Biomedical subjects

B C Gladen

Publications and source records attributed to B C Gladen.

At least 37 records · Page 2Linked to original sources

PubMed1996

Developmental toxicity of inorganic arsenic in whole embryo: culture oxidation state, dose, time, and gestational age dependence.

Arsenic is a known teratogen and developmental toxicant in many animal models. The aim of the present study was to determine the influence of arsenic oxidation state, concentration, duration of exposure, and embryonic gestational age on arsenic-induced developmental toxicity. For these studies whole embryo culture was used since this experimental model allows an assessment of the direct effect of the toxicant on the embryo and precise control of the variables of interest. ICR and CD1 mouse embryos were prepared for whole embryo culture and exposed to concentrations of trivalent (1, 2, 5, 7.5, 10, 20, and 30 microM of sodium arsenite) and pentavalent arsenic (5, 10, 20, 50, and 100 microM of sodium arsenate) at different developmental stages (3, 4-6, 8-10, or 20-23 pairs of somites) and for different exposure periods (1, 4, 6, or 24 hr). Embryonic growth, development, malformation rates, and viability were evaluated. A comparison of the ED50s of the two oxidation states showed that arsenite was about three times more potent than arsenate with respect to both malformations and lethality. The pattern of malformations was similar for both arsenite and arsenate and involved nonclosure of the cranial neural tube, prosencephalic hypoplasia, dysmorphogenesis of the optic and otic anlagen, and pharyngeal arch defects. ICR conceptuses were more sensitive than CD1s with regard to perturbation in embryonic growth by both forms of arsenic. ICRs were also more sensitive to otic, pharyngeal arch, and somite dysmorphogenesis induced by arsenite. With increasing gestational age there was an increasing resistance to arsenic-induced effects. In comparison to the 4-6 somite stage, the ED50 for induction of dysmorphogenesis was increased about twice at the 8-10 somite and over three times in 20-23 somite stage embryos. Exposure to arsenite/arsenate for a 1-hr period was sufficient to induce maldevelopment. A 6-hr exposure induced prosencephalic, otic, and optic abnormal development at a rate similar to that produced by a 24-hr exposure. The malformation pattern produced by exposure to arsenite/arsenate in vitro closely corresponds to that produced by maternal administration at the same gestational stage. This indicates that the arsenic embryopathy may be the result of a direct impact of the agent on the conceptus.

Animals↗

PubMed1996

Matched-pair case-control studies when risk factors are correlated within the pairs.

BACKGROUND: If pair members are independent, simple matched-pair case-control studies are known to yield consistent estimates of the population odds ratio. If pair members are not independent, this is not necessarily true. It has been shown previously that the usual matched-pair estimate remains consistent if the exposure of interest is correlated within the pairs. However, the effect of correlation of unmeasured risk factors within the pairs has not been studied. METHODS: We examine the effect of within-pair correlation of unmeasured risk factors independent of the measured exposure. This is done within the context of a simple matched-pair case-control study. We compare the large-sample expectation of the usual matched-pair estimate to the population odds ratio. RESULTS: We show that the usual estimate may be inconsistent in the presence of this correlation. However, if the disease is rare, the magnitude of the bias will be negligible. CONCLUSIONS: Correlation of unmeasured risk factors independent of the measured exposure is not a practical problem in this setting.

Bias↗

PubMed1996

Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility.

The reproductive system of male mice homozygous for a mutation in the estrogen receptor (ER) gene (ER knock-out; ERKO) appears normal at the anatomical level. However, these males are infertile, indicating an essential role for ER-mediated processes in the regulation of male reproduction. Adult ERKO male mice have significantly fewer epididymal sperm than heterozygous or wild-type males. Although spermatogenesis is occurring in some seminiferous tubules of 3- to 5-month-old ERKO males, other tubules either have a dilated lumen and a disorganized seminiferous epithelium with few spermatogenic cells or lack a lumen and contain mainly Sertoli cells. There are no obvious differences in seminiferous tubules at 10 days of age between wild-type and ERKO mice, but the lumen in ERKO males is dilated in all seminiferous tubules by 20 days. However, spermatogenesis progresses and similar numbers of sperm are present in the cauda epididymis of ERKO and wild-type males until 10 weeks of age. Disruption of spermatogenesis and degeneration of the seminiferous tubules become apparent after 10 weeks in the caudal pole of the testis and progresses in a wave to the cranial pole by 6 months. However, the seminal vesicles, coagulating glands, prostate, and epididymis do not appear to be altered morphologically in ERKO mice. Serum testosterone levels are somewhat elevated, but LH and FSH levels are not significantly different from those in wild-type males. Sperm from 8- to 16-week-old mice have reduced motility and are ineffective at fertilizing eggs in vitro. In addition, ERKO males housed overnight with hormone-primed wild-type females produce significantly fewer copulatory plugs than do heterozygous or wild-type males. These results suggest that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequency, low sperm numbers, and defective sperm function.

Animals↗

PubMed1995

DDE and shortened duration of lactation in a northern Mexican town.

OBJECTIVES: Worldwide declines in the duration of lactation are cause for public health concern. Higher levels of dichlorodiphenyl dichloroethene (DDE) have been associated with shorter durations of lactation in the United States. This study examined whether this relationship would hold in an agricultural town in northern Mexico. METHODS: Two hundred twenty-nine women were followed every 2 months from childbirth until weaning or until the child reached 18 months of age. DDE was measured in breast milk samples taken at birth, and women were followed to see how long they lactated. RESULTS: Median duration was 7.5 months in the lowest DDE group and 3 months in the highest. The effect was confined to those who had lactated previously, and it persisted after statistical adjustment for other factors. These results are not due to overtly sick children being weaned earlier. Previous lactation lowers DDE levels, which produces an artifactual association, but simulations using best estimates show that an effect as large as that found here would arise through this mechanism only 6% of the time. CONCLUSIONS: DDE may affect women's ability to lactate. This exposure may be contributing to lactation failure throughout the world.

Adolescent↗

PubMed1994

A 6-year follow-up of behavior and activity disorders in the Taiwan Yu-cheng children.

OBJECTIVES: The relationship of behavior and activity levels to the interval between outbreak and year of birth and to age of children is explored in Taiwanese children exposed in utero to heat-degraded polychlorinated biphenyls (PCBs)--the Yu-cheng children. Additionally, the relationship of the scores to chemical, physical, and cognitive findings is described. METHODS: With Rutter's Child Behavior Scale A and a modified Werry-Weiss-Peters Activity Scale, 118 Yu-chen children and matched controls were followed biannually from 1985 to 1991. RESULTS: At each year, the Yu-cheng children scored 7% to 43% worse (mean = 23%) than control children on the Rutter scale. At any fixed age, the Yu-cheng children scored 11% to 63% (mean = 28%) worse. The effect for children born later did not differ from that for those born earlier; neither was there any improvement as the children aged. A similar but weaker picture was seen for the activity score. These behavioral findings were not related to physical or cognitive findings or to serum PCB levels. CONCLUSIONS: In utero exposure to heat-degraded PCBs appears to cause mildly disordered behavior and increased activity level; the effect persists over time and is similar in children born up to 6 years after the mothers were exposed.

Case-Control Studies↗

PubMed1994

Models relating the timing of intercourse to the probability of conception and the sex of the baby.

The probability that conception will result from intercourse on particular days of the menstrual cycle is of biological, demographic, and personal interest to many. We describe an existing model for conception as related to the timing of intercourse, and develop a method for fitting it by means of the expectation-maximization (EM) algorithm, using widely available software (GLIM). We then generalize the model to allow for effects on its parameters due to reproductively toxic exposures. A further extension allows one to address the question of whether the pattern of intercourse in a conception cycle has an influence on the sex of the resulting baby. We illustrate the methods by application to data from a prospective study of couples trying to begin a pregnancy.

Abortion, Spontaneous↗

PubMed1993

Breast-feeding and cognitive development.

Eight-hundred fifty-five newborns were enrolled in a prospective study between 1978 and 1982 and then followed through school age. To determine whether the mode of infant feeding affected developmental scores or school grades, prospective data were collected on how the children were fed; 788 of the children had Bayley tests at 6 months, 720 at 12 months, 676 at 18 months and 670 at 2 years. McCarthy testing was done on 645 children at 3 years, 628 at 4 years and 636 at 5 years. Testers were not specifically blind to feeding method. The families provided report cards from grade 3 or higher for 366 children. There were statistically significant but small increases in scores among breast-fed children on at least some subscales of the Bayley and McCarthy at all time points from 2 years through 5 years and slightly higher English grades on report cards in both crude analyses and in multivariate analyses that allowed adjustment for the most plausible confounding variables. We conclude that, in a volunteer, 95% white sample of middle class children, those breast-fed scored slightly better than those bottle fed; the effect is small but still detectable at school age.

Breast Feeding↗

PubMed1992

Detection of multiple tumor suppressor genes for Syrian hamster fibrosarcomas by somatic cell hybridization.

Identification of tumor suppressor gene loci in rodent cell culture systems has relied upon the use of somatic cell hybridization studies. Although normal rodent fibroblasts are capable of suppressing the tumorigenicity of a variety of tumor cells, the lack of complementation in tumor cell x tumor cell hybrids has left the possibility that a single tumor suppressor gene may be responsible for tumor suppression in a particular rodent cell culture system. Using this same approach, we found no evidence for complementation resulting in suppression of the transformed phenotype when three viral oncogene-transformed Syrian hamster embryo (SHE) cell lines and one spontaneously transformed baby hamster kidney (BHK) cell line were fused to benzo[a]pyrene-transformed SHE cells (BP6T-M3). However, v-src oncogene-transformed cell line (srcT) x BP6T-M3 hybrids did demonstrate limited suppression of the transformed phenotype, suggesting at least two complementing tumor suppressor genes in this system. We were able to confirm and extend this finding using another experimental approach with preneoplastic hamster cell lines that are immortal in culture but nontumorigenic in nude mice. We propose that fusion of these preneoplastic cells to various tumor cells may reveal tumor suppressor genes not evident in the tumor cell x tumor cell complementation studies. Subclones of two nontumorigenic, immortal hamster cell lines, 10W and DES4, displayed differing abilities to suppress BP6T-M3 cells in somatic cell hybrids, as quantitated by the ability of the hybrid cells to form colonies in soft agar. With a panel of preneoplastic hamster cell x BP6T-M3 hybrids, a distinct pattern of suppression or expression of the transformed phenotype was observed. Marked differences in this pattern were seen when the same 10W and DES4 subclones were fused to other hamster fibrosarcoma cell lines, indicating different tumor suppressing activities of multiple tumor suppressor genes. Analysis of this data suggests that as few as three or as many as six different tumor suppressor genes may be active in the Syrian hamster embryo cell culture system. Thus, this system may provide a useful model for identifying and studying the effects and regulation of a number of different tumor suppressor genes for fibrosarcomas.

Animals↗

PubMed1992

Does early exposure to maternal smoking affect future fertility in adult males?

Animal data suggest that prenatal exposure to certain tobacco smoke components such as nicotine may affect the development of the male gonadal axis, which may in turn affect future adult fertility. There are no previous epidemiologic studies on the potential effects of early (prenatal and childhood) exposure to maternal smoking on the reproductive system in adult male offspring. To investigate this question, we used data from a follow-up study of reproductive function and fertility among young adult sons of mothers who had participated in a randomized clinical trial of diethylstilbestrol use during pregnancy. We observed no significant effects of early exposure to maternal smoking on conventional semen characteristics, hormone levels (follicle stimulating hormone [FSH], luteinizing hormone [LH] and testosterone), urogenital abnormalities and diseases, or perceived infertility problems. Current active smoking by the men was, however, associated with a significant decrease in the percentage of sperm with normal morphology.

Adult↗

PubMed1992

32P-postlabeling analysis of the formation and persistence of DNA adducts in mammary glands of parous and nulliparous mice treated with benzo[a]pyrene.

The susceptibility of the rodent mammary gland to known chemical carcinogens can vary with the stage of gland development. Full-term pregnancy (parity) can confer permanent structural and functional changes in the gland that are associated with decreased breast cancer risk in humans and protection from mammary carcinogenesis in rodents. In this study, the formation and persistence of benzo[a]pyrene (B[a]P)-derived DNA adducts in vivo was determined in the abdominal mammary organs of adult nulliparous and parous BALB/c mice treated orally with the carcinogen. Mammary DNA isolated from animals in both groups revealed only one major adduct on TLC maps by P1-nuclease 32P-postlabeling analysis. The major adduct co-migrated with the (+)-enantiomer of anti-BPDE-dGp. Much lower levels of the (-)-enantiomer were detected. Most of the adduct quantitated was probably contributed by cells of the stromal compartment, since the gland-free organ (cleared fat pad) generated essentially equivalent profiles and level of adduct by 32P-postlabeling. Comparable levels of the B[a]P-derived adduct were observed in the intact mammary organ of both nulliparous and parous mice during a time course from 1 to 28 days after treatment. In both cases, adduct removal occurred exponentially with a half-life of approximately 16 days. The capacity for de novo formation of reactive metabolites by the mammary organ was demonstrated in vitro: digests of DNA from mammary mince exposed to B[a]P generated an adduct on TLC maps that also co-migrated with the (+)-anti-BPDE-dGp standard. Thus, our cumulative findings confirm the capacity of mammary cells to form potentially carcinogenic DNA adducts; however, the functional changes that occur in the mouse mammary gland as a result of parity did not influence the profile, level or persistence of adduct following exposure to a known carcinogen. Other factors, such as changes in mammary cell cycle kinetics or responsiveness to promotional stimuli may be more causally related to reduction in incidence of neoplasia observed in parous animals.

Animals↗

PubMed1992

Neurotoxicology of PCBs and related compounds.

Polychlorinated biphenyls (PCBs) are a family of 209 chemicals with two linked phenyl rings and variable chlorination. They are clear oils at room temperature. They were produced from the 1930s until banned in the 1970s because of toxicity and evidence of widespread environmental contamination. They were used mostly as insulators in electrical equipment; their widespread occurrence in the environment is more a consequence of uncontrolled disposal than of deliberate dissemination. In Asia, there have been two outbreaks of poisoning due to cooking oil contaminated by thermally degraded PCBs. Studies in workers exposed chronically to "clean" PCBs, workers exposed acutely to thermally degraded PCBs in clean-up of fires, and adult patients in Asia who ingested contaminated rice oil consistently show slowed nerve conduction and sometimes show headache, lassitude, and other CNS symptoms. In children exposed to background levels in the US, those with the highest transplacental exposure show hypotonia and hyporeflexia at birth and slowed motor development through age two, a defect in visual memory processing at 7 mon, and defects in short term memory at 4 years. Despite the presence of PCBs in breast milk, no association between breast milk exposure and any measured outcome has been seen other than lower activity levels at 4 years among long term breast fed children at the highest PCB levels. In Asia, children who were in utero at or after the 1968 exposure in Japan or the 1979 exposure in Taiwan showed clinically evident developmental delay. In Taiwan, the children were shown to have a variety of ectodermal defects, but the association between these defects and developmental delay was weak.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

PubMed1991

The effects of ethylene dibromide on semen quality and fertility in the rabbit: evaluation of a model for human seminal characteristics.

Mature (12 months old) male New Zealand White rabbits (8-10/group) were dosed subcutaneously with ethylene dibromide (EDB) in corn oil (untreated and vehicle controls, 15, 30, or 45 mg/kg body wt/day for 5 days). Weekly semen samples (for 6 weeks preexposure, during treatment, and 12 weeks postdosing [pd]) were analyzed for sperm concentration, number, morphology, viability, and motion parameters (velocity, linearity, beat cross-frequency, amplitude of lateral head displacement (ALH), and circularity), and semen pH, osmolality, volume, fructose, citric acid, carnitine, protein, and acid phosphatase (AP). Male fertility was assessed preexposure and at 4 and 12 weeks pd by artificial insemination of three females/male/time point with one million motile sperm. The percentage pregnant females, litter size, fetal body weights, and structural development were assessed. In the 45 mg/kg dose group of males there was 30% mortality and liver damage in 43% of the survivors as evidenced by increased levels of serum enzymes. Also in this group, EDB produced significant decreases in sperm velocity, percentage motility, and ALH (up to 25% at various times pd). There were also dose-related decreases in semen pH (up to 2%) and total ejaculate volume (up to 23%, 15 and 30 mg/kg dose groups only). AP activities were significantly elevated (up to 116%) 2 weeks pd in the 45 mg/kg dose group. All other semen parameters evaluated were unaffected. Male fertility and fetal structural development were also unaffected. Of the seven semen parameters perturbed by EDB in humans (Schrader et al., 1988), four were also affected in the rabbit (sperm velocity, percentage motility, pH, and volume), whereas sperm number, viability, and morphology were not. Thus, some of the male reproductive effects of EDB in the human have been modelled in the rabbit, although the rabbit appears not to be as sensitive, since semen parameters were affected only at doses close to the LD50 (55 mg/kg). The present study (together with other published data) suggests that the rabbit appears to be a potential model for male reproductive toxicity in humans, warranting further evaluation.

Acid Phosphatase↗

PubMed1991

PCBs, DDE, and child development at 18 and 24 months.

To determine whether perinatal exposure to "background" levels of polychlorinated biphenyls (PCBs) or dichlorodiphenyldichloroethene (DDE) affected child development, we followed a cohort of children through the age of 2 years; 676 were tested at 18 months and 670 at 24 months with the Bayley Scales. Transplacental and cumulative exposures from breast milk to both chemicals were estimated for each child from analyses of breast milk and other samples. Bayley testing was done without knowing the chemical levels. At 18 and 24 months, adjusted scores on the psychomotor scales were 4 to 9 points lower among children in the top fifth percentile of transplacental PCB exposure, significantly so at 24 months. There were no consistent effects apparent from exposure to PCBs through breast milk, nor from DDE exposure. We conclude that there is a small delay in motor maturation attributable to transplacental exposure to PCBs that is still detectable at 24 months. There is no evidence of an effect from the larger but later exposure through breast milk, although effects may emerge as the children age.

Breast Feeding↗

PubMed1991

Effects of perinatal polychlorinated biphenyls and dichlorodiphenyl dichloroethene on later development.

OBJECTIVE: Determining whether early developmental effects of perinatal exposure to polychlorinated biphenyls (PCBs) or dichlorodiphenyl dichloroethene (DDE) persist. DESIGN: Cohort followed from birth; ages now 5 1/2 to 10 1/2 years. SETTING: General community. PARTICIPANTS: Volunteer sample of 859 children, of whom 712 had been examined with the McCarthy Scales of Children's Abilities at 3, 4, or 5 years; 506 sent report cards. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Neither transplacental nor breast-feeding exposure to PCBs or DDE affected McCarthy scores at 3, 4, or 5 years. There was no statistically significant relationship between poorer grades and PCB or DDE exposure by either route. CONCLUSIONS: The deficits seen in these children on the Bayley Scales of Infant Development through 2 years of age are no longer apparent.

Adipose Tissue↗

PubMed1990

Semen analysis and fertility assessment in rabbits: statistical power and design considerations for toxicology studies.

Semen analysis is commonly used in evaluating human response to reproductive toxicants. Serial semen samples can be collected from rabbits and fertility assessed by artificial insemination, hence this species is potentially well suited for male reproductive toxicity studies that might be extrapolated to humans. However, the size and cost of rabbits often restricts the number of animals used, reducing the sensitivity of such studies. Therefore, it was of interest to optimize study design for semen analysis and fertility assessment in rabbits. Semen samples were collected weekly from sexually mature New Zealand white rabbits and a range of parameters was analyzed (Semen--pH, volume, osmolality; Sperm--number and concentration, morphology, viability, percentage motility, motion characteristics; Seminal plasma--fructose, citric acid, carnitine and protein concentrations, acid phosphatase activity). Male fertility was assessed by inseminating female rabbits with the minimum number of motile sperm required for normal fertility, determined to be one million. The within- and between-buck variabilities were determined for all parameters and used to calculate the statistical power of different study designs. The variability of sperm number and concentration was decreased when measured in four ejaculates collected within a short period of time rather than in a single ejaculate; this was not true of other endpoints measured. In addition, use of preexposure observations further increased the statistical power for all of the parameters. These data can be used to determine the optimum design for studies of male reproductive toxicity using rabbits, with particular regard to cost and the number of animals used.

Acid Phosphatase↗

PubMed1990

Dermatological findings in children exposed transplacentally to heat-degraded polychlorinated biphenyls in Taiwan.

We studied 128 children who were transplacentally exposed to polychlorinated biphenyls and dibenzofurans in Taiwan, their parents and siblings who were directly exposed, and 115 control children. Direct exposure of the mothers stopped in 1979 and the children were born as late as 1985. At birth, exposed children had increased rates of hyperpigmentation, eyelid swelling and discharge, deformed nails, acne, natal teeth and swollen gums compared to controls. On examination, they had a much higher rate of dystrophic finger-nails and pigmented or dystrophic toe-nails than controls. They also had an increased rate of hyperpigmentation and acne. In addition they had more generalized itching, localized skin infections and hair loss. The findings seen in transplacentally exposed children differ from those seen in people directly exposed, particularly in the latter group in higher prevalence of acne.

Acne Vulgaris↗

PubMed1989

Kinetics of pulmonary surfactant phosphatidylcholine metabolism in the lungs of silica-treated rats.

Exposure of rats to silica by intratracheal injection increased the intra- and extracellular compartments of pulmonary surfactant phospholipid. These changes were dose and time dependent, but both pools were not affected equally. Seven days after the instillation of 10 mg of silica, the intracellular pool increased 13.3-fold, from 1.49 +/- 0.30 to 19.86 +/- 0.77 mg of surfactant phospholipid per pair of lungs, and the extracellular pool increased 7.4-fold, from 1.87 +/- 0.79 to 13.79 +/- 0.72 mg of surfactant phospholipid per pair of lungs. To investigate the physiologic processes responsible for these massive accumulations of surfactant. [14C]choline was injected into the tail veins of control and silica-treated rats and the specific activity of surfactant phospholipids within the intracellular and extracellular pools was determined at various times between 0 and 26 hr after injection. All of the processes measured were increased in response to silica exposure, but not to the same extent. At 1 hr, incorporation of [14C]choline into the intracellular surfactant pool was increased 12.6-fold above controls, from 4.8 +/- 1.1 x 10(3) to 60.6 +/- 26.6 x 10(3) dpm. The flux of [14C]choline-labeled phospholipid from the intracellular to the extracellular pool was increased 7.3-fold, from 102 +/- 10 to 749 +/- 39 micrograms/hr in silica-treated animals, but its disappearance from the extracellular pool was increased only 5.0-fold, from 87 +/- 8 to 434 +/- 21 micrograms/hr. The half-life of [14C]choline-labeled phospholipids in the intracellular pool of surfactant was increased from 10.1 +/- 1.0 to 18.3 +/- 5.3 hr and that in the extracellular surfactant pool from 14.8 +/- 1.4 to 21.9 +/- 4.9 hr. Expansion of the intra- and extracellular pools of surfactant phospholipids may be explained on the basis of a metabolic imbalance in which the intracellular production of surfactant is increased above its secretion rate into the extracellular compartment, and the secretion rate is elevated above the rate at which surfactant phospholipids are cleared from the alveoli.

Animals↗

PubMed1988

Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan.

In 1979, a mass poisoning occurred in Taiwan from cooking oil contaminated by thermally degraded polychlorinated biphenyls. Because these chemicals persist in human tissue, children born to female patients after the outbreak were exposed in utero. In 1985, 117 children born to affected women and 108 unexposed controls were examined and evaluated. The exposed children were shorter and lighter than controls; they had abnormalities of gingiva, skin, nails, teeth, and lungs more frequently than did controls. The exposed children showed delay of developmental milestones, deficits on formal developmental testing, and abnormalities on behavioral assessment. These findings are most consistent with a generalized disorder of ectodermal tissue. This syndrome is one of very few documented to result from transplacental exposure to pollutant chemicals.

Conjunctivitis↗