Richard A. Doherty

Intra-uterine Methylmercury Poisoning in Iraq

A disastrous epidemic of methylmercury poisoning occurred in rural Iraq early in 1972, due to the ingestion of home-made bread prepared from wheat treated with a methylmercury fungicide. We report the clinical and laboratory evaluation of 15 infant-mother pairs exposed to methylmercury during pregnancy, including mercury determinations in blood samples of mothers and infants, and in milk samples from mothers, during the first seven months following the epidemic.

Effects of methylmercury on developing mouse cerebellar cortex

Methylmercury is known to cause neurologic impairment of the developing central nervous system in humans and in several animal models, but the nature of the injury that underlies the functional deficits is not clear. Treatment of 2-day-old mice with methylmercury at 8 mg Hg/kg resulted in brain concentrations of 2.7 μg Hg/g tissue and the following changes in the external granular layer of the cerebellar cortex 24 h after treatment. The total number of cells in five regions of the external granular layer was significantly reduced by methylmercury treatment (analysis of variance, P < 0.025). The mitotic activity of the external granular layer was not significantly altered by methylmercury. Rather, cells appeared to be injured or dying in the treated animals, as indicated by condensed nuclei. The number of cells with nuclei measuring ≤3 μm in diameter was increased after methylmercury (P < 0.002). The percentage of late mitotic figures (anaphase/mitotic figures) was also reduced in the methylmercury-treated animals (P < 0.002). The incomplete mitosis may contribute to the decreased cell number by causing cell death. This mitotic arrest, presumably due to loss of spindle microtubules, may be an important mechanism in methylmercury-caused neurotoxicity in developing animals.

Blood clearance half-times in lactating and nonlactating members of a population exposed to methylmercury.

An epidemic of methylmercury poisoning occurred in rural Iraq early in 1972 due to the ingestion of homemade bread prepared from wheat treated with a methylmercury fungicide. We report observations of the blood mercury clearance half-times of lactating women and nonlactating groups who were exposed during the epidemic. Blood clearance half-times calculated by linear regression analysis show that in lactating females, the mean half-time is 42 days and in nonlactating females and males, the mean half-time is 75 days. Experiments in mice also show such differences in whole body half-time: 5.6 days in lactating females and 9.3 days in nonlactating females.

Effects of three diets on mercury excretion after methylmercury administration

In contrast to adults, suckling mice excrete minimal amounts of their mercury body burdens until the approximate time of weaning to a solid diet, when there is an abrupt increase in mercury elimination. Increased gut absorption of inorganic Hg in rats fed a milk diet has been reported. These observations suggest that dietary components may influence absorption and excretion of Hg compounds. This possibility was examined by determining the effects of (1) an evaporated whole milk diet, (2) a chemically defined liquid diet, and (3) a pelleted rodent diet on Hg retention in mice after administration of an apparently non-toxic dose of methylmercury (MeHg). Whole body Hg elimination and fecal and urinary Hg excretion were measured daily for two weeks. Two weeks after MeHg administration, Hg concentrations in whole body, brain, liver, kidney and whole blood were determined. The diet groups showed differences in whole body Hg retention and fecal Hg excretion.

Are Developmental Changes in Methylmercury Metabolism and Excretion Mediated by the Intestinal Microflora

Methylmercury, unlike mercuric mercury, is rapidly and almost completely absorbed from the mammalian gut, hence the body burden of mercury after exposure to methylmercury is related to the rate of mercury excretion. By comparison to adult mice, sucking mice excrete very little mercury after methylmercury exposure until the 16th-18th postnatal days, when there is an abrupt increase in fecal mercury excretion coinciding with the time of weaning. Several explanations of this developmental change in mercury elimination can be proposed, including an increase in biliary secretion of mercury compounds at weaning, changes in binding of mercury to gut contents or ohanges in the rate of demethylation of methylmercury by the intestinal microflora. It is probable that more than one of these factors are responsible but evidence is presented here to support the view that bacterial demethylation plays an important role. It is known that the majority of mercury in feces, after methylmercury exposure of adult animals, is in the mercuric form and that there is an increase in the amount of mercuric mercury in young mice at weaning when the rate of mercury elimination increases. The major changes in intestinal flora which occur during weaning are reflected in an increase in the ability of the gut contents of weaned mice to demethylate methylmercury in vitro. Similarly, feces from neonatal and preweaned human infants show negligible rates of methylmercury demethylation in vitro by comparison to weaned infants and adults. Further evidence for the implication of the gut flora in determining rates of mercury excretion has been obtained by modification of the gut flora by diet and antibiotics. We conclude that the conversion of methylmercury to the poorly absorbed mercuric mercury by the intestinal flora is a major factor determining excretion rate and therefore body burden of mercury after methylmercury exposure.

Supernumerary microchromosomes identified as inverted duplications of chromosome 15: A report of three cases

SummarySupernumerary bisatellited microchromosomes detected in three unrelated patients were identified as inverted duplications of chromosome 15. Each of these chromosomes contained a small euchromatic interstitial band presumably derived from the proximal portion of region 15q1. The clinical significance of this material was difficult to assess. Two of our cases were ascertained as the result of routine amniotic fluid studies. One of the affected fetuses had an unusual form of mosaicism 46,XY/48,XY, + inv dup(15), + inv dup(15), but no apparent developmental abnormalities. The inv dup (15) of the second fetus was familial in origin; no phenotypic abnormalities or evidence of mosaicism were detected in the carrier parent. The third inv dup(15) was found in a 20.5-month-old boy referred for developmental retardation. The clinical findings in this case were similar to those seen in patients with large inv dup(15)s and did not suggest Prader-Willi syndrome.

METHYLMERCURY EXCRETION: DEVELOPMENTAL CHANGES IN MOUSE AND MAN

During winter 1971-72 massive poisoning occurred throughout rural Iraq due to ingestion of homemade bread prepared from seed wheat treated with a methylmercury(CH3Hg) fungicide. Thousands of children and adults were poisoned and hundreds of deaths occurred (Science181:230,1973). Prenatal and early postnatal exposure were documented(Ped.54:5,1974!AJDC130:1070,1976)and long term followup studies of exposed fetuses and infants are in progress. Using a mouse model to determine potentially significant variables relating to CH3Hg toxicity in the developing mammal, we have observed that compared to adults, suckling mice excrete minimal amounts of their body burdens of mercury. Groups of young mice were exposed to a single non-toxic dose of CH3203Hg(0.4 mg/Kg. per os)at 2,4,6.., or 28 days of age. Whole body counts and urinary and fecal excretion were followed for each exposure group. From birth to 15 days, elimination half-times of mercury ranged from 2500 to 200 days. Between 16 and 18 days an abrupt increase to the adult elimination half-time of 8 days occurred. Decreases in whole body counts were accurately reflected in counts recovered in excreta. Studies are underway to determine whether a similar developmental change in excretion occurs in the exposed human infant. Since elimination half-time has been shown to be directly related to cumulative body burden as a function of duration of exposure, these observations are of importance in estimating exposure risks of human fetuses and infants.

High resolution analysis of hemoglobins: polyacrylamide isoelectric focusing.

Abstract For the analysis of hemoglobins, polyacrylamide isoelectric focusing has significant advantages. Unlike standard clinical methods, this method clearly separates hemoglobins F from A, and D from S. Compared to starch gel electrophoresis, this method provides higher resolution, greater reproducibility, readier quantification, higher sensitivity, and greater convenience. Hemoglobin A 2 quantitation is readily provided by gel scanning at two wavelengths.

Issues in implementing prenatal screening for cystic fibrosis: Results of a working conference

Purpose: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice.Methods: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed.Results: Judged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique.Conclusions: Once adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis.

Use of serum creatine kinase, pyruvate kinase, and genetic linkage for carrier detection in Duchenne and Becker dystrophy

Carrier detection in Duchenne dystrophy (DD) and Becker dystrophy (BD) can be achieved with DNA probes that recognize restriction fragment length polymorphisms (RFLPs). In 22 families, we found that 16 of 23 females at risk for being DD or BD carriers could be provided with more definitive indications of carrier status beyond the use of creatine kinase/ pyruvate kinase and pedigree analysis. RFLP analysis was not possible for six individuals despite potentially informative probes, because family members critical to the analysis were unavailable. In only one instance were all eight probes uninformative.