equivalents (TEQ) for mothers were 0.3 in the Atlantic group, 2.1 in the Baltic group, and 134 ng/kg body wt. in the 2,3,7,8-TCDD positive control group. Immune function and host resistance to rat cytomegalovirus (RCMV) were assessed in offspring aged 11, 25, 46 or 59 days. Rat pups in the positive control TCDD-spiked group exhibited immunosuppression characterized by reduced thymus weight and cellularity, reduced thymocyte and splenocyte proliferative responses to T-dependent mitogens in vitro, reduced virus-associated natural killer (NK) cell and specific antibody responses. While less pronounced, a similar pattern of effects was observed in the rat pups exposed only to the Baltic Sea herring oil. These immunotoxic effects were transient in both exposure groups, with a time-related recovery in immune function possibly due to the half-life of TCDD in rats and the waning exposure levels in the rapidly growing pups. We previously demonstrated that the same Baltic Sea herring led to impaired natural killer cell and T-lymphocyte function in harbour seals during the course of a long-term captive feeding study. The collective results of these studies in rats and seals indicate the immunotoxic potential of environmental mixtures at current levels in the aquatic environment, and suggest that the developing immune system of young mammals may be at particular risk.

Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat.

Pregnant Wistar WU rats were administered PCBs (0, 5 or 25 mg Aroclor 1254 per kg body weight) by gavage on day 10 to 16 of gestation. Levels of biogenic amines were measured in the lateral olfactory tract, prefrontal cortex, striatum, hippocampus and hypothalamus in male and female offspring 21 and 90 days after birth. 5-Hydroxyindole acetic acid (5-HIAA) concentrations and the ratio of 5-HIAA/5-hydroxytryptamine (5-HT, serotonin) were significantly increased in the lateral olfactory tract, prefrontal cortex and hippocampus on postnatal day 90 in male and female offspring following maternal PCB treatment. No effects were observed on regional brain levels of dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine and homovanillic acid. The results indicate that pre- and postnatal exposure to Aroclor 1254 results in regionally specific long-term alterations in the serotonergic system.

Persistent alterations in regional brain glial fibrillary acidic protein and synaptophysin levels following pre- and postnatal polychlorinated biphenyl exposure.

Pregnant Wistar WU rats were exposed to 0, 5, and 25 mg of the commercial polychlorinated biphenyl (PCB) mixture Aroclor 1254 per kilogram of body weight on Days 10 to 16 of gestation. Pregnant rats were sacrificed on Gestation Day 20 to observe effects on fetal body and brain weights. Male and female offspring were sacrificed on Postnatal Days 21 and 90 (PND21 and PND90, respectively) and examined for treatment-related effects on neurochemical parameters. The concentrations of the neuronal and glial cell markers, synaptophysin and glial fibrillary acidic protein (GFAP), were measured in diverse brain regions from the offspring using immunochemical techniques. The level of calcineurin (a calmodulin-regulated protein phosphatase) activity was measured in cerebellar homogenates. In addition, ethoxyresorufin O-deethylase (EROD) activity was determined in hepatic microsomes as a measure of a well-characterized response to PCB exposure in experimental animals. The major alterations of GFAP levels following maternal PCB treatment were significant increases in the lateral olfactory tract (LOT) and the cerebellum (CB) and significant decreases in the brain stem (BS) of the offspring on PND21 and 90. Synaptophysin levels were significantly decreased relative to controls in the LOT, prefrontal cortex, and striatum of the offspring on PND90. In the BS, synaptophysin levels were significantly decreased relative to controls in male and female weanlings on PND21 and males on PND90; however, significant increases were observed in the BS of females on PND90. No effect of maternal PCB treatment was observed on levels of GFAP and synaptophysin in the dorsal hippocampus on PND21 and 90. Due to analytical restrictions statistical comparisons of GFAP levels were limited to examining the effect of maternal PCB treatment per brain region per sex per time point. Calcineurin activity was decreased in the female CB on PND21, but a significant increase in activity was observed in the female CB on PND90. No effect of maternal PCB treatment was observed on the cerebellar calcineurin activity in male offspring on PND21 and 90. EROD activity was highly induced in maternal microsomes from both PCB treatment groups, but only slightly induced in fetal hepatic microsomes. On PND21 weanling hepatic microsomal EROD activity was highly induced following gestational and lactational PCB exposure; however, on PND90 EROD activity was unaffected by maternal PCB treatment in male offspring and significantly decreased in female offspring. The results of the present study indicate that gestational and lactational exposure to the commercial PCB mixture results in long-term alterations in a neuronal and glial cell markers in specific brain regions of rats. These marker proteins may be useful for determining the structure-activity relationships in PCB-induced developmental neurotoxicity.

Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254).

The effect of daily oral maternal exposure to 0, 5, or 25 mg/kg body wt of a polychlorinated biphenyl (PCB) mixture (Aroclor 1254) on Days 10 to 16 of gestation on plasma and brain thyroid hormone concentrations and peripheral thyroid hormone concentrations and peripheral thyroid hormone metabolism were examined in fetal and weanling rats. Plasma thyroid hormone levels and hepatic microsomal thyroid hormone glucuronidation were also examined in pregnant rats and the adult offspring. Plasma and brain levels of PCBs and hydroxylated PCB metabolites were analyzed in fetal, weanling, and adult offspring. Maternal exposure to Aroclor 1254 significantly decreased fetal (Gestation Day 20) and neonatal (Postnatal Day 4) plasma total thyroxine (T4) and free T4 levels in a dose-dependent manner. Effects of maternal Aroclor 1254 exposure on plasma total and free T4 concentrations were less pronounced in offspring at 21 days of age and absent 90 days after birth. Plasma concentrations of thyroid-stimulating hormone were unaltered in fetuses, neonates, weanling rats, and adult offspring following maternal treatment with Aroclor 1254. the concentration of T4 was severely depressed in the forebrain and cerebellum of fetal rats on Day 20 of gestation following maternal Aroclor 1254 exposure. Brain triiodothyronine (T3) concentrations in the Aroclor-exposed fetuses were significantly decreased relative to control values only in the low-dose group. On Day 21 postpartum T4 concentrations were significantly decreased in the forebrains of female weanling rats from the 25 mg Aroclor 1254/kg dose group, and no reductions were observed in forebrain T3 concentrations in male or female neonates. The deiodination of T4 to T3 was significantly increased in fetal forebrain homogenates by both PCB treatments. In female weanling brain homogenates the deiodination of T4 to T3 was significantly decreased in the low-dose group and unaltered in the high-dose group. No alterations in brain thyroid hormone metabolism were observed in forebrain homogenates from adult offspring exposed pre- and postnatally to Aroclor 1254. Hepatic microsomal T4 glucuronidation was significantly decreased in fetal microsomes following perinatal PCB exposure and significantly increased in weanling hepatic microsomes in a dose-dependent manner. An accumulation of mainly one PCB metabolite, 2,3,3',4',5-pentachloro-4-biphenylol was observed in fetal plasma and forebrain on Gestation Day 20 and in neonatal and weanling rat plasma on Postnatal Days 4, 21, and 90. The plasma level of 2,3,3',4',5-pentachloro-4-biphenylol was higher than that of the persistent PCB congener 2,2',4,4',5,5'-hexachlorobiphenyl in the control and PCB-exposed offspring up to Postnatal Day 21, and even after 90 days, the 2,3,3',4',5-pentachloro-4-biphenylol was present in amounts approximately equal to those of CB 153. Although PCB levels were relatively high in the weanling rat forebrain, no hydroxylated PCB metabolites were detected. On Day 90 postpartum, plasma levels of PCBs and 2,3,3',4',5-pentachloro-4-biphenylol were still elevated in the offspring of PCB-treated dams relative to controls. These results suggest that the accumulation of hydroxylated PCB metabolites in fetal plasma can reduce fetal plasma T4 levels and accordingly fetal brain T4 levels. However, in late gestational fetuses, the induction of brain type II thyroxine 5'-deiodinase activity compensates for decreases in brain T4 levels, so that brain T3 levels are maintained.

Fetal, neonatal, and long-term alterations in hepatic retinoid levels following maternal polychlorinated biphenyl exposure in rats.

This study was undertaken to investigate the effects of perinatal polychlorinated biphenyl (PCB; Aroclor 1254) exposure on hepatic and plasma retinoid levels in fetal rats, their dams, and neonatal and adult offspring. Pregnant Wistar rats were treated with 0, 5, or 25 mg Aroclor 1254/kg body wt from Days 10 to 16 of gestation. Hepatic retinoid (retinol, retinyl palmitate, and retinyl stearate) levels were determined in fetuses and dams from Day 20 of gestation, in male and female neonates 21 days postpartum, and in young adult offspring 90 days after birth. Retinol levels were determined in fetal and maternal plasma (Gestation Day 20) and plasma from the offspring 21 and 90 days after birth. Maternal and fetal plasma retinol levels were decreased by 35 and 38% on Day 20 of gestation following exposure to the highest dose of Aroclor 1254. Male, but not female, neonatal plasma retinol levels were significantly decreased (23%) in the high-dose group. No effects of PCB treatment were seen on plasma retinol levels in the offspring 90 days after birth. Only slight reductions in fetal and maternal hepatic retinol and retinyl palmitate concentrations were observed after prenatal PCB exposure. Male neonatal hepatic retinyl palmitate levels were reduced by 25 and 50% in the 5 and 25-mg Aroclor 1254/kg dose groups, respectively, while female neonatal hepatic retinyl palmitate levels were significantly reduced only in the high-dose group. Ninety days after birth, male hepatic retinyl palmitate levels were only slightly reduced in the highest dose group; however, hepatic retinol concentrations were significantly reduced by 50% in both PCB treatment groups. Female adult offspring exhibited significant reductions in hepatic retinyl palmitate levels (25%) in both PCB treatment groups, while hepatic retinol levels exhibited an unusual increase of more than 100% of controls in the low-dose group, while levels in the high-dose group were similar to controls. This study demonstrates that even a relatively low maternal dose of Aroclor 1254 results in long-term alterations in retinoid status of the offspring in the rat.

Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats.

The metabolism and distribution of a single oral dose of 25 mumol 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (14C-TCB) were investigated in pregnant female Wistar rats and their fetuses. TCB was administered on day 13 of gestation and the elimination was followed for 7 days. Non-pregnant rats were treated similarly for comparison. Fecal elimination of 14C-TCB derived radioactivity was significantly lower in pregnant rats than in non-pregnant rats. The major metabolite found in adult liver and plasma, placental tissue, whole fetuses and fetal plasma was 3,3',4',5-tetrachloro-4-biphenylol (4-OH-TCB). Tissue levels (liver, abdominal fat, skin, skeletal muscle, kidney and plasma) of 14C-TCB-derived radioactivity declined by 65-85% over a 7-day period following administration in the adult animals. However, 14C-TCB-derived radioactivity accumulated more than 100-fold in the fetuses over the same time period, and GC/MS analysis revealed that the fetal accumulation in radioactivity was due primarily to 4-OH-TCB, and not the parent compound. On day 20 of gestation, concentrations of 4-OH-TCB were 14 times greater in fetal plasma than maternal plasma. Treatment with 14C-TCB significantly reduced plasma thyroxine levels by at least 28% up to 7 days after administration in non-pregnant animals and up to 4 days after administration in pregnant rats (31% decrease). By 7 days after administration plasma thyroxine levels had returned to control levels in the TCB-treated pregnant rats. However, fetal plasma thyroxine levels were significantly decreased by 35% in fetuses from 14C-TCB-treated dams 7 days after TCB administration. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity was significantly induced in TCB-treated dams relative to controls at 4 and 7 days after administration, while no EROD activity was detected in hepatic microsomes from control or TCB treated fetal rats at day 20 of gestation. These data suggest that hydroxylated metabolites of polychlorinated biphenyls may play a role in the development toxicity of these compounds.

beta-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 beta-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 beta-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 beta-naphthoflavone pretreated male rat, an apparent Km and Vmax of 4.5 microM 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 polychlorinated biphenyls (PCBs) and dioxins on growth and development.

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question. Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation. Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure. In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development.

Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants.

Dioxins [polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF)] and polychlorinated biphenyls (PCB) are potentially hazardous compounds. Animal studies have demonstrated that PCDD, PCDF, and PCB can alter thyroid hormone homeostasis. We investigated thyroid hormone levels in 105 mother-infant pairs. To estimate maternal and infant exposure, four nonplanar PCB congeners were measured in maternal plasma during the last month of pregnancy and in umbilical cord plasma. Seventeen PCDD and PCDF congeners, three planar PCB congeners, and 23 nonplanar PCB congeners were measured in human milk. Higher PCDD, PCDF, and PCB levels in human milk, expressed as toxic equivalents, correlated significantly with lower plasma levels of maternal total triiodothyronine and total thyroxine, and with higher plasma-levels of TSH in the infants in the 2nd wk and 3rd mo after birth. Infants exposed to higher toxic equivalents levels had also lower plasma free thyroxine and total thyroxine levels in the 2nd wk after birth. We conclude that elevated levels of dioxins and PCB can alter the human thyroid hormone status.

Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats.

The effects of prenatal oral administration of 0.2, 0.6, and 1.8 mg/kg body wt of 3,3',4,4'5,5'-hexachlorobiphenyl (HCB) on Day 1 of gestation and a combination of 1 mg/kg 3,3',4,4'-tetrachlorobiphenyl (TCB) from Day 2 to Day 18 with 0.6 mg HCB/kg body wt on Day 1 of gestation on thyroid hormone status and peripheral thyroid metabolism were studied in pregnant Wistar rats and their fetuses and offspring. Plasma total thyroxine and free thyroxine levels were reduced by HCB in a dose-dependent fashion in pregnant rats (Days 12 and 20 of gestation) and neonates (Day 21 postpartum), while only a combined dose of HCB and TCB was effective in decreasing fetal thyroid hormone levels by 65% on Day 20 of gestation. The activity of type II thyroxine 5'-deiodinase (5'D-II), the enzyme responsible for the deiodination of thyroxine (T4) to biologically active triiodothyronine in the brain, was examined in whole brain homogenates in fetuses and neonates. Decreases in plasma thyroid hormones were accompanied by significant increases, up to 100%, in 5'D-II activity in brain homogenates from fetuses (Day 20 of gestation) and neonates (Days 7 and 21 postpartum). The glucuronidation of 125I-T4 by hepatic microsomes was increased by at least 100% relative to control levels by all treatments in fetuses (Day 20 of gestation) and increased at least 40% in neonates (Days 7 and 21 postpartum) by a dose of 0.6 and 1.8 mg HCB/kg and the combined dose. These data indicate that prenatal HCB and/or TCB administration result in increased peripheral T4 metabolism. The increase in 5'D-II activity suggests that local hypothyroidism occurs in the brains of fetal and neonatal rats exposed to HCB and/or TCB. Since these effects occur during a period in which thyroid hormones play an important role in brain maturation, they may help explain the mechanism of developmental neurotoxicity induced by polychlorinated biphenyls.