Lee A. Meserve

Thyroxine normalizes polychlorinated biphenyl (PCB) dose-related depression of choline acetyltransferase (ChAT) activity in hippocampus and basal forebrain of 15-day-old rats

Neonatal exposure to the toxic chemical polychlorinated biphenyl (PCB) induces hypothyroidism (depressed thyroid hormones). Neonatal rats made hypothyroid by other means (chemical or surgical) have subnormal activity of choline acetyltransferase (ChAT), which catalyzes synthesis of acetylcholine, in the hippocampus and basal forebrain. The present study examined whether neonatal rats with PCB-induced hypothyroidism had depressed ChAT activity in these two brain areas, and whether alterations in ChAT activity were secondary to hypothyroidism rather than/in addition to a direct effect of PCB. Neonatal rats were exposed to PCB by feeding pregnant female rats chow containing various concentrations of PCB (0, 62.5, 125 or 250 ppm) throughout pregnancy and lactation. During postnatal days 4-14, neonatal rats exposed to the highest concentration of PCB were injected with either saline, triiodothyronine (T3), or thyroxine (T4), or were not injected at all. Circulating thyroid hormone levels (T4 and T3) and brain ChAT activity were determined at 15 days of age. All concentrations of PCB depressed circulating T4 levels and ChAT activity in a dose-response manner, but did not modify T3 levels. Injections of T4, but not T3, elevated ChAT activity in PCB-exposed rats to near control levels. Thus, altered ChAT activity in PCB-exposed rats may partially result from the hypothyroidism accompanying PCB poisoning. The possible molecular mechanism(s) of action of PCB on brain ChAT activity remains unclear.

Dose- and age-dependent alterations in choline acetyltransferase (ChAT) activity, learning and memory, and thyroid hormones in 15- and 30-day old rats exposed to 1.25 or 12.5 ppm polychlorinated biphenyl (PCB) beginning at conception

1. Polychlorinated biphenyls (PCB) were released into the environment through improper disposal for decades, causing widespread contamination. Slow biodegradation and lipophilic properties of PCB caused its persistence and concentration through food webs. Exposure to these environmental contaminants through maternal transfer during early development has been associated with neurological and endocrinological alterations in several different organisms. 2. The present study extended a preliminary investigation which suggested low level exposure to PCB altered acetylcholine biosynthesis enzyme, choline acetyltransferase (ChAT), activity in the hippocampus and basal forebrain and caused aberrations in thyroid hormone and behavior. 3. Dietary exposure of 15-day-old animals to 1.25 ppm of Aroclor 1254 (LPCB) during gestation and lactation significantly elevated ChAT activity in both areas of the brain. Animals exposed to 12.5 ppm of Aroclor 1254 (HPCB) until 15 days of age demonstrated significant elevations of ChAT activity in the basal forebrain. Thyroxine (T4) concentrations were slightly elevated in 15-day-old LPCB animals and significantly depressed in HPCB exposed pups; triiodothyronine (T3) concentrations were not altered. 4. At 30 days both LPCB and HPCB treatment groups displayed significantly depressed ChAT activity in both areas of the brain. T3 and T4 concentrations were subnormal, although T4 was not significantly depressed in LPCB animals. 5. In the Morris water maze all animals, when tested between 25 and 29 days of age, improved their latency time to the platform over 10 spatial learning trials. However, when combined means of trials 8-10 were compared, HPCB exposed animals had significantly increased latency time to the podium compared to control and LPCB animals.

Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats

Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation-dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders.

Effects of polychlorinated biphenyls on maternal odor conditioning in rat pups

Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants that can have damaging effects on physiologic, motoric and cognitive function. Results from studies on PCBs and behavior have shown that exposure can alter learning and memory processes and that these shifts in cognitive abilities can be related to changes in hormonal and neural function. Little experimentation has been done on the impact of exposure to PCBs on social and emotional development. Previous work has shown that exposure to PCBs in children can alter play behavior. Importantly, exposure to PCBs has been found to change aspects of maternal-offspring interactions in rodents. The present study examined the impact of PCBs on maternal odor conditioning in rat pups 12-14 days of age. A modified version of the conditioned place preference paradigm was used that incorporated a maternal-associated odor cue (lemon scent) as the conditioned stimulus. PCBs significantly depressed the preference for the maternal-associated cue but did not impair discrimination for a novel odor. These effects could arise due to changes in the social dynamics between the dam and offspring after co-exposure to PCBs. For example, dams exposed to PCBs during gestation have been found to show elevated grooming directed towards pups exposed to PCBs. This change in maternal care can have dramatic effects on behavioral and hormonal systems in the developing rat pup. In conclusion, perinatal PCBs alter important social behaviors of both the mother and pup, and these alterations could have long-lasting effects on behavioral, cognitive and emotional development.

Reduced growth of intra- and infra-pyramidal mossy fibers is produced by continuous exposure to polychlorinated biphenyl.

Exposure to polychlorinated biphenyl (PCB) has been shown to produce cognitive deficits in both humans and laboratory animals. However, no study to date has identified long-term brain changes which could account for these problems. This study employed Timms silver sulfide staining to visualize the hippocampal mossy fibers in Sprague-Dawley rats continuously exposed to either 125 ppm Aroclor 1254 or untreated control food beginning in utero. Reduced growth of hippocampal intra-and infra-pyramidal (II-P) mossy fibers were found in PCB treated rats compared to controls. Other measured hippocampal subdivisions remained relatively unaffected by PCB treatment, as did cortical thickness. The changes observed in hippocampal morphology in response to PCB exposure are the first to provide a potential explanation for at least part of the long-term PCB-induced cognitive deficits.

Characterization of a glucocorticoid-sensitive hippocampal protein

Increased synthesis of a rat hippocampal protein with an apparent molecular weight (Mr) of 35,000 Da occurs in response to elevation of serum corticosterone levels. Subcellular fractionation has localized this protein in the cytosol. Two-dimensional gel electrophoresis indicated that this protein has an isoelectric point (IEP) of 6.6. A similar protein in liver has a slightly higher Mr and an IEP of 6.8. Increased synthesis of one additional hippocampal protein with an Mr of 46,000 Da and an IEP of 6.2 and of two other liver proteins, one with an Mr of 53,000 Da and an IEP of 6.2 and the other with an Mr of 45,000 Da and a range of IEPs from 8.7 to 7.8, was also seen after injection of corticosterone into rats. One possible identity of the 35,000 Da protein is glycerol 3-phosphate dehydrogenase (GPDH), based upon the reported Mr and IEP of this enzyme. The 35,000 Da hippocampal protein co-eluted from a gel filtration column with GPDH activity. No alteration of hippocampal GPDH activity was seen in intact rats 4 or 24 h after injection of either corticosterone or the type II receptor-specific agonist RU 28362. However, daily administration of corticosterone to rats beginning 10 days after adrenalectomy returned hippocampal GPDH activity to normal values after 2-3 days. In contrast, synthesis of the 35,000 Da protein was maximally increased 4 h after a single injection of steroid and not elevated at later times.

Retrospective Study Of The Effects Of Zinc Supplementation In An Elderly Institutionalized Population With Decubitus Ulcers

Abstract The present pilot study was a retrospective analysis of 70 institutionalized elderly (37F 33 M, mean age 81.7 + 8.3 years) with documented decubitus ulcers (stage II-IV). The study compared 26 patients who received 440 mg zinc sulfate/day (100 mg elemental zinc/day) for 30 days with 44 patients not receiving zinc sulfate. There were no significant differences between groups in age, sex, % ideal body weight, mobility, continence, or glucocorticoid use. Food intake was 2 =0.32). Some of the effects of the zinc sulfate supplement appeared to be modulated by multi-vitamin/mineral supplementation at RDA levels. CONCLUSIONS: This preliminary study suggests several adverse effects related to zinc sulfate supplementation in excess (6 times) of the RDA. Further study is needed to substantiate these Findings. The maximal safe dose of zinc supplementation is not known. Findings from the present study emphasize the importance of carefully evaluating zinc supplementation practices.

Effects of Maternal Ingestion of Aroclor 1254 (PCB) on the Developmental Pattern of Oxygen Consumption and Body Temperature in Neonatal Rats

Polychlorinated biphenyl (PCB) is an environmental pollutant that has been implicated in depression of reproductive success in Great Lakes gulls, production of congenital deformities in humans, and increased incidence of carcinogenesis in laboratory mice. PCB has also been shown to be a thyrotoxin in both adult and developing animals. Most recently, the hypothyroid effects of PCB exposure have been reported to elicit effects similar to those of hypothyroidism caused by other methods. This study was done to determine the effects of PCB ingestion in pregnant and lactating rats on the development of thermoregulation in neonatal animals. Body temperature and rate of oxygen consumption was evaluated in rat puts on days 4 through 14 after birth. Because the major thermomregulatory hormones are thyroid hormones, thyroid hormone status and thyroid weights were evaluated at the end of the study on postnatal day 15. 19 refs., 2 figs., 1 tab.

Polychlorinated biphenyl exposure alters oxytocin receptor gene expression and maternal behavior in rat model

Polychlorinated biphenyl (PCB) is a persistent organic pollutant known to induce diverse molecular and behavioral alterations. Effects of PCB exposure could be transmitted to future generations via changes in behavior and gene expression. Previous work has shown that PCB-exposure can alter social behavior. The present study extends this work by examining a possible molecular mechanism for these changes. Pregnant rats (Sprague-Dawley) were exposed through diet to a combination of non-coplanar (PCB 47 - 2,2′,4,4′-tetrachlorobiphenyl) and coplanar (PCB 77 - 3,3′,4,4′-tetrachlorobiphenyl) congeners. Maternal care behaviors were examined by evaluating the rate and quality of nest building on the last 4 d of gestation and dam/pup interactions on postnatal days 1, 2, 4 and 6. On postnatal day 17, dams were euthanized and hypothalamic tissue was removed for expression analyses of the oxytocin receptor (OXTR) and cytochrome P450 1a1 (Cyp1a1). PCB altered nest building and maternal care behaviors. Specifically, there was a significant increase in time spent in low crouch and high crouch nursing posture on PND 4 and PND 6 respectively. Molecular analysis revealed that PCB exposure upregulated OXTR expression in the hypothalamus of dams. These results provide a possible molecular mechanism for PCB-induced changes in social interactions during early development.

Effects of polychlorinated biphenyl (PCB) exposure on response perseveration and ultrasonic vocalization emission in rat during development

The 3 major symptoms of autistic spectrum disorders include 1) social behavioral alterations, 2) problems in communication and 3) higher-order motoric deficits of perseveration and stereotyped movements. Previous work has shown that early developmental exposure to polychlorinated biphenyls (PCBs) alters rat pup social motivation and juvenile rat social recognition/investigation. The present work extends this previous research by examining how perinatal PCB exposure alters motoric functions and communication abilities at different stages of development. Action perseveration was examined using performance measures from a T-maze environment. Communication abilities were evaluated by monitoring ultrasound emission in rat pups during a brief isolation from the litter. T-maze learning and performance were significantly impaired in PCB exposed animals. Additionally, PCB exposure led to reduced ultrasound emission rates during brief isolation from the natal group. When combined with the previous work using the same developmental exposure regimen, it seems clear that PCB exposure at moderate doses can lead to alterations in 1) social behavior, 2) action choice and perseveration, and 3) communication abilities making it a potential candidate as an endocrine disruptor involved in the production of autistic spectrum disorder in the human population.