Biomedical subjects

R E Peterson

Publications and source records attributed to R E Peterson.

At least 19 recordsLinked to original sources

PubMed2005

Growth, morphogenesis, and differentiation during mouse prostate development in situ, in renal grafts, and in vitro.

BACKGROUND: In vitro organ culture and renal grafting of the urogenital sinus (UGS) have both been used as models of prostate development. However, neither has been rigorously examined for its fidelity to replicate the canonical process of prostate differentiation in situ. METHODS: We assessed size, morphology, histology, and the mRNA expression of differentiation marker genes of the E14 male mouse UGS grown for 0-28 days as sub-renal capsule allografts in nude mice or in culture containing androgen and compared these to UGS development in situ. RESULTS: Development of grafted tissues was morphologically and histologically similar to development in situ but differentiation occurred more rapidly. UGS growth in organ culture resulted in bud formation, but did not trigger cellular differentiation. However, the potential for differentiation was maintained and could be rescued by grafting tissues into nude mice. CONCLUSIONS: In vitro organ culture and renal grafting of UGS tissues may be appropriate models for studying prostatic bud formation, but only grafting is an appropriate model for prostatic differentiation.

Animals↗

PubMed2005

Tetrachlorodibenzo-p-dioxin exposure alters radial arm maze performance and hippocampal morphology in female AhR mice.

Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter spatial learning in rats tested on a radial arm maze (RAM). TCDD is believed to exert most of its effects through binding to the aryl hydrocarbon receptor (AhR). To determine whether the AhR mediates TCDD-induced alterations in spatial learning, we tested male and female AhR-knockout (AhR-/-), heterozygous (AhR+/-) and wild-type (AhR+/+) mice on the RAM. AhR+/- male and female mice were time mated, and treated dams were dosed with 5 microg TCDD/kg body weight on day 13 of gestation. When offspring reached adulthood, male and female AhR+/+, AhR+/- and AhR-/- mice from TCDD-exposed and unexposed litters were tested on the eight-arm RAM. After testing, we examined hippocampal morphology as visualized by the Timm's silver sulfide stain. TCDD-exposed female AhR+/- mice made more errors than their respective controls on the RAM and exhibited a decrease in the size of the intra- and infrapyramidal mossy fiber (IIP-MF) field of the hippocampus. None of the other TCDD-exposed groups differed from their respective control groups with regard to maze performance or hippocampal morphology. The reduction of IIP-MF field indicates a possible morphological basis for the learning deficit that was observed in the female AhR+/- mice. It is hypothesized that the effect of TCDD exposure is AhR dependent and that TCDD may alter GABAergic activity in the hippocampus of female mice during development.

Animals↗

PubMed2004

2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits regression of the common cardinal vein in developing zebrafish.

A role for the aryl hydrocarbon receptor (AHR) pathway in vascular maturation has been implicated by studies in Ahr-null mice. In this study the hypothesis that activation of AHR signaling by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters common cardinal vein (CCV) development in the zebrafish embryo was investigated. The CCV is a paired vessel that grows across the yolk, connecting to the heart. It is extensively remodeled and regresses as the heart migrates dorsally within the pericardium. TCDD significantly reduced CCV growth as early as 44 h post fertilization (hpf), and CCV area was reduced to 63% of control at 62 hpf. This vascular response to TCDD was at least as sensitive as previously defined endpoints of TCDD developmental toxicity in zebrafish. TCDD also blocked regression of the CCV (by 80 hpf), possibly contributing to the "string-like" heart phenotype seen in TCDD-exposed zebrafish larvae. Dependence of the block in CCV regression on zebrafish (zf) AHR2 was investigated using a zfahr2 specific morpholino to knock down expression of AHR2. The zfahr2 morpholino had no effect on CCV regression in the absence of TCDD, but did protect against the TCDD-induced block of CCV regression. This demonstrates that the TCDD-induced block in CCV regression is AHR2 dependent. It is significant that decreased CCV growth occurs before and inhibition of CCV regression occurs concurrent with overt signs of TCDD developmental toxicity. This suggests that alterations of vascular growth and remodeling may play a role in TCDD developmental toxicity in zebrafish.

Animals↗

PubMed2001

Role of the aryl hydrocarbon receptor in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed male mice.

Experiments were conducted to determine the role of the aryl hydrocarbon receptor (AhR) in the development of control and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-exposed C57Bl/6 male mice. Male and female mice heterozygous for the AhR (Ahr+/-) were mated, and pregnant females were dosed orally on gestation day 13 with corn oil vehicle or TCDD (5 microg/kg). Pups were necropsied on postnatal day (PND) 21, 35, and 90. Comparison of vehicle-exposed wild-type (Ahr+/+) pups with vehicle-exposed AhR knockout (AhRKO; Ahr-/-) pups confirmed and extended previous reports that development of the liver, heart, spleen, thymus, and kidney is affected by absence of the AhR. Lung, submandibular gland, testis, and epididymis weights were also affected, indicating that the AhR plays a role in normal development of these organs as well. The presence or absence of the AhR had no effect on the incidence of hydronephrosis, daily sperm production, or cauda epididymal sperm numbers in vehicle-exposed mice. TCDD caused numerous effects in wild-type mice that were absent in AhRKO mice; specifically, hydronephrosis, increases in relative liver and heart weight, decreases in absolute heart and lung weight, and decreases in absolute and relative thymus, submandibular gland, epididymis, and testis weight. In several cases, TCDD produced one effect in wild-type mice (reductions in body weight and absolute thymus, submandibular gland, and epididymis weight on PND 21; and reductions in absolute and relative submandibular gland and absolute testis weight on PND 35) but caused the opposite effect in AhRKO mice. In yet other cases (reduced relative spleen weight on PND 21 and reductions in absolute and relative thymus weight on PND 35), TCDD produced similar effects in wildtype and AhRKO mice. There were also cases in which TCDD significantly affected AhRKO mice without significantly altering the same endpoint in wild-type mice; absolute liver, lung, and kidney weight were increased and relative submandibular gland weight was decreased on PND 21; relative heart weight was reduced and absolute lung weight increased on PND 35; and relative liver weight was decreased on PND 90. Although many effects of TCDD required the presence of the AhR, these results provide evidence either for multiple forms of the AhR in mice (one or more of which are still present in AhRKO mice), or for AhR-independent effects of low-level TCDD exposure.

Animals↗

PubMed2001

Müller cell differentiation in the zebrafish neural retina: evidence of distinct early and late stages in cell maturation.

The vertebrate neural retina is mainly composed of cells of neuroectodermal origin. The primary cell types found in all vertebrate retinas are several categories of neurons and the archetypical retina glial cell the Müller cell. Although the neurons and the single glial cell type of the retina are specialized for very distinct functions, they all have a common developmental origin within the tissue. How the distinctions between cell types, in particular between neurons and glia, arise during embryonic development remains a central issue in neurobiology. In this report, we examine the genesis of Müller glial cells during zebrafish (Danio rerio) eye development. Particular emphasis is placed on the expression of the Müller cell maturation markers carbonic anhydrase and glutamine synthetase. In addition, we report that the HNK-1 monoclonal antibody, which identifies a particular glycoconjugate frequently found on cell surface recognition molecules, also identifies zebrafish retina Müller cells early in development. The expression patterns of these three markers clearly show that the Müller cells mature in stages: HNK-1 labeling and glutamine synthetase arise earlier than carbonic anhydrase expression. In addition, the embryonic zebrafish neural retina is characterized by the presence of amoeboid, carbonic anhydrase-positive microglial cells even before the genesis of retinal neuroectodermal glia. The stepwise maturation of the glia is likely to be indicative of an overall retinal maturational program in which cell differentiation and the expression of certain phenotype-defining gene products may be separately regulated.

Animals↗

PubMed2001

Investigation of Prx1 protein expression provides evidence for conservation of cardiac-specific posttranscriptional regulation in vertebrates.

Gene targeting experiments have defined that the homeobox gene Prx1 is essential for normal craniofacial, limb, and vascular development. Although its RNA expression pattern is well established, Prx1 protein expression in the developing embryo has not been examined. A novel Prx1 antibody was produced to define the normal Prx1 protein expression pattern in the developing mouse embryo. In craniofacial and limb mesenchyme, Prx1 protein expression is consistent with previously published data on RNA localization. However, a remarkable discrepancy was found in cardiac tissue. Prx1 protein is undetectable in the murine embryonic and adult heart, despite the presence of Prx1 transcripts. These data demonstrate that Prx1 expression is posttranscriptionally regulated. This discrepancy between the presence of Prx1 transcript and the absence of detectable protein was also observed in embryonic chick heart, suggesting conservation of the regulatory mechanism in vertebrates. This observation provides a new explanation of why the Prx null mice lack cardiac malformations.

Aging↗

PubMed2001

Disruption of erythropoiesis by dioxin in the zebrafish.

2,3,7,8-Tetrachlorodibenzo-p- dioxin (TCDD, or dioxin) causes early life stage mortality in a variety of fish species. We have used the zebrafish (Danio rerio) to study the cardiovascular effects of TCDD treatment over the time course of zebrafish development. Early TCDD exposure (6 ng/ml) starting at 4 hr postfertilization (hpf) produced reductions in blood flow and in the number of circulating erythrocytes. These defects were consistently observable by 72 hpf. However, these responses were not observed when TCDD exposure was delayed until 96 hpf or later. These results suggest a model in which TCDD interferes with cardiovascular and erythropoietic developmental processes that are normally completed by 96 hpf. This model is strengthened by the finding that TCDD exposure blocks the step in hematopoiesis in which developing zebrafish switch from the primitive phase to the definitive phase of erythropoiesis. We observed no effect of TCDD on the levels of circulating primitive erythrocytes before 72 hpf and the expression of markers for early hematopoiesis, GATA-1 and GATA-2. However, early TCDD exposure prevented the appearance of definitive phase erythrocytes. TCDD produced a small delay in the migration of blood cells expressing SCL from the intermediate cell mass to the dorsal mesentery and dorsal aorta. Despite the decrease in blood flow produced by TCDD, confocal microscopy of the trunk vasculature by using a Tie2/green fluorescence protein endothelial marker at 48, 60, 72, and 96 hpf of TCDD-exposed (4 hpf) revealed no apparent defects in blood vessel structure.

Anemia↗

PubMed2001

In utero and lactational treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs mammary gland differentiation but does not block the response to exogenous estrogen in the postpubertal female rat.

These experiments tested whether in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters mammary gland differentiation, estrogen receptor alpha (ERalpha) expression levels, or the response to estrogen in the female postpubertal rat mammary gland. Pregnant Holtzman rats were administered a single oral dose of 1 microg/kg TCDD or vehicle on gestation-day 15. Exposed and non-exposed female offspring were weaned on postnatal day 21 and ovariectomized at 9 weeks of age. Two weeks later, both TCDD and control animals were divided into 3 groups, receiving treatment with placebo, 0.025, or 0.1 mg 17beta-estradiol pellet implants. After 48 h, mammary tissue was removed for analysis following euthanasia. TCDD-exposed mammary glands demonstrated impaired differentiation as measured by the distribution of terminal ductal structures and increased expression levels of ERalpha. The response to exogenous estrogen was tested in TCDD-exposed animals and compared to control non-exposed animals. Estrogen stimulation of the TCDD-exposed glands induced progesterone receptor expression and mammary gland differentiation as measured by a shift in distribution from terminal end buds and terminal ducts to Types I and II lobules. Control glands were better differentiated at baseline and did not exhibit any significant changes in the distribution of terminal ductal structures following estrogen stimulation. The increase in progesterone receptor-expression levels by exogenous estrogen in control glands was similar to the TCDD-exposed glands. These experiments demonstrate that in utero and lactational exposures to TCDD impair mammary gland differentiation but that TCDD-exposed mammary glands retain the ability to differentiate in response to estrogen.

Actins↗

PubMed2001

Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.

Androgen Antagonists↗

PubMed2001

Relative potencies of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners to induce cytochrome P4501A mRNA in a zebrafish liver cell line.

Induction of cytochrome P4501A (CYP1A) mRNA by polychlorinated dibenzo-p-dioxin (PCDD), polychlorinated dibenzofuran (PCDF), and polychlorinated biphenyl (PCB) congeners was measured in a zebrafish liver (ZF-L) cell line. The ZF-L cells were far less sensitive to PCDD, PCDF, and PCB congeners than were other fish cell lines. The 2,3,7,8-PCDDs, 2,3,7,8-PCDFs, and PCB 126 caused dose-related induction. All other PCBs tested, including other coplanar as well as ortho-substituted congeners, were ineffective at inducing CYP1A. The potency of each congener that gave a response, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin, was determined. The ZF-L cell-derived relative potency values (REPs) are similar to other in vitro REPs in that the ZF-L cell-derived REPs are generally higher than those derived from in vivo models. Furthermore, the ZF-L cell-derived REPs are generally within fivefold of REPs determined in a variety of rainbow trout systems when the same endpoint in the same tissue are compared. Analysis of these data indicates that REPs based on molecular and biochemical responses in sensitive and insensitive species are similar, but overestimate relative in vivo toxicity in the rainbow trout. The ZF-L cell-derived REPs expand the database of REPs, providing additional information that will be useful in quantifying the uncertainty associated with applying consensus fish-specific toxic equivalency factors in ecological risk assessment.

Animals↗

PubMed2000

Identification and expression of alternatively spliced aryl hydrocarbon nuclear translocator 2 (ARNT2) cDNAs from zebrafish with distinct functions.

In order to further establish zebrafish as a vertebrate model for studying the mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity it is necessary to characterize the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AhR/ARNT) signaling pathways in this species. In this study, three zfARNT2 cDNAs were isolated, expressed, and characterized and named zfARNT2b, zfARNT2c, and zfARNT2a. zfARNT2b, zfARNT2c, and zfARNT2a encode proteins with theoretical molecular weights of 81, 79, and 45 kDa, respectively. zfARNT2b and zfARNT2a proteins are identical over the first 403 amino acids but differ in their C-terminal domains as a result of alternative mRNA splicing. zfARNT2c is nearly identical to zfARNT2b, with the exception of an in frame 15 amino acid deletion adjacent to the basic region of zfARNT2c. Using quantitative RT-PCR methods the tissue distribution of each zfARNT2 isoform was determined. In COS-7 cells expressing zfARNT2b and zfAhR2, 10 nM TCDD causes a nine-fold induction of a dioxin responsive reporter gene. In COS-7 cells expressing zfARNT2a or zfARNT2c, TCDD does not induce reporter gene expression. In contrast, all three zfARNT2 proteins induce reporter gene activity under control of hypoxia responsive elements when cotransfected with the zebrafish endothelial specific PAS protein 1. DNA gel shift analysis suggests that the decreased function of zfARNT2a is due to inefficient binding of zfARNT2a/zfAhR2 complexes to dioxin responsive elements. These results also indicate that alternative mRNA splicing results in formation of ARNT proteins with distinct functional properties.

Alternative Splicing↗

PubMed2000

Hemodynamic dysfunction and cytochrome P4501A mRNA expression induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin during embryonic stages of lake trout development.

Lake trout embryos exposed to [(3)H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) manifest toxicity after hatching by subcutaneous edema of the yolk sac, pericardial edema, meningeal edema, subcutaneous hemorrhages, and a marked congestion of blood flow in various vascular beds culminating in death. Our objective was to determine if this syndrome was associated temporally with morphologic lesions in the vascular endothelium, increased vascular permeability, and cytochrome P4501A (CYP1A) mRNA induction. Lake trout embryos exposed as fertilized eggs to TCDD were found to exhibit marked reductions in perfusion of the peripheral vasculature during the early sac fry stage of development (stage F(1)9), which consistently preceded other gross lesions and mortality observed later in sac fry development (stage F(2)10). This reduction in blood flow was manifested as severe capillary congestion and hemoconcentration in certain vascular beds. Transmission electron microscopic (TEM) examination of endothelial cells in these vascular beds failed to reveal cellular necrosis at hatching (stage E(5)8) and throughout sac fry development (stages F(1)9-F(2)10). Rather, only subtle ultrastructural changes in endothelial cells were found consisting of increased vacuolation, separation of intercellular junctions, and cytoplasmic blebbing, consistent with the TCDD dose and time course for developmental cardiovascular toxicity, which began to manifest itself in some embryos approximately 1 week prior to hatching (E(5)8). To assess permeability of yolk sac vasculature to certain constituents in blood, sac fry (stage F(2)10) were analyzed for the presence of plasma proteins, granulocytes, and serum creatine kinase activity in yolk sac subcutaneous edema fluid from control and TCDD-exposed treatment groups. TCDD dose- and time-related increases in yolk sac edema volume, plasma protein content of edema fluid, granulocyte concentration, and creatine kinase activity in the fluid were observed in midstage and late stage of sac fry development (stage F(2)10). Thus, yolk sac subcutaneous edema fluid is an ultrafiltrate of blood and results from increased vascular permeability. In contrast to the changes in vascular blood flow and permeability induced by TCDD during stages F(1)9 and F(2)10 of sac fry development, respectively, CYP1A mRNA levels were induced by TCDD as early as the 10-somite embryo (stage E(2)5). TCDD also caused a dose-related increase in CYP1A mRNA levels in sac fry at hatching (stage E(5)8) and throughout sac fry development (stages F(1)9-F(2)10). We conclude that subtle, ultrastructural changes in vascular endothelial cells consistently precede increases in vascular permeability and sac fry mortality; however, induction of CYP1A mRNA occurs prior to any observable morphological lesions, changes in vascular permeability, or sac fry mortality.

Animals↗

PubMed2000

Human risk assessment and TEFs.

The concept of toxic equivalency factors (TEFs) has been developed to facilitate risk assessment and regulatory control of exposure to complex PCDD, PCDF and PCB mixtures. Recently the European Centre for Environment and Health of the World Health Organization (WHO-ECEH) and the International Programme on Chemical Safety (IPCS) jointly re-evaluated the TEFs of PCDDs, PCDFs and dioxin-like PCBs for mammals and derived consensus TEFs for birds and fish (Stockholm, 1997). From a mechanistic point of view it can be concluded that, although the quantitative response will vary depending on the congener involved, the occurrence of a common mechanism (binding to the Ah receptor) legitimates the use of the TEF concept across species. But there also is criticism regarding the TEF concept. Pharmacokinetic differences between species can significantly influence the TEF value, and uncertainties due to additive or non-additive interactions, to differences in species responsiveness and to differences in the shape of the dose-response curve might hamper the derivation of consensus TEF values. In this context it should be noted, however, that using TCDD alone, as the only measure of exposure to dioxin-like PCDDs, PCDFs and PCBs, would severely underestimate the risk from exposure to these compounds. Therefore, it can be concluded that, for pragmatic reasons, the TEF concept remains the most feasible approach for risk assessment purposes, in spite of the uncertainties associated with its use.

Animals↗

PubMed2000

Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces developmental defects in the rat vagina.

At puberty, female rats exposed in utero to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit a persistent thread of mesenchymal tissue surrounded by keratinized epithelium that partially occludes the vaginal opening. Our objective was to determine the earliest time during fetal development that morphological signs of this vaginal canal malformation could be detected and to obtain greater insight into mechanisms involved in this effect. Pregnant rats were administered a single dose of vehicle (control) or TCDD (1.0 microg/kg, po) on gestation day (GD) 15 and were sacrificed on GD 18, 19, 20, and 21 for histological evaluation of female. Gestational exposure to TCDD affected vaginal morphogenesis as early as GD 19, 4 days after exposure of pregnant dams. In exposed fetuses, the thickness of mesenchymal tissue between the caudal Mullerian ducts was increased, which resulted in a failure of the Mullerian ducts to fuse, a process normally completed prior to parturition. In addition, TCDD exposure appeared to inhibit the regression of Wolffian ducts. Thus, TCDD interferes with vaginal development by impairing regression of the Wolffian ducts, by increasing the size of interductal mesenchyme, and by preventing fusion of the Mullerian ducts. Taken together, these effects appear to cause the persistent vaginal thread defect observed in rats following in utero and lactational TCDD exposure.

Abnormalities, Drug-Induced↗

PubMed2000

Physiological role of the aryl hydrocarbon receptor in mouse ovary development.

The aryl hydrocarbon receptor (AhR) regulates the toxicity of environmental contaminants such as 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). As the physiological role of the AhR in the ovary is unknown, the purpose of this study was to test the hypothesis that the AhR regulates the appearance and numbers of ovarian follicles. Ovaries were harvested from AhR-deficient (AhRKO) and wild-type mice on gestational day 18 (GD 18) and postnatal days (PND) 2-3, 8, 32-35, and 53. Complete serial sections of ovaries were evaluated histologically for the presence of germ cells and follicles. On GD 18, there was no difference in the number of germ cells per ovary between AhRKO and wild-type fetuses. However, by PND 2-3, AhRKO mice had significantly more fully formed primordial follicles (AhRKO = 38,440 +/- 3632 versus wild-type = 21,120 +/- 2688) and fewer single germ cells than wild-type mice (AhRKO = 12,696 +/- 1192 vs. wild-type = 18,160 +/- 720). On PND 8 and 32-35, there was no difference in the number of follicles between AhRKO and wild-type mice but by PND 53, AhRKO mice had significantly fewer antral follicles than wild-type (AhRKO = 3416 +/- 480 vs. wild-type = 6776 +/- 1024). Taken together, these results suggest that the AhR may play a role in the formation of primordial follicles and the regulation of antral follicle numbers.

Animals↗

PubMed2000

Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse uterus: critical role of the aryl hydrocarbon receptor in stromal tissue.

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the role of aryl hydrocarbon receptor (AhR) in estradiol (E(2))-induced uterine epithelial mitogenic activity and secretory protein mRNA expression were determined. Ovariectomized wild-type (wt) and AhR-knockout (AhRKO) mice received oil, E(2), or 5 microg/kg TCDD+E(2). E(2) stimulated similar large increases in the uterine epithelial labeling index (LI) and mRNA abundance for the E(2)-dependent epithelial secretory protein, lactoferrin (LF), in both wt and AhRKO mice. However, uterine epithelial LI and LF mRNA were significantly reduced by TCDD+E(2) in wt but not AhRKO mice. To determine the roles of stromal and epithelial AhR in the TCDD effect, uterine stroma and epithelium from AhRKO and wt mice were enzymatically separated and recombined into four types of tissue recombinants that either contained or lacked AhR in one or more tissue compartments. Tissue recombinants were grafted into nude mice, which were later ovariectomized and given oil, E(2), or TCDD+E(2). Epithelial LI was significantly reduced by TCDD in grafts containing stromal AhR, regardless of epithelial AhR status. However, LI was unaffected by TCDD in grafts lacking stromal AhR, even when epithelial AhR was present. Thus, TCDD inhibits E(2)-induced uterine epithelial mitogenic and secretory activity, and this requires AhR. Anti-proliferative effects of TCDD on uterine epithelia appear to be mediated indirectly through stromal AhR, suggesting that liganded AhR alters epithelial function by disrupting normal E(2)-induced stromal activity. This is the first demonstration that TCDD impairs uterine epithelial function by altering normal stromal-epithelial interactions in vivo.

Animals↗

PubMed2000

2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring.

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.

3-Hydroxysteroid Dehydrogenases↗

PubMed2000

Lactobacillus arizonensis sp. nov., isolated from jojoba meal.

Five strains of simmondsin-degrading, lactic-acid-producing bacteria were isolated from fermented jojoba meal. These isolates were facultatively anaerobic, gram-positive, non-motile, non-spore-forming, homofermentative, rod-shaped organisms. They grew singly and in short chains, produced lactic acid but no gas from glucose, and did not exhibit catalase activity. Growth occurred at 15 and 45 degrees C. All strains fermented cellobiose, D-fructose, D-galactose, D-glucose, lactose, maltose, D-mannitol, D-mannose, melibiose, D-ribose, salicin, D-sorbitol, sucrose and trehalose. Some strains fermented L-(-)-arabinose and L-rhamnose. D-Xylose was not fermented and starch was not hydrolysed. The mean G+C content of the DNA was 48 mol%. Phylogenetic analyses of 16S rDNA established that the isolates were members of the genus Lactobacillus. DNA reassociation of 45% or less was obtained between the new isolates and the reference strains of species with G+C contents of about 48 mol%. The isolates were differentiated from other homofermentative Lactobacillus spp. on the basis of 16S rDNA sequence divergence, DNA relatedness, stereoisomerism of the lactic acid produced, growth temperature and carbohydrate fermentation. The data support the conclusion that these organisms represent strains of a new species, for which the name Lactobacillus arizonensis is proposed. The type strain of L. arizonensis is NRRL B-14768T (= DSM 13273T).

Acetonitriles↗