Biomedical subjects

M Christopher Newland

Publications and source records attributed to M Christopher Newland.

8 recordsLinked to original sources

PubMed2006

Brain and blood mercury and selenium after chronic and developmental exposure to methylmercury.

Fish contain methylmercury and the potentially protective element, selenium. Blood and brain concentrations of these elements were determined in female rats after consuming AIN-93-based diets containing 0.06 or 0.6 ppm of selenium (Se) and drinking water containing 0, 0.5, or 5 ppm of mercury as methylmercury (MeHg) for 6 or 18 months. Brain and blood concentrations of mercury and selenium were also evaluated in neonates after gestational exposure. For adult rats in the high-Se, high-Hg condition, brain selenium content was 0.35 ppm and 1.8 ppm after 6 and 18 months, respectively, but for every other adult-onset condition, it was 0.1 ppm. Blood selenium varied less than two-fold despite a 10-fold difference in diet. After 6 months, mercury content in the brain showed a greater than 10-fold difference between the mercury groups, and interacted somewhat with dietary selenium. After 18 months, no mercury was detected in the brains of the 0.5 ppm groups, and their blood mercury also fell. For the 5.0 ppm groups, brain mercury increased slightly (low Se diet) or several-fold (high Se diet) over that seen at 6 months, and blood mercury also increased. Neonatal selenium concentrations were more labile than adults, and mercury in neonates was generally higher. All animals exposed to 5 ppm of mercury experienced a molar excess of mercury over selenium. Animals exposed to 0.5 ppm mercury showed a balance between mercury and selenium or a selenium excess, depending on the condition.

Animals↗

PubMed2006

Gestational exposure to methylmercury and selenium: effects on a spatial discrimination reversal in adulthood.

Selenium, a nutrient, and methylmercury, a developmental neurotoxicant, are both found in fish. There are reports that selenium sometimes ameliorates methylmercury's neurotoxicity, but little is known about the durability of this protection after low-level gestational exposure. Developmental methylmercury exposure disrupts behavioral plasticity, and these effects extend well into adulthood and aging. The present experiment was designed to examine interactions between developmental low-level methylmercury and nutritionally relevant dietary selenium on discrimination reversals in adulthood. Female rats were exposed, in utero, to 0, 0.5, or 5 ppm mercury as methylmercury via drinking water, approximating mercury exposures of 0, 40, and 400 microg/kg/day. They also received both prenatal and postnatal exposure to a diet containing selenium from casein only (0.06 ppm) or 0.6 ppm selenium, creating a 2 (chronic Se)x3 (gestational MeHg) full factorial design, with six to eight rats per cell. Behavior was evaluated with a spatial discrimination procedure using two levers and sucrose reinforcers. All groups acquired the original discrimination similarly. Rats exposed to low selenium (0.06 ppm), regardless of MeHg exposure, required more sessions to complete the first reversal and made more omissions during this reversal than high selenium (0.6 ppm) animals, but the two diet groups did not differ on subsequent reversals. Rats exposed to MeHg, regardless of selenium exposure, made more errors than controls on the first and third reversals, which was away from the original discrimination. MeHg-exposed animals also had shorter choice latencies than controls during the first session of a reversal. Low selenium increased the number of omissions during a reversal, whereas high MeHg exposure produced perseverative responding (errors) on the lever that was reinforced during the original discrimination. However, there was no interaction between selenium and MeHg exposure.

Age Factors↗

PubMed2006

Gestational exposure to methylmercury and n-3 fatty acids: effects on high- and low-rate operant behavior in adulthood.

Fish in the diet is the major source of methylmercury (MeHg) exposure, but eating fish also provides important nutrients. Many fish species contain essential long chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), an omega-3 (or n-3) fatty acid, that is important for neural development and function. To examine interactions between MeHg and n-3 fatty acids, female Long-Evans rats were exposed, in utero, to 0, 0.5, or 5 ppm MeHg via drinking water, approximating exposures of 0, 40, and 400 mug/kg/day. They also received pre- and postnatal exposure to a diet containing either fish oil or coconut oil, creating a 2 (Diet)x3 (MeHg) full factorial design, with 6-8 rats per cell. The diets were high or marginal, respectively, in n-3 fatty acids but approximately equal in n-6 fatty acids. No exposure-related effects on developmental milestones or growth were noted. Behavior was evaluated using a series of rapidly increasing fixed ratio (FR) schedules of sucrose reinforcement; 1, 5, 25 and 75 lever presses were required for sucrose delivery, with three sessions provided at each requirement. This phase was followed by four sessions of a differential-reinforcement-of-low-rate-behavior (DRL) schedule, in which presses preceded by 10 s (or more) without a press were reinforced. Subsequently, several progressive ratio (PR) schedules that increased response requirements throughout a single session by a rate of 5%, 10%, or 20% were imposed. Rats exposed during gestation to MeHg had significantly higher response rates than controls under the large FR schedules, during the first session of DRL, and the PR 5% schedule, but neither fish oil nor coconut oil modified MeHg's effects. This finding is consistent with hypotheses that developmental MeHg exposure produced perseverative responding or altered the sensitivity of behavior to its reinforcing consequences and that certain reinforcement contingencies can unmask MeHg's effects.

Animals↗

PubMed2005

Urolithiasis in rats consuming a dl bitartrate form of choline in a purified diet.

Urolithiasis appeared in rats maintained to study the effects of nutrients and methylmercury on development and aging. After a year, the mortality rate was approximately 10%, and by 2 years, it had increased to nearly 30%. Clinical signs and urinary tract pathology were examined as a function of diet, duration on diet, gender, methylmercury exposure, genetics, and other potential risk factors by using survival analyses and qualitative comparisons. Urolithiasis in female rats appeared 15 weeks after beginning a purified diet and after 5 weeks for male rats. After 97 weeks, the mortality rate of female rats was 22% and for male rats was 64%. Lifetime urolithiasis-associated mortality was about 2% in a group of rats that consumed the contaminated diet for < 30 weeks. No urolithiasis occurred in siblings or cohorts of the rats described here that were maintained on a standard rodent chow containing choline chloride. Urolithiasis was traced to racemic, rather than levo-, bitartaric acid in some purified diets shipped in 2001 and 2002. It is unknown when the impurity first appeared in the diet, so estimates of exposure duration are upper limits. Chronic methylmercury exposure increased vulnerability. Some families (dam + offspring) had multiple cases of urolithiasis, but probability models constructed to evaluate familial clustering revealed no evidence for a genetic predisposition to urolithiasis apart from gender. Removing racemic tartaric acid did not decrease mortality once rats had been on the diet for 20 to 30 weeks, but it helped when exposure duration was shorter.

Animal Feed↗

PubMed2003

Punishment in human choice: direct or competitive suppression?

This investigation compared the predictions of two models describing the integration of reinforcement and punishment effects in operant choice. Deluty's (1976) competitive-suppression model (conceptually related to two-factor punishment theories) and de Villiers' (1980) direct-suppression model (conceptually related to one-factor punishment theories) have been tested previously in nonhumans but not at the individual level in humans. Mouse clicking by college students was maintained in a two-alternative concurrent schedule of variable-interval money reinforcement. Punishment consisted of variable-interval money losses. Experiment 1 verified that money loss was an effective punisher in this context. Experiment 2 consisted of qualitative model comparisons similar to those used in previous studies involving nonhumans. Following a no-punishment baseline, punishment was superimposed upon both response alternatives. Under schedule values for which the direct-suppression model, but not the competitive-suppression model, predicted distinct shifts from baseline performance, or vice versa, 12 of 14 individual-subject functions, generated by 7 subjects, supported the direct-suppression model. When the punishment models were converted to the form of the generalized matching law, least-squares linear regression fits for a direct-suppression model were superior to those of a competitive-suppression model for 6 of 7 subjects. In Experiment 3, a more thorough quantitative test of the modified models, fits for a direct-suppression model were superior in 11 of 13 cases. These results correspond well to those of investigations conducted with nonhumans and provide the first individual-subject evidence that a direct-suppression model, evaluated both qualitatively and quantitatively, describes human punishment better than a competitive-suppression model. We discuss implications for developing better punishment models and future investigations of punishment in human choice.

Choice Behavior↗

PubMedDate not supplied

Gestational exposure to methylmercury retards choice in transition in aging rats.

Developmental exposure to methylmercury has behavioral effects that extend into adulthood and aging. In this study, methylmercury's prolonged effects on the acquisition of choice and sensitivity to changes in reinforcement rates were studied. Pregnant female rats were exposed to drinking water containing 0, 0.5, or 6.4 ppm Hg as methylmercury, resulting in about 40 and 500 microg/kg/day of mercury intake. Maternal exposure began at least 4 weeks before mating, and continued to postnatal day 16. Then all mercury exposure ended. The behavior of 1.7- and 2.3-year-old offspring was maintained under various concurrent schedules of reinforcement. Thus, one reinforcement schedule maintained left-lever responding and a separate one maintained right-lever responding. The animal could switch ("changeover") between the two levers at any time. For the first 30 min of a 3-h session, the left and right levers each produced reinforcement at the same rate and left:right response ratios were about 1:1. After 30 min, either the left lever became richer than the right; the right lever became richer than the left, or there was no change. Terminal reinforcer ratios (left:right) used were 9:1, 4:1, 3:1, 1:1, 1:3, 1:4, and 1:9. Response rates on the two levers were tracked continuously through a session. This novel procedure for examining choice, and its acquisition, in a single session, was validated through many comparisons with the extant literature. Both response rates and changeover rates were influenced by the reinforcer ratios for the 1.7-year-olds. Changeover rates were not influenced by reinforcement rate for their 2.3-year-old littermates. For the 1.7-year-olds, there was no effect of methylmercury on changeover or response rates and there was no interaction between exposure and reinforcer ratio. In controls and most methylmercury-exposed rats, response ratios (the measure of choice) approximately matched reinforcer ratios by the end of the single session. This is commonly interpreted as reflecting sensitivity to reinforcement rates. Methylmercury exposure did not affect this measure systematically. The single-session transition from baseline (response ratios about 1:1) to terminal performance was retarded in many methylmercury-exposed rats relative to controls, especially in the older rats. The 2.3-year-old control rats required about 20 to 25 reinforcers to complete one half of the 9:1 and 4:1 transitions, respectively, and exposed rats required about twice as many. Thus, prenatal methylmercury exposure specifically retarded the acquisition of choice in older rats. Methylmercury did not interfere with the final expression of choice. Moreover, two rate measures, lever-press rates and changeover rates, were not systematically affected by methylmercury. The acquisition of choice appears to be very sensitive to subtle consequences of developmental methylmercury exposure. The specific tactics greatly reduced the time required to study behavior in transition from a month in previous reports to a single session here.

Aging↗

PubMedDate not supplied

Neuromotor deficits and mercury concentrations in rats exposed to methyl mercury and fish oil.

It has been suggested that docosahexaenoic acid (DHA) or other n-3 polyunsaturated fatty acids (PUFAs) may prevent or ameliorate methyl mercury's neurotoxicity. To examine interactions between PUFAs and methyl mercury exposure, sixty-six female Long-Evans rats were exposed to methyl mercury continuously via drinking water from fifteen weeks of age. Water included methyl mercury concentrations of 0, 0.5, and 5.0 ppm, creating estimated intakes of about 0, 40, and 400 microg/kg/day across exposure groups. An additional fifty-eight female offspring were exposed to methyl mercury only during gestation. Rats consumed one of two diets, each based on AIN-93 formulation, providing a 2 (generation) X 2 (diet) X 3 (methyl mercury exposure) factorial experimental design. A "coconut oil" diet (1/3 of fats were provided by coconut oil) was marginally adequate in n-3 PUFAs and contained no DHA. A "fish oil" diet was rich in n-3 fatty acids, including DHA. The diets were approximately equal in n-6 fatty acids. Forelimb grip strength declined with age for all groups, but the decline was greatest for those exposed chronically to 400 microg/kg/day of methyl mercury. This high-dose group also displayed hind limb crossing, gait disorders, and diminished running wheel activity. Dietary n-3 fatty acids did not influence these effects. Chronic exposure to 400 microg/kg/day of methyl mercury resulted in blood and brain concentrations of about 70 and 10 ppm, respectively, approximately 50-fold higher than concentrations seen in rats exposed to 40 microg/kg/day. Rats that became ill and died before the experiment ended had higher concentrations of mercury than their cohorts who survived to the end. Organic mercury was highly correlated with total mercury in these rats but inorganic mercury remained approximately constant. Some deaths were due to urolithiasis (kidney or bladder stones) associated with a dietary contaminant and that was eventually fatal to 22% of the females in the colony. Neurobehavioral effects are reported on rats that did not become ill.

Age Factors↗

PubMedDate not supplied

Transferring behavioral technology across applications.

Application flows naturally from good science, and behavioral toxicology is no exception. Phenomena discovered and procedures developed in behavioral laboratories are being applied on a wide scale in commercial, industrial, and governmental settings. In behavioral toxicology, this transfer of technology has occurred in an ad hoc manner, albeit with a degree of sophistication. The development of technology transfer in other disciplines is instructive. A symposium at the May 2001 meeting of the Behavioral Toxicology Society examined this issue, and some participants provide their contributions here. Henry Pennypacker examines the issue of whether behavioral procedures can meet the demanding standards required to transfer technology to commercial endeavors and concludes that, under some conditions, they can. He notes that the shortage of well-developed and transferred behavioral technologies results from a lack of understanding of the process of technology transfer on the part of behavior analysts. In the field of engineering, the results of basic research are transformed to candidate technologies that meet standardized criteria with respect to three properties: quantification, repetition, and verification. Kent Anger describes the challenging steps in the trail from the laboratory to wide-scale application-steps that are essential for the scaling up of any behavioral technique. Finally, Paul Mele describes the legal background to patenting and copyrighting ideas, a process that behaviorists have rarely used. Together, these topics identify the requirements and warn of the challenges and intricacies that await those who seek to transfer behavioral technology beyond the laboratory.

Animals↗