Biomedical subjects
Publications and source records attributed to Bernard Weiss.
Exogenous thymine must be converted to thymidine to enable a thyA (thymidylate synthase) mutant to grow. The deoxyribose in the thymidine comes from dUMP, which must first be dephosphorylated. The nucleotidase YjjG is critical for this step. A yjjG thyA mutant cannot use thymine for growth on a glucose minimal medium.
Fifteen years ago, in 1991, the U.S. Centers for Disease Control and Prevention (CDC) established 10 microg/dL as the lowest level of concern for children's blood lead levels. This value is extremely important because, historically, policy makers and public health officials generally have acted to remove sources of lead exposure only after the CDC's level of concern had been exceeded. A growing body of evidence, however, reveals that blood lead levels below 10 microg/dL may impair neurobehavioral development. There is now sufficient and compelling scientific evidence for the CDC to lower the blood lead action level in children. This review argues that a level of 2 microg/dL is a useful and feasible replacement. Although it can be argued, in turn, that no threshold for the health effects of lead is demonstrable, analytically a blood level of 2 microg/dL is readily and accurately measured and provides a benchmark for successful prevention. Lowering the level of concern would encourage and accelerate the investments needed to ensure that children are protected from lead exposure in their homes, schools, and play settings. Such a program would also offer economic advantages because of the coupling between lead, educational attainment, earnings and anti-social conduct. By lowering the blood action level, CDC will promote policies and initiatives designed to further reduce children's exposure to this potent developmental neurotoxicant.
There is increasing concern over the impact of low-dose exposures to environmental chemicals on children's neurobehavioral function. To determine subtle alterations in children's function, it is necessary to move beyond global measures such as IQ and employ tests that can detect small, subtle neurodevelopmental effects across a broad array of behavioral domains. We investigated the sensitivity and specificity of a battery of 63 neurodevelopmental tests or tasks designed to detect outcomes representing the type of subtle neurodevelopmental deficits caused by exposure to neurotoxicants in school-aged children. We studied Neonatal Intensive Care Unit (NICU) graduates, a population known to be at risk for both major and mild anomalies in perception, motor functioning, learning, memory and cognition. This population served as a surrogate to evaluate the capacity of these tests and tasks to predict such deficits. The subjects' histories of previous exposures to any environmental neurotoxicants was not ascertainable, but exposures to elevated levels was not suspected. Over one-third of the 63 measures proved capable of detecting pre-diagnosed lower IQ, the presence of a learning disability (LD) or a neonatal risk profile with at least 70% sensitivity and specificity. Some tests were differentially sensitive and specific, depending upon the presence or absence of one or more of several covariates such as gender, age, hearing status, or familiarity with computers. Tests were also eliminated from the battery if they were affected by too many covariates. We propose calling the final battery of tests that are specific and sensitive to subtle neurodevelopmental changes the Rochester test battery (RTB). Further studies are needed to confirm the capability of the RTB to detect subtle changes associated with neurotoxic exposures.
Evidence from an outbreak of methyl mercury (MeHg) poisoning in Iraq suggested that adverse effects of prenatal exposure on child development begin to appear at or above 10ppm measured in maternal hair. To test this hypothesis in a fish-eating population, we enrolled a cohort of 779 children (the main cohort) in the Seychelles Child Development Study (SCDS). The cohort was prenatally exposed to MeHg from maternal fish consumption, and the children started consuming fish products at about 1 year of age. Prenatal exposure was measured in maternal hair and recent postnatal exposure in the child's hair. The cohort has been examined six times over 11 years using extensive batteries of age-appropriate developmental tests. Analyses of a large number of developmental outcomes have identified frequent significant associations in the appropriate direction with numerous covariates known to affect child development, but only one adverse association between prenatal MeHg exposure and a developmental endpoint. Because such results could be ascribed to chance, there is no convincing evidence for an association between prenatal exposure and child development in this fish-eating population. Secondary analyses have generally supported the primary analyses, but more recently have suggested that latent or delayed adverse effects might be emerging at exposure above 10-12ppm as the children mature. This suggests that the association between prenatal exposure and child development may be more complex than originally believed. This paper reviews the SCDS main cohort study results and presents our current interpretations.
In Escherichia coli, nitrosative mutagenesis may occur during nitrate or nitrite respiration. The endogenous nitrosating agent N2O3 (dinitrogen trioxide, nitrous anhydride) may be formed either by the condensation of nitrous acid or by the autooxidation of nitric oxide, both of which are metabolic by-products. The purpose of this study was to determine which of these two agents is more responsible for endogenous nitrosative mutagenesis. An nfi (endonuclease V) mutant was grown anaerobically with nitrate or nitrite, conditions under which it has a high frequency of A:T-to-G:C transition mutations because of a defect in the repair of hypoxanthine (nitrosatively deaminated adenine) in DNA. These mutations could be greatly reduced by two means: (i) introduction of an nirB mutation, which affects the inducible cytoplasmic nitrite reductase, the major source of nitric oxide during nitrate or nitrite metabolism, or (ii) flushing the anaerobic culture with argon (which should purge it of nitric oxide) before it was exposed to air. The results suggest that nitrosative mutagenesis occurs during a shift from nitrate/nitrite-dependent respiration under hypoxic conditions to aerobic respiration, when accumulated nitric oxide reacts with oxygen to form endogenous nitrosating agents such as N2O3. In contrast, mutagenesis of nongrowing cells by nitrous acid was unaffected by an nirB mutation, suggesting that this mutagenesis is mediated by N2O3 that is formed directly by the condensation of nitrous acid.
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BACKGROUND: The outcomes of exposure to neurotoxic chemicals early in life depend on the properties of both the chemical and the host's environment. When our questions focus on the toxicant, the environmental properties tend to be regarded as marginal and designated as covariates or confounders. Such approaches blur the reality of how the early environment establishes enduring biologic substrates. OBJECTIVES: In this commentary, we describe another perspective, based on decades of biopsychological research on animals, that shows how the early, even prenatal, environment creates permanent changes in brain structure and chemistry and behavior. Aspects of the early environment-encompassing enrichment, deprivation, and maternal and neonatal stress-all help determine the functional responses later in life that derive from the biologic substrate imparted by that environment. Their effects then become biologically embedded. Human data, particularly those connected to economically disadvantaged populations, yield equivalent conclusions. DISCUSSION: In this commentary, we argue that treating such environmental conditions as confounders is equivalent to defining genetic differences as confounders, a tactic that laboratory research, such as that based on transgenic manipulations, clearly rejects. The implications extend from laboratory experiments that, implicitly, assume that the early environment can be standardized to risk assessments based on epidemiologic investigations. CONCLUSIONS: The biologic properties implanted by the early social environment should be regarded as crucial elements of the translation from laboratory research to human health and, in fact, should be incorporated into human health research. The methods for doing so are not clearly defined and present many challenges to investigators.
Manganese neurotoxicity is linked primarily to inhalation exposure, and its clinical features are almost totally based on high doses, such as those experienced by miners. Manifestations of lower level exposures can take two forms. One is the appearance of neurobehavioral deficits. A second, equally subtle, form is as a promoter, borrowing the term used in carcinogenesis, of neurodegenerative disease. Such low-level environmental exposures may be more potent than expected if they occur as ultrafine particles able to penetrate directly into the brain. The neurological disorder linked most closely to manganese is Parkinson's disease (PD). Although most observers recognize that the features of manganese-induced parkinsonism differ from those of idiopathic PD, they overlap considerably. The overlaps should be expected because the underlying lesions, although distinguishable, are closely linked because they belong to structures with complex interdependent circuitry. Such interdependence makes it feasible to undertake an analysis of how manganese neurotoxicity might elevate the risks of PD. A relatively small increment in risk, expressed as a leftward shift in the age prevalence of PD, incurs significant economic costs.
This project was undertaken to more completely understand the consequences of lifetime exposure to methylmercury. A series of experiments examined how perinatal or lifetime exposure to methylmercury affected behavioral performances in the adult mouse at different ages. One hundred female B6C3F1/HSD mice were assigned to one of three dose groups, 0 ppm, 1 ppm, or 3 ppm methylmercury chloride administered in a 5 nM sodium carbonate drinking solution. Four weeks after initiating dosing, the females were bred with male CBA/J HSD mice to produce the trihybrid offspring B6C3F1/HSD x CBA/J HSD. The methylmercury-treated litters were split into two subgroups, one exposed throughout its lifetime to the original dose, the other exposed through postnatal day 13. Altogether, then, five groups were studied: Control, 1 ppm perinatal, 1 ppm lifetime, 3 ppm perinatal, and 3 ppm lifetime. Three neurobehavioral indices were evaluated: (1) delayed spatial alternation (a test of memory) and (2) running in a wheel to earn food pellets (schedule-controlled operant behavior) were assessed starting at 5 and 15 months of age; (3) hindlimb splay, a measure of motor function, was assessed at 5, 15, and 26 months of age. Subjects tested at one age were littermates of those tested at the other ages. MeHg altered the hindlimb splay distance; control mice differed from methylmercury-exposed mice, the 1 ppm lifetime and 3 ppm lifetime groups differed from each other, and the analysis yielded an age by dose interaction. MeHg exposure altered different measures of wheel running under the 3 ppm lifetime condition. In the delayed alternation procedure, the mouse was required to respond to one of two locations in a strictly alternating sequence. More mice from the treated groups, except for the 1 ppm perinatal group, failed to meet the criterion at longer delay values. Overall, the results show that exposure to low levels of methylmercury produces behavioral effects that depend on the test procedure, the dose, the duration of exposure, and the age. Lifetime evaluations of exposure to toxicants, beginning with early development, should be a component of the risk assessment process for neurotoxicity.
Developmental, learning, and behavioral disabilities are a significant public health problem. Environmental chemicals can interfere with brain development during critical periods, thereby impacting sensory, motor, and cognitive function. Because regulation in the United States is based on limited testing protocols and essentially requires proof of harm rather than proof of lack of harm, some undefined fraction of these disabilities may reflect adverse impacts of this "vast toxicological experiment" (H. L. Needleman, as quoted in B. Weiss & P. J. Landrigan, 2000, p. 373). Yet the hazards of environmental pollutants are inherently preventable. Psychologists can help prevent developmental disabilities by mobilizing and affecting public policy, educating and informing consumers, contributing to interdisciplinary research efforts, and taking action within their own homes and communities to reduce the toxic threat to children.
In the midst of research focusing on the neurodevelopmental effects of mercury vapor in rats, we detected significant levels of mercury (30-60 ng/g) in the blood of nonexposed control subjects. We determined that the dominant form of the mercury was organic and that the standard laboratory chow we used in our vivarium was the source of the contamination. The dietary levels were deemed of potential biologic significance, even though they might have fallen below the limits of measurement specified by the supplier. All investigators employing animals in research must assess such potential contamination because dietary agents may alter a) conclusions based on intentionally administered doses, b) outcomes by interacting with other agents that are the primary focus of the research, and c) outcomes of research unrelated to the toxic effects of experimentally administered agents.
There is significant public concern about the potential health effects of exposure to mercury vapour (Hg(0)) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg(0), evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects. Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg(0) is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg(0) released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg(0) and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg(0) levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20-30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.
Mercury is ubiquitous in the global environment, ensuring universal exposure. Some forms of mercury are especially neurotoxic, including clinical signs at high doses. However, typical human exposures occur at low to moderate doses. Only limited data about neurotoxicity at low doses are available, and scientists differ in their interpretation. Dose-response data on neurodevelopment are particularly limited. Despite or perhaps because of the lack of sufficient or consistent scientific data, public concern about a link between mercury exposure and developmental disabilities has been rising. After reviewing the data, the US Environmental Protection Agency proposed a reference dose (an estimate of a daily dose that is likely to be without a risk of adverse effects over a lifetime) for methyl mercury that is substantially lower than previous guidelines from the World Health Organization, the US Agency for Toxic Substances and Disease Registry, and the US Food and Drug Administration. Some questions have been raised about the Environmental Protection Agency's guidelines, but the issue remains unresolved. Meanwhile, consumer groups have raised questions about the potential link between mercury exposure and autism spectrum disorders as well as other adverse neurodevelopmental outcomes. This hypothesis has prompted some parents to seek regulatory, legal, or medical remedies in the absence of firm evidence. This article reviews what is known about mercury neurotoxicity and neurodevelopmental risk. Our intent is to focus the debate about mercury on 1) additional research that should be sought and 2) defining the principal issues that public policy makers face.
Pesticides are a broad group of heterogeneous chemicals that have a significant public health benefit by increasing food production productivity and decreasing food-borne and vector-borne diseases. However, depending on the agent and the exposure, they may pose health risks. Because of their behavior, acute accidental toxic exposures occur more commonly in children. Because of the dietary habits and greater intake of foods per kilogram in children and because some infants are breastfed, there is also concern about the effects on them of low-level environmental exposures. In the absence of direct conclusive evidence, consistent and relevant observations have led some investigators to infer that chronic low-dose exposure to certain pesticides might pose a potential hazard to the health and development of infants and children. Other investigators have concluded that such inferences can be neither supported nor refuted at the present time. The pediatrician has a role to play in recognizing the symptoms of acute exposure and to be able to provide appropriate treatment. It is essential to study whether there are subtle neurologic effects that may result from low-level pesticide exposures in individual patients.
Cells exposed to DNA damaging agents in their natural environment do not undergo continuous cycles of replication but are more frequently engaged in gene transcription. Luciferase gene expression analysis with DNA templates containing uracil or 8-oxoguanine, placed at a defined position, indicated that in nondividing Escherichia coli cells, efficient mutagenic lesion bypass does occur in vivo during transcription. Sequence analyses of the transcript population revealed that RNA polymerase inserts adenine opposite to uracil, and adenine or cytosine opposite to 8-oxoguanine. Surprisingly, deletions were also detected for 8-oxoguanine-containing templates, indicating RNA polymerase slippage over this lesion. Genetic analyses showed that, in E. coli, 8-oxoguanine is subject to transcription-coupled repair. Consequently, DNA damages alter transcription fidelity in vivo, which may lead to the production of mutant proteins that have the potential to change the phenotype of nondividing cells.
Pregnant Sprague-Dawley rats received a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin on day 8 of gestation. Each litter contributed a single male-female pair trained to press a lever to obtain food pellets under two operant behavior procedures. Initially, each lever press was reinforced. The fixed-ratio (FR) requirement was then increased every four sessions from the initial setting of 1 to values between 6 and 71. We then studied responses for 30 days under a multiple schedule combining FR 11 and another schedule requiring a pause of at least 10 sec between responses (DRL 10-sec). TCDD evoked a sexually dimorphic response pattern. Generally, TCDD-exposed males responded at lower rates than control males. In contrast, exposed females responded at higher rates than controls. Each response measure from the mult-FR DRL schedule yielded a male-female difference score. We used the differences in response rate to calculate benchmark doses based on the relative displacement from modeled zero-dose performance of the effective dose at 1% (ED(01)) and 10% (ED(10)), as determined by a second-order polynomial fit to the dose-effect function. For the male-female difference in FR rate of responding, the mean ED(10) was 2.77 ng/kg with a 95% lower bound of 1.81 ng/kg. The corresponding ED(01) was 0.27 ng/kg with a 95% lower bound of 0.18 ng/kg. For the male-female difference in DRL rate, the mean ED(10) was 2.97 ng/kg with a 95% lower bound of 2.02 ng/kg. The corresponding ED(01) was 0.30 ng/kg with a 95% lower bound of 0.20 ng/kg. These values fall close to, but below, current estimates of human body burdens of 13 ng/kg, based on TCDD toxic equivalents.
Measures of cognitive and other behaviors not specifically related to reproduction are often sex-linked. Males and females perform differently on many tasks and often interact with members of their species in dissimilar ways. If such differences are diminished, reversed, or widened by prenatal chemical exposures, a reasonable inference is that exposure interfered with sexual differentiation of the brain, largely, but not exclusively, through interference with the actions of gonadal hormones. Explicit recognition of sex differences in performance is not a prominent feature of toxicity testing, however, except for reproduction studies, and is not a recognized criterion in developmental neurotoxicity testing. In contrast to the low visibility accorded sex differences in testing protocols for the assessment of developmental neurotoxicity, the literature is filled with examples showing that the developing male and female respond differently to many chemical agents, with subsequent expression in behavior. Quite often, even when such differences are reported, further analyses are not carried out nor are subsequent studies conducted for clarification. Moreover, many investigators include only male subjects. Both polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) studies provide several examples of striking differences between the behavioral responses of male and female offspring to developmental exposure. They offer examples, as well, of how to approach the study and analysis of such differences. Given the societal importance of risk assessments applied to potential developmental neurotoxicants, studies should be deemed questionable if they fail to include outcome measures based on sexual dimorphisms in nonreproductive behaviors.
This article discusses three examples of delay (latency) in the appearance of signs and symptoms of poisoning after exposure to methylmercury. First, a case is presented of a 150-day delay period before the clinical manifestations of brain damage after a single brief (<1 day) exposure to dimethylmercury. The second example is taken from the Iraq outbreak of methylmercury poisoning in which the victims consumed contaminated bread for several weeks without any ill effects. Indeed, signs of poisoning did not appear until weeks or months after exposure stopped. The last example is drawn from observations on nonhuman primates and from the sequelae of the Minamata, Japan, outbreak in which low chronic doses of methylmercury may not have produced observable behavioral effects for periods of time measured in years. The mechanisms of these latency periods are discussed for both acute and chronic exposures. Parallels are drawn with other diseases that affect the central nervous system, such as Parkinson disease and post-polio syndrome, that also reflect the delayed appearance of central nervous system damage.