Biomedical subjects

L E Gray

Publications and source records attributed to L E Gray.

At least 37 records · Page 2Linked to original sources

PubMed1998

Tiered screening and testing strategy for xenoestrogens and antiandrogens.

Anthropogenic chemicals that disrupt endocrine function during critical stages of development can produce profound reproductive alterations in both wildlife and humans. Of the tens of thousands of chemicals in existence, few have been tested for their ability to disrupt the endocrine system. Newly enacted legislation requires that the USEPA develop a chemical screening and testing program for endocrine effects. At present, the Endocrine Disrupters Screening and Testing Advisory Committee (EDSTAC) is considering a screening battery (Tier 1) to detect (anti)estrogenic (E) (anti)androgenic (A) and antithyroid activities using in vivo and in vitro assays. In addition, the battery should detect alterations of hypothalamic-pituitary function, steroid/thyroid hormone synthesis as well as receptor-mediated effects in mammals and other taxa. Chemicals positive in Tier 1 should be labeled as potential endocrine disrupters and subjected to testing (Tier 2). The present discussion will provide examples of in vitro (receptor binding, gene expression and steroidogenesis) and in vivo assays for screening. Short-term in vivo assays which have been used to detect estrogenicity for over 70 years are still useful in this regard. Identification of (anti)androgenic activity is easily accomplished by examination of growth of androgen-dependent tissues in young castrated male rats, determination of the age at puberty (balanopreputial separation) or by examination of reproductive malformations after in utero exposure (hypospadias, testicular non-descent, retained nipples, a vaginal pouch, prostate agenesis, and reduced anogenital distance). Pubertal assays with intact animals will not only detect chemicals that alter E-A function via their nuclear receptors, but also will detect altered hormone synthesis and alterations of the hypothalamic-pituitary-gonadal axis. While in utero assays are critical for testing, presently they are not included in screening because they can be relatively long-term studies.

Androgen Antagonists↗

PubMed1998

Xenoendocrine disrupters: laboratory studies on male reproductive effects.

Wildlife from ecosystems contaminated with endocrine disrupting chemicals (EDCs) display a variety of reproductive alterations including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. It has been proposed that EDCs also may have contributed to increases in testicular cancer and hypospadias and the reported decline in human sperm counts. Combined in vivo and in vitro studies are necessary to fully characterize EDC induced alterations of reproduction. We have identified several pesticides (vinclozolin, procymidone, p,p'-DDE) which bind rat and human androgen receptors, block androgen-induced gene expression in vitro and in vivo, delay puberty, reduce sex accessory gland size and alter sex differentiation in the male rat. Some of the phthalates, which are estrogenic in vitro but not in vivo, cause malformations in male rats that appear to result from antagonism of androgens in utero. In contrast, xenoestrogens affect male offspring but they are not malformed or infertile. Prenatal administration of an Ah receptor agonist (2,3,7,8-TCDD or PCB 169) produces a different spectrum of effects including reduced ejaculated sperm numbers in male rats.

Androgen Antagonists↗

PubMed1998

Antiandrogens as environmental endocrine disruptors.

Steroid hormone receptors control fundamental events in embryonic development and sex differentiation through their function as ligand-inducible transcription factors. The consequences of disrupting these processes can be especially profound during development due to the crucial role hormones play in controlling transient and irreversible developmental processes. Several environmental chemicals, including metabolites of the fungicide vinclozolin and the pesticide DDT, disrupt male reproductive development and function by inhibiting androgen receptor mediated events. A variety of in vitro and in vivo approaches have been used to determine the molecular basis of environmental antiandrogen toxicity. These chemicals commonly bind androgen receptor with moderate affinity and act as antagonists by inhibiting transcription of androgen dependent genes.

Androgen Antagonists↗

PubMed1997

Vinclozolin and p,p'-DDE alter androgen-dependent gene expression: in vivo confirmation of an androgen receptor-mediated mechanism.

Vinclozolin and p,p'-DDE induce antiandrogenic developmental effects in vivo and are potent inhibitors of androgen receptor (AR) binding and AR-dependent gene expression in vitro. To determine whether this molecular mechanism is operative in vivo, the effects of these compounds on two androgen-regulated prostatic mRNAs were studied. Rats were sham operated or castrated and immediately implanted with one or two empty 2.5-cm silastic capsules or with one (1x) or two (2x) 2.5-cm capsules containing testosterone (T). T-implanted rats were treated by gavage for 4 days with vehicle (corn oil), vinclozolin (200 mg/kg/day), p,p'-DDE (200 mg/kg/day), or the antiandrogen flutamide (100 mg/kg/day) as a positive control. Vinclozolin, p,p'-DDE, and flutamide all induced a reciprocal decline in seminal vesicle (p < 0.01) and prostate (p < 0.01) weight as well as a reduction in immunohistochemical staining of AR in epididymal nuclei compared to vehicle-treated T-implanted controls. Specific AR antagonism was assessed by determining the ability of these chemicals to induce a testosterone-repressed prostatic message (i.e., TRPM-2) and/or repress a testosterone-induced prostatic message (i.e., prostatein subunit C3). Densitometry scans of Northern blots indicated that vinclozolin, p,p'-DDE, and flutamide each induced TRPM-2 mRNA and repressed C3 mRNA compared to vehicle-treated T-implanted controls. These antiandrogenic effects were competitively reduced in castrate rats implanted with two 2.5-cm T capsules (2x), where serum T levels were elevated more than twofold above physiological levels. Taken together, these data indicate that vinclozolin and p,p'-DDE act as antiandrogens in vivo by altering the expression of androgen-dependent genes.

Androgen Antagonists↗

PubMed1997

In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring.

Prenatal administration of a single dose of 1 microg TCDD/kg induces malformations of the external genitalia and subfertility in female offspring (L. E. Gray, Jr., and J. S. Ostby (1995) Toxicol. Appl. Pharmacol. 133, 285-294). A cross-fostering study indicated that in utero but not lactational TCDD exposure (1 microg TCDD/kg on gestational Day 15) induces cleft phallus, vaginal thread formation, and reduced ovarian weight. TCDD treatment on the 15th day of pregnancy at 0, 0.05, 0.20, or 0.80 microg TCDD/kg delayed vaginal opening at 0.80 microg/kg in the progeny. A persistent vaginal thread was displayed by 27% of the progeny at 0.20 and 92% at 0.80 microg TCDD/kg. These effects did not appear to result from abnormal ovarian function during prepubertal development; neither serum estradiol levels nor ovarian estradiol production were reduced in 21- or 28-day-old progeny of dams exposed to 1 microg TCDD/kg. In addition, partial to complete clefting of the phallus was displayed in TCDD-treated rats (10% at 0.20 and 60% at 0.80 microg TCDD/kg) and these dosage levels also increased the length of the urethral slit, increased distance from the urethral opening to the tip of the phallus, and decreased distance from the urethral opening to the vaginal orifice. Although fertility rates were normal, time-to-pregnancy was delayed by treatment with 0.80 microg TCDD/kg. When necropsied at 20 months of age, females from the TCDD-dose groups displayed histopathological alterations of the reproductive tract. In summary, administration of TCDD at dosage levels of 0.2, 0.8, and 1.0 microg/kg produces morphological reproductive alterations in female rat offspring as a consequence of in utero exposure.

Abnormalities, Drug-Induced↗

PubMed1997

A dose-response analysis of the reproductive effects of a single gestational dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male Long Evans Hooded rat offspring.

Male rats exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) display reduced fertility as a consequence of the direct action of TCDD on the epididymides, as well as delayed puberty and altered reproductive organ weights. The current study provides dose-response data for the reproductive effects of TCDD, administered during pregnancy, with an emphasis on the effects of TCDD on testicular, epididymal, and ejaculated sperm numbers. Long Evans Hooded rats were dosed by gavage with 0, 0.05, 0.20, or 0.80 microg TCDD/kg on Day 15 of gestation. After birth, growth, viability, and developmental landmarks were monitored in both male and female offspring. Shortly after puberty (49 and 63 days of age) and at 15 months of age, male offspring were necropsied. Growth and viability of the pups were reduced only at 0.80 microg TCDD/kg, eye opening was accelerated (all dosage groups), and puberty was delayed (at 0.20 and 0.80 microg TCDD/kg). Treated progeny displayed transient reductions in ventral prostate and seminal vesicle weights, while epididymal sperm reserves and glans penis size were permanently reduced. Ejaculated sperm numbers were reduced (45% in the 0.8 and by 25% in the 0.05 and 0.2 microg TCDD/kg dosage groups) to a greater degree than were cauda or caput/corpus epididymal or testicular (unaffected) sperm numbers. In conclusion, administration of TCDD on Day 15 of pregnancy at 0.05 microg/kg altered eye opening and reduced ejaculated sperm counts, while higher dosage levels also delayed puberty and permanently reduced cauda epididymal sperm reserves.

Animals↗

PubMed1996

Vinclozolin does not alter progesterone receptor (PR) function in vivo despite inhibition of PR binding by its metabolites in vitro.

Vinclozolin, a dicarboximide fungicide, alters morphological sex differentiation in male rats following perinatal exposure. The occurrence of these abnormalities correlates with the in vivo formation of two antiandrogenic metabolites of vinclozolin, (i.e. 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (Mt) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2)), which are potent inhibitors of rat androgen receptor binding. As steroid hormone receptors exhibit promiscuity in their ability to bind different ligands, the present study evaluated the ability of these vinclozolin metabolites to bind to the estrogen (ER) and progesterone (PR) receptors in vitro, and to alter ER and PR function following in vivo exposure. To this end, in vitro ligand binding assays demonstrated that both M1 and M2 can compete with endogenous ligand for binding to the PR (Ki = 400 and 60 microM, respectively). In contrast, neither metabolite exhibited the ability to bind ER. Subsequent in vivo studies to evaluate the potential of vinclozolin to alter ER or PR function demonstrate that, (1) the estrogen-dependent increases in uterine weight and PR induction were not altered by vinclozolin; (2) the distribution of nuclear and cytosolic PR was not altered following short-term vinclozolin exposure; and (3) vinclozolin did not disrupt ovulation in cycling female rats. These studies indicate that although vinclozolin metabolites can compete for binding to the PR in vitro, concentrations of these metabolites do not reach sufficient levels to disrupt female reproductive function following short-term in vivo exposure to vinclozolin. In addition, these studies demonstrate the importance of correlating in vitro receptor binding data with in vivo studies in order to understand the physiological consequences of exposure to environmental toxicants.

Anilides↗

PubMed1996

Autonomic and behavioral thermoregulation in golden hamsters exposed perinatally to dioxin.

Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause s a permanent change in thermoregulatory control of male offspring of the rat, characterized by a reduced core temperature (Tc over a wide range of ambient temperatures (Ta). To examine the similarities in this effect across species, the thermoregulatory effects of perinatal TCDD were evaluated in the golden hamster, a species which is very resistant to the lethal effects of TCDD. Adult male hamsters exposed on Gestational Day 11.5-11.75 to 2.0 microgram TCDD/kg by gavage were subjected to a variety of behavioral and autonomic thermoregulatory measurements. Nocturnal Tc of TCDD-treated animals was 0.4 to 1.0 degrees C below that of controls over a Ta range of 14 to 34 degrees C. Hypothermia persisted in spite of normal metabolic responses to cold exposure. The hypothermic effect of perinatal TCDD exposure was found to persist over a 24-hr period in unrestrained hamsters monitored by radiotelemetry. The TCDD-treated hamster offspring placed in a temperature gradient exhibited a preference for warm Ta's for 2 to 3 hr; however, when maintained over a 22-hr period in the gradient there was no effect of TCDD on behavioral thermoregulation. TCDD had no effect on motor activity measured over a 24-hr period. TCDD resulted in an approximately 30% reduction in body weight compared to controls; however, this weight loss appeared to have no bearing on the thermoregulatory deficiencies of the TCDD-treated animals. TCDD-treated hamsters displayed a normal metabolic response to cold exposure; thus, it would appear that perinatal exposure to TCDD leads to a dysfunction in the central control of body temperature. The perinatal effects of TCDD on thermoregulation in the rat and hamster appear to be similar.

Animals↗

PubMed1996

Three-dimensional quantitative structure--activity relationships for androgen receptor ligands.

Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, was used to examine androgen receptor-binding affinities of a series of structurally diverse natural, synthetic, and environmental chemicals of interest. The CoMFA/3D-QSAR model successfully illustrates that the overall steric and electrostatic properties of structurally diverse ligands for the androgen receptor are necessary and sufficient to describe the binding affinity. The practical utility of models of this type is demonstrated using parent compounds in the training set and known as well as putative biological metabolites as test set molecules. The ability of the model to accurately predict binding affinity of test set molecules suggests that structure-based 3D-QSAR models may be used to supplement the process of hazard identification. The application of 3D-QSAR models within a toxicological framework is, at present, limited by the quantity and quality of biological data for relevant biomarkers of toxicity.

Hazardous Substances↗

PubMed1996

Ligand-based identification of environmental estrogens.

Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, was used to examine the estrogen receptor (ER) binding affinities of a series of structurally diverse natural, synthetic, and environmental chemicals of interest. The CoMFA/3D-QSAR model is statistically robust and internally consistent, and successfully illustrates that the overall steric and electrostatic properties of structurally diverse ligands for the estrogen receptor are both necessary and sufficient to describe the binding affinity. The ability of the model to accurately predict the ER binding affinity of an external test set of molecules suggests that structure-based 3D-QSAR models may be used to supplement the process of endocrine disruptor identification through prioritization of novel compounds for bioassay. The general application of this 3D-QSAR model within a toxicological framework is, at present, limited only by the quantity and quality of biological data for relevant biomarkers of toxicity and hormonal responsiveness.

Animals↗

PubMed1996

Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop.

The hypothesis has been put forward that humans and wildlife species adverse suffered adverse health effects after exposure to endocrine-disrupting chemicals. Reported adverse effects include declines in populations, increases in cancers, and reduced reproductive function. The U.S. Environmental Protection Agency sponsored a workshop in April 1995 to bring together interested parties in an effort to identify research gaps related to this hypothesis and to establish priorities for future research activities. Approximately 90 invited participants were organized into work groups developed around the principal reported health effects-carcinogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity-as well as along the risk assessment paradigm-hazard identification, dose-response assessment, exposure assessment, and risk characterization. Attention focused on both ecological and human health effects. In general, group felt that the hypothesis warranted a concerted research effort to evaluate its validity and that research should focus primarily on effects on development of reproductive capability, on improved exposure assessment, and on the effects of mixtures. This report summarizes the discussions of the work groups and details the recommendations for additional research.

Animals↗

PubMed1995

Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist.

The increase in the number of reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of 'oestrogenic' chemicals such as DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) into the environment. Although these phenotypic alterations are thought to be mediated by the oestrogen receptor, they are also consistent with inhibition of androgen receptor-mediated events. Here we report that the major and persistent DDT metabolite, p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), has little ability to bind the oestrogen receptor, but inhibits androgen binding to the androgen receptor, androgen-induced transcriptional activity, and androgen action in developing, pubertal and adult male rats. The results suggest that abnormalities in male sex development induced by p,p'-DDE and related environmental chemicals may be mediated at the level of the androgen receptor.

Androgen Antagonists↗

PubMed1995

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants.

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Animals↗

PubMed1995

Assessment of offspring development and behavior following gestational exposure to inhaled methanol in the rat.

The prospect of widespread human exposure associated with its use as an alternative fuel has sparked concern about the toxic potential of inhaled methanol (MeOH). Previous studies have revealed congenital malformations in rats following inhaled MeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5, 727-736) but these studies did not include postnatal behavioral assessment. In the present study, pregnant Long-Evans rats were placed in exposure chambers containing 15,000 ppm MeOH or air for 7 hr/day on Gestational Days (GD) 7-19. The total alveolar dose of methanol was estimated at about 6.1 g/kg/day, for a total dose of about 42.7 g/kg for the entire study. Maternal body weights were recorded daily and blood methanol concentrations were determined at the end of exposure on GD 7, 10, 14, and 18. Following birth (Postnatal Day 0 [PND 0]), a number of tests were performed at various points in development, including: offspring mortality and body wt (PND 1,3), motor activity (PND 13-21, 30, 60), olfactory learning (PND 18), behavioral thermoregulation (PND 20-21), T-maze learning (PND 23-24), acoustic startle response (PND 24, 60), reflex modification audiometry (PND 60), pubertal landmarks (PND 31-56), passive avoidance (PND 72), and visual-evoked potentials (PND 160). Maternal blood MeOH levels, measured from samples taken within 15 min after removal from the exposure chamber, declined from about 3.8 mg/ml on the first day of exposure to 3.1 mg/ml on the 12th day of exposure. MeOH transiently reduced maternal body wt (4-7%) on GD 8-10, and offspring BW (5%) on PND 1. No other test revealed significant effects of MeOH. Prenatal exposure to high levels of inhaled MeOH appears to have little effect on this broad battery of tests beyond PND 1 in the rat.

Administration, Inhalation↗

PubMed1995

Hamster Leydig cells are less sensitive to ethane dimethanesulfonate when compared to rat Leydig cells both in vivo and in vitro.

It has been reported that ethane dimethanesulfonate (EDS) is a Leydig cell toxicant that affects rats and hamsters (Kerr et al., 1987), while, in contrast, the Leydig cells of mice are relatively insensitive to the toxicant. In the rat, there is a rapid decline in levels of testosterone (T) within hours after EDS administration. However, T production, spermiogenesis, and fertility are restored within a few weeks as new Leydig cells are formed from undifferentiated cells in the interstitium of the testis. In an earlier study, we found, as expected, that ejaculated sperm counts (ESCs) reached a nadir 10 days after adult rats were dosed with EDS at 65 mg/kg ip along with serum and testicular T, testis and seminal vesicle weights, and in vitro T production, while, in contrast, EDS at 65 mg/kg had no effect on these endpoints in the Syrian hamster (Gray et al., 1992). In the current study, when EDS was administered to 6, 12, and 18 month old hamsters at 100 mg/kg, it produced subtle effects on serum T and sex accessory gland weights, while dramatic effects were seen in similarly exposed rats. In addition, when testes were examined by light microscopy all treated rats displayed severely reduced Leydig cell numbers, while, in contrast, only one-third of the EDS-treated hamsters were affected, having moderately reduced Leydig cell numbers. In support of the histological data, 3 beta-HSD enzyme activity was reduced by 99% of control in EDS-treated rats, but it was reduced by only 35% of control in EDS-treated hamsters. An in vitro analysis of the effects of EDS on LH-stimulated T production by quartered testes demonstrated that the hamster testis was less sensitive to the direct effects of EDS than the rat testis. The IC50 after 3 hr in culture was greater than 1800 micrograms EDS/ml for the hamster quarter testes, while the IC50 for the rat quarter testes was 320 micrograms EDS/ml. In summary, these results demonstrate in vivo and in vitro that Leydig cells of hamsters are less sensitive to EDS than those of the adult rat.

Aging↗

PubMed1995

Exposure to TCDD during development permanently alters reproductive function in male Long Evans rats and hamsters: reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic status.

Prenatal administration of relatively low doses of TCDD alters reproductive development and fertility of the progeny. Fertility was reduced in the progeny of Wistar rats exposed to 0.5 micrograms TCDD/kg/day from Gestational Day (GD) 6 to GD 15. In a three-generation reproduction study, TCDD reduced fertility of Sprague-Dawley rats in the F1 and F2 but not the F0 (no developmental exposure) generation at 0.01 microgram/kg/day in the diet. Furthermore, administration of TCDD on GD 15 (at 0.064 to 1 microgram/kg) both demasculinized and feminized morphology and behavior of Holtzman male rat offspring. Our objectives were to expand the observations of Mably et al. (1992, Toxicol, Appl. Pharmacol. 114, 97-107, 108-117, 118-126) on the effects of gestational administration of a single dose of TCDD to another strain of rat and another species, the hamster. In the first study, Long Evans (LE) hooded rats were dosed by gavage with 1 microgram TCDD/kg on GD 8 (during the period of major organogenesis) or GD 15 (the gestational day used by Mably et al.). In the second study, pregnant Syrian hamsters, a species relatively insensitive to the lethal effects of TCDD, were dosed on GD 11, equivalent to GD 15 in the rat, with TCDD at 2 micrograms/kg. When LE rats were dosed on GD 15, or when hamsters were dosed on GD 11, puberty (preputial separation) was delayed by about 3 days, ejaculated sperm counts were reduced by at least 58%, and epididymal sperm storage was reduced by 38%. Testicular sperm production was less affected. The sex accessory glands were also reduced in size in LE rat offspring treated on GD 15 despite the fact that serum testosterone (T), T production by the testis in vitro, and androgen receptor (AR) levels were not reduced. Some reproductive measures, such as anogenital distance and male sex behavior, were altered by TCDD treatment in rat but not hamster offspring. Since T and AR levels appeared normal in the sex accessory glands and the epididymis following perinatal TCDD exposure, the alterations in these tissues are not likely to have resulted from an alteration of the androgenic status of the male offspring.

Aging↗

PubMed1995

Temperature regulation and metabolism in rats exposed perinatally to dioxin: permanent change in regulated body temperature?

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to lower thyroxine levels and cause hypothermia in the adult rat; however, there is little known regarding the perinatal effects of TCDD on metabolism and temperature regulation of the offspring. To address this issue, thermoregulatory responses were assessed in adult male rat offspring exposed perinatally to 1.0 micrograms TCDD/kg body wt by gavage on Gestational Day 15. Individual castrated offspring were placed in a gradient-layer calorimeter for 5 hr during their nocturnal period while ambient temperature (Ta) was maintained at 10, 16, 24, or 28 degrees C. Metabolic rate (M), as measured from the total heat loss in the calorimeter, was determined along with evaporative heat loss (EHL), dry thermal conductance, and body core temperature (Tc). Animals exposed to TCDD had a significantly lower body temperature at TaS of 10, 16, and 24 degrees C and a higher thermal conductance. M was unaffected by TCDD, indicating that TCDD did not impair the effector to regulate Tc during cold exposure. EHL was also unaffected by TCDD. Skin blood flow of the interscapular area was measured in anesthetized rats with laser Doppler velocimetry and found to be the same in control and TCDD groups. The reduction in body temperature over a wide range of TaS concomitant with normal thermoregulatory effector function suggests that perinatal exposure to TCDD results in a reduction in the regulated body temperature (i.e., decrease in set-point).

Adipose Tissue, Brown↗

PubMed1995

In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring.

Exposure to pesticides or toxic substances that disrupt the endocrine system during sex differentiation can permanently alter reproductive function and produce morphological pseudohermaphrodism. While some developmental toxicants affect either the male or the female, in utero exposure to 0.5 micrograms TCDD/kg/day from Gestational Day (GD) 6 to GD 15 induces infertility in both sexes (K.S. Khera and J.A. Ruddick, Chlorodioxins--Origins and Fate, pp. 70-84, Am. Chem. Soc., Washington, DC, 1973). Although a number studies have focused on the effects of a single dose of TCDD on sex differentiation of the male rat and hamster, the reproductive alterations that account for female-mediated infertility after in utero exposure to TCDD have not been described. Hence, it was our objective to describe the anatomical and functional reproductive alterations in female progeny after gestational administration of TCDD. In the first experiment, LE Hooded rats were given a single dose of 1 microgram TCDD/kg by gavage on CD 8 (i.e., a period that includes major organogenesis) or GD 15 (i.e., a period prior to sex differentiation and a dosing regime that alters sex differentiation of the male LE rat). In a second experiment, Holtzman rats were dosed with TCDD at 1 microgram/kg on GD 15, to determine if the progeny of this strain displayed malformations of the external genitalia and vaginal orifice as did LE rats. TCDD-treated female LE offspring displayed a number of unusual reproductive alterations. In the GD 15 group, puberty was delayed, more than 65% of the female offspring displayed complete to partial clefting of the phallus, and 80% displayed a permanent "thread" of tissue across the opening of the vagina. In the GD 8 treatment group, 25% displayed partially cleft phallus and 14% had a vaginal thread. GD 15 TCDD administration also induced a high incidence of malformations in Holtzman female progeny (100% clefting and 83% with a vaginal thread). At necropsy (> 550 days old), ovarian weight was significantly reduced by 23% in both rat strains. In the LE rat, vaginal and behavioral estrous cyclicity, estrous cycle-mediated running wheel activity, and female sexual behaviors at proestrus (darting and lordosis to mount ratios) were not affected by gestational GD 15 TCDD treatment. However, untreated stud males had difficulty attaining intromission and took longer to ejaculate and vaginal bleeding was displayed during mating by GD 15 TCDD-exposed female offspring.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗