Chronic low-level lead toxicity in the rat. I. Maternal toxicity and perinatal effects.
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Abnormalities, Drug-Induced↗
Biomedical subjects
B C Gladen
Publications and source records attributed to B C Gladen.
On the role of 'habitual aborters' in the analysis of spontaneous abortion.
Analyses of spontaneous abortion rates often include special provisions to account for the presumed distorting effects that arise because of the presence of habitual aborters. In this paper, I establish a framework for investigating the effects of the presence in study groups of such women. I then examine the strengths and weaknesses of some of the analysis strategies in current use, both in situations where the study group is homogeneous and where there are high-risk women present. I show that the concept of habitual aborter is not useful and can be misleading, and I suggest that one take a broader view of heterogeneity.
Abortion, Habitual↗
Testicular toxicity of boric acid (BA): relationship of dose to lesion development and recovery in the F344 rat.
High-dose boric acid (BA) produces testicular lesions in adult rats, characterized by inhibited spermiation followed by atrophy. The present study addressed whether inhibited spermiation can be separated from atrophy based on dose, compared testis boron (B) dosimetry to lesion development, determined how inhibited spermiation was reflected by common reproductive endpoints, and examined reversibility of the testicular lesions. Rats were fed 3000, 4500, 6000, or 9000 ppm BA for up to 9 weeks and examined. Recovery was assessed for up to 32 weeks post treatment. Inhibited spermiation could be separated from atrophy based on dose (inhibited spermiation: 3000/4500 ppm; atrophy: 6000/9000 ppm), with each lesion aspect expressed at different threshold testis B concentrations (inhibited spermiation: 5.6 micrograms B/g and atrophy: 11.9 micrograms B/g) with no B accumulation during the 9-week exposure. These data suggest that separate mechanisms may be operating for these lesion aspects based on testis B concentration and that B dose rate was important for testicular toxicity. Inhibited spermiation was most reliably reflected by informed testicular histology, with the more severe cases decreasing epididymal sperm count to levels that could affect fertility. After treatment, serum and testis B levels in all dose groups rapidly fell to background levels at the earliest time points evaluated (7 days and 8 weeks posttreatment, respectively). The severely inhibited spermiation at 4500 ppm was resolved by 16 weeks posttreatment, but areas of focal atrophy were detected that did not recover posttreatment. Also, no signs of recovery from atrophy were observed (6000 and 9000 ppm). Atrophic tubules contained a normal complement of spermatogonia (2.6 to 2.9 germ cells/100 Sertoli cells), with occasional dividing and degenerating germ cells. Elevations in serum FSH and LH levels suggested an intact hormonal response to the atrophy. In summary, 1) the different aspects of the BA-induced testicular lesion can be separated using different doses, 2) inhibited spermiation does not necessarily proceed to atrophy, and 3) there is no recovery from the atrophy despite the absence of testis B after treatment. The ability to separate inhibited spermiation from atrophy based on dose and testis B dosimetry will be useful in evaluating possible mechanisms. Furthermore, the presence of dividing spermatogonia during long-term BA-induced atrophy suggests that this model should be useful for identifying critical components involved in the reinitiation of spermatogenesis.
Animals↗
In utero PCB/PCDF exposure: relation of developmental delay to dysmorphology and dose.
In 1979, there was an outbreak of food poisoning in central Taiwan due to cooking oil contaminated with polychlorinated biphenyls and their thermal degradation products. Starting in 1985, we studied 128 children born to exposed women after the oil was removed from the market; the exposure of these children was transplacental or through breast milk. We also studied matched controls. The exposed children exhibited developmental delays as measured by parental report, by neurologic examination, and by standard cognitive tests; delay was seen at all ages and persisted over time. Delay was greater in children who were smaller in size and in children who had exhibited neonatal symptoms of intoxication. Children with a history of nail deformity also were delayed. However, there was little relationship between other physical findings or measures of maternal exposure and developmental delay. There was some indication that the child's prenatal exposure was more important to developmental delay than was exposure through breast milk.
Abnormalities, Drug-Induced↗
Variability of lipid hydroperoxides in pregnant and nonpregnant women.
Lipid peroxidation is thought to be important in numerous disease states, including pregnancy complications. Study of its role requires markers, but the variability of available markers in non-diseased populations has not been well-characterized. We examined the variability over time of blood lipid hydroperoxides, as measured by iodometric analysis, in 49 healthy young women, 21 nonpregnant and 28 pregnant. Lipid hydroperoxides from the same woman were very similar from one day to the next but were less stable over periods of a month or more. The correlation between measurements on consecutive days was 0.98; the correlation between measurements a month or more apart was 0.11. Variability over time was not attributable to seasonal effects or, among the pregnant women, to differences over the course of pregnancy. Knowledge of the variability of this and other markers of oxidative damage enables the development of appropriate study designs.
Adult↗
Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature.
The literature on lipid peroxide levels in uncomplicated pregnancy is limited, but some reasonable conclusions are possible. Despite the lack of precision in the predominant measure of lipid oxidation, there is agreement across a large number of studies that the level of lipid peroxides in blood is generally higher in pregnant women than in nonpregnant women. During gestation, elevations appear by the second trimester and may taper off later in gestation, decreasing further after delivery. Lipid peroxides also are produced in placenta, but their pattern of change over the course of pregnancy is unclear. Lipid peroxides are important because their uncontrolled production can result in oxidative stress, with significant damage to cell integrity. There is a growing literature that associates oxidative stress with preeclampsia, a major cause of maternal and fetal morbidity. The higher levels of lipid peroxides seen in blood and the production of lipid peroxides in the placenta, even in uncomplicated pregnancies, make new baseline studies a priority. These studies should include measurements of lipids and blood volume, because they can influence marker values, with sensitive and specific measures of lipid peroxidation made at various points of gestation. From our review of the existing literature we conclude that the importance of oxidative stress in reproduction is just beginning to be appreciated and studied.
Adult↗
Correlations among human plasma levels of dioxin-like compounds and polychlorinated biphenyls (PCBs) and implications for epidemiologic studies.
In studies of the potential health effects of background-level exposure to organochlorine compounds (e.g., polychlorinated biphenyls, polychlorinated dibenzodioxins, and polychlorinated dibenzofurans), investigators have often measured either polychlorinated biphenyls or polychlorinated dibenzodioxins/polychlorinated dibenzofuransbut not both. We measured polychlorinated biphenyls (including specific non-, mono-, and di-ortho congeners) and specific polychlorinated dibenzodioxins/dibenzofurans among 63 Canadian blood donors. Levels of these compounds were, in general, fairly correlated. For example, Pearson's correlation coefficient between log total polychlorinated biphenyl and log total polychlorinated dibenzodioxins was .52. These results suggest that in epidemiologic studies of health effects of background-level exposures to these compounds, the quantitative dose-response relation observed for a given compound (or class of compounds acting through a similar mechanism) may easily be miscalibrated or confounded.
Adolescent↗
Urinary porphyrins in children exposed transplacentally to polyhalogenated aromatics in Taiwan.
In 1979, there was a large (greater than 2,000 cases) outbreak of poisoning due to contaminated rice oil in central Taiwan. The causal agent was a mixture of thermally degraded polychlorinated biphenyls (PCBs), polychlorinated quaterphenyls, and polychlorinated dibenzofurans, which had become mixed with the oil during processing. Patients remained symptomatic for several years afterward, and the chemicals persisted in their tissue. Women who became pregnant had children with high perinatal mortality and a dysmorphic syndrome. We examined urines from 75 children born to exposed mothers after the oil was confiscated, 74 controls, and 12 sibs of the exposed children. Four of the transplacentally exposed children, 2 controls, and 1 sib had a type B hepatic porphyria (i.e., uroporphyrin greater than coproporphyrin); total porphyrin excretion was elevated in the exposed children as a group (95 vs. 81 micrograms/L); and 8 of the 75 exposed children and 2 controls had total urinary porphyrin concentrations of greater than 200 micrograms/L.
Albuminuria↗
Serial levels of serum organochlorines during pregnancy and postpartum.
In utero exposure to dichlorodiphenyldichloroethene and polychlorinated biphenyls, within the range found in the general U.S. population, may produce detectable effects in offspring. To design studies of the effects of in utero organochlorine exposure, we obtained data on the relationship between gestational and perinatal maternal levels in females on several occasions. We studied 67 pregnant women in the United States who agreed to have their blood drawn once during each trimester and once postpartum. We examined the Pearson correlation coefficient between the natural logarithm of levels (microg/g serum lipid). The correlation, r, among levels in the first and third trimester was .86 and .77 for dichlorodiphenyldichloroethene and for polychlorinated biphenyls. Correlations among levels determined at other times (i.e., second trimester and postpartum) were similar. On the basis of these results, we suggest that in studies of the effects of in utero or perinatal exposure to the aforementioned compounds, the time when specimens are collected is not critical.
Dichlorodiphenyl Dichloroethylene↗
Male fertility, sister chromatid exchange, and germ cell toxicity following exposure to mixtures of chlorinated phenoxy acids containing 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Fertility and sperm number, motility, and morphology were analyzed in male C57BL/6 mice exposed to various mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlor-ophenoxyacetic acid (2,4,5-T), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet for 8 wk. Somatic cell (bone marrow) sister chromatid exchange frequencies were also evaluated in mice injected with similar chemical mixtures. The concentration of the test chemicals was such that the average daily feeding dose in the three mixtures or control was 40 mg/kg 2, 4-D, 40 mg/kg 2,4,5-T, and 2.4 micrograms/kg TCDD; 40 mg/kg 2,4-D, 40 mg/kg 2,4,5-T and 0.16 microgram/kg TCDD; 20 mg/kg 2, 4-D, 20 mg/kg 2,4,5-T, and 1.2 micrograms/kg TCDD; or no chemical added (control). No significant dose-related effects were observed in the treated mice compared to the control group.
2,4,5-Trichlorophenoxyacetic Acid↗
Issues in the statistical analysis of sperm motion data derived from computer-assisted systems.
Computer-assisted sperm motion measurements present certain features that must be accounted for in statistical analyses. Some are specific to this type of data, whereas others are standard considerations. For example, the measurement of multiple sperm from individuals creates correlations that must be accounted for if each sperm's measurement is used, and unequal variances may arise that need to be addressed if an average measurement from the individual is used. Also, the limitations on the ranges of some measurements create discrepancies between observed and actual means and may make treatment-related effects more difficult to detect--a circumstance that has an impact on study design. When variables that are truly continuous are measured in a discrete fashion, odd effects may arise and care is needed. Other considerations, such as the shapes of distributions and correlations among various measurements, should also be examined. Attention to these details of statistical analysis are vital to proper interpretation of data.
Animals↗