Suppression of antibody response of female mice exposed to DES

Suppression of cell-mediated immunocompetence after subchronic exposure to diethylstilbestrol in female B6C3F1 mice

1983 Study Abstract

The effect of the nonsteroidal estrogenic compound, diethylstilbestrol (DES) on cell-mediated immunocompetence in the mouse has been assessed.

Adult female B6C3F1 mice were injected (s.c.) with 0.2, 1.0 and 4.0 mg/kg of DES daily for 14 days. All immunological tests and toxicological parameters were determined at least 24 hr after the last exposure.

Thymic involution and hepatomegaly were noted at the lowest dose of DES. The most sensitive indicator of immunosuppression by DES was the delayed hypersensitivity response (DHR) to keyhole limpet hemocyanin in mice sensitized without adjuvant. The lowest dose of DES produced a 93% decrease, compared with a 39% decrease for the same DHR model in mice sensitized to keyhole limpet hemocyanin plus adjuvant and a 63% decrease for the DHR to sheep erythrocytes. A 35% decrease of the acute inflammatory response to carrageenin was produced by the lowest dose of DES. Day 2 proliferative responses to both concanavalin A and phytohemagglutinin (T-cell mitogens) were depressed by the lowest dose of DES, whereas significant suppression of the response to lipopolysaccharide (B-cell mitogen) was only noted at the highest dose of DES. The effects of DES on Day 3 proliferative responses were less dramatic. The mixed lymphocyte response was significantly suppressed by 1.0 and 4.0 mg/kg of DES on all days in culture. The reversibility of the DES effects was studied by resting the mice for 30 days between exposure and measuring a given parameter. All effects on organ weights and the depression of both the sheep erythrocytes DHR and the carrageenin inflammatory response were reversed.

References

  • Suppression of cell-mediated immunocompetence after subchronic exposure to diethylstilbestrol in female B6C3F1 mice, The Journal of pharmacology and experimental therapeutics, NCBI PubMed, PMID: 6225865, 1983.
  • Featured image my.vanderbilt.edu.
DES DIETHYLSTILBESTROL RESOURCES

Effect of DES on the immune responsiveness

Effects of single administration of diethylstilbestrol on murine langerhans cells

2005 Study Abstract

Diethylstilbestrol (DES) is a synthetic compound with potent estrogenic actions useful in the treatment of prostate carcinoma despite the fact that it can also induce some forms of neoplasia.

Both effects are thought to be related to its estrogenic actions and very little attention has been focused on the possible effect of DES on the immune response.

Skin is the largest organ of the body and constitutes the first line of defense against xenobiotics. The Skin Immune System (SIS) has become the center of attention of research for the development of new therapeutic approaches for neoplasic diseases. Langerhans cells (LC), as an element of SIS, are “professional” antigen presenting cells resident in the skin that participate in the immune response associated with tolerance and acquired immunity to antigens.

Hence in this work we studied the effect of DES on LC of murine skin as a model to analyze the possible effect of DES on the immune response.

Male CD-1 mice (20 to 35 g body weight) were treated topically (TO) or subcutaneously (SC) with DES (10 and 100 mg/kg, dissolved in ethanol) and sacrificed at 12, 84 and 228 hr. LC were quantified in the ear skin of mice using both an enzymatic histochemical technique to demonstrate ATP-ase activity; and an indirect immunohistochemical assay for detecting class II molecules of the major histocompatibility complex (MHC-II).

DES induced a significant time- and dose- dependent reduction in the number of LC (P < 0.05). Data presented here suggest that estrogens may exert a modulatory action on LC.

References

  • Effects of single administration of diethylstilbestrol on murine langerhans cells, Proceedings of the Western Pharmacology Society, NCBI PubMed, PMID: 16416678, 2005.
  • Featured image maths.ox.ac.uk.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal DES exposure linked to Hashimotos thyroiditis

Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases

2006 Study Abstract

Most autoimmune diseases occur more commonly in females and many of these young women wish to become mothers. For pregnancy to proceed successfully immunomodulation and physiological changes preparing the reproductive system need to occur.

Pregnancy occurring in a chronically ill mother who requires medications in order to maintain her own health and who may have already incurred significant organ pathology gives rise to several problems and so four questions arise:

  1. What will be the effect of the pregnancy on the underlying disease?
  2. What will be the effect of the disease on the outcome of pregnancy?
  3. How to manage the disease, just prior to, throughout and immediately after the pregnancy?
  4. The long term fetal and childhood effects of maternal disease and its management.

This paper reviews the current literature pertaining to these questions in patients with systemic lupus erythematosus (SLE) and other chronic rheumatic and autoimmune diseases.

Diethylstilbestrol

… “Other evidence suggests that the risk of autoimmune disease, particularly Hashimotos thyroiditis, is also increased in individuals exposed to DES in utero.” …

References

  • Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases, Lupus, NCBI PubMed, PMID: 17153855, 2006.
  • Featured image cleveland clinic.
DES DIETHYLSTILBESTROL RESOURCES

How DES exposure leads to reduced fertility in males

Diethylstilbestrol induces morphological changes in the spermatogonia, Sertoli cells and Leydig cells of adult rat

2019 Study Abstract

It is now established that diethylstilbestrol (DES) has damaging effects on the male reproductive system. However, to date there have been no studies morphological analysis of adult rat testes upon treatment with DES.

Here, we examined whether DES has any significant morphological effect on steroidogenesis and spermatogenesis.

DES was injected subcutaneously at 3 μg/day and 30 μg/day in adult male Sprague-Dawley (SD) rats for two different treatment lengths (1 or 3 weeks), after which rats were necropsied. TUNEL labeling, cell counting, and morphological analysis were used to evaluate the effects of DES.

A high dose of DES and longer exposure severely affected the cellular development of the testis. Specifically, DES treatment disrupted both steroidogenesis and spermatogenesis by decreasing the number of spermatogonia, Sertoli cells, and Leydig cells in a dose- and time-dependent manner.

Thus, DES may account for decreases in the number of spermatogenic cells, Sertoli cells and Leydig cells, which in turn may lead to reduced fertility in males.

References

  • Diethylstilbestrol induces morphological changes in the spermatogonia, Sertoli cells and Leydig cells of adult rat, Research in veterinary science, NCBI PubMed, PMID: 31082573, 2019 Apr.
  • Featured image Bart Plantenga.
DES DIETHYLSTILBESTROL RESOURCES

Immunosuppressive effects of DES exposure

Immunotoxic effects of diethylstilbestrol on host resistance: comparison with cyclophosphamide, 1984

Abstract

To evaluate the usefulness of host resistance assays for measurement of immunotoxicologic effects of chemicals, the immunosuppressive effects of exposure to diethylstilbestrol (DES) were compared with the effects of treatment with the known immunosuppressive drug cyclophosphamide (CPS).

A panel of six host resistance models was evaluated, including

  • infection with the bacterium Listeria monocytogenes,
  • herpes simplex virus type 2 (HSV-2),
  • and encephalomyocarditis virus (EMC),
  • the yeast Cryptococcus neoformans,
  • the parasite Naegleria fowleri,
  • and transplantation of the B16F10 melanoma tumor.

The results demonstrate a general correlation between the effects of CPS and DES on host resistance. Acute treatment with CPS (200 mg/kg) markedly depressed resistance to the microbial infections with L. monocytogenes and HSV, and exposure to DES usually also decreased resistance in a dose dependent manner. Moreover, CPS had no marked effect on resistance to N. fowleri and EMC virus, and exposure to DES also had a neglible or slight effect. There were, however, two model systems in which the effects of CPS and DES diverged. Whereas treatment with DES produced no significant effect on resistance to C. neoformans, acute treatment with CPS prior to the fungal infection produced a marked increase in resistance. Also, while treatment with CPS markedly increased B16F10 lung metastases, treatment with DES significantly decreased the incidence and number of lung metastases.

The data support the general validity of host resistance assays, particularly with models of short disease course, for measuring immunosuppression. However, the results also emphasize the complexity of interpreting effects of environmental chemicals on host resistance, because of the interplay of such factors as relative times of exposure to the chemical in relation to pathogenesis of infection, the length of the disease course, the nature of the operative host defense mechanisms, and the compensatory recovery of these mechanisms.

References

  • Immunotoxic effects of diethylstilbestrol on host resistance: comparison with cyclophosphamide, Journal of leukocyte biology, NCBI PubMed, PMID: 6323603, 1984.
  • Featured image vanderbilt edu.
DES DIETHYLSTILBESTROL RESOURCES

DES exposure linked to laterality process disruption

Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship?, 2004

Abstract

Schizophrenia is a psychiatric disease affecting around 1% of the population, the negative signs of which are correlated with inactivity of the prefrontal dorsolateral cortex, while an increased, more deeply localized, activity in the mesolimbic pathway may explain the positive signs. Several events occurring during pregnancy are likely to be involved in its genesis: hormonal supplementation by diethylstilbestrol, severe maternal denutrition, exposure to influenza virus, repeated psychological stress.

From multicentric studies and meta-analyses in the psychiatric literature, the risk of schizophrenia appears to be multiplied by two if pregnancy is complicated, mainly by diabetes, Rhesus incompatibility, bleeding, preeclampsia, premature rupture of membranes and preterm birth. When delivery is linked to an abnormal presentation or happens via a caesarean birth for acute foetal distress, the time when the first signs of psychosis appear seems to be earlier in adolescence or in early adulthood.

Cerebral imaging of schizophrenic patients shows ventriculomegaly and gray matter reduction, mainly in hippocampal volumes and in the dorsolateral prefrontal cortex. Similar alterations in the neuronal pathways have been experimentally reproduced in rats after repeated prenatal stress and perinatal hypoxia. A region on the distal portion of chromosome 1 has shown evidence for linkage to schizophrenia.

Exposure to diethylstilbestrol (DES) in the second trimester of pregnancy is likely to disrupt the laterality process, leading to an outstanding number of left-handed individuals, be they boys or girls. In the same way data from the literature suggest that people exposed to DES have a higher risk of presenting depressive signs. Nevertheless it may not be the only cause, since it is obvious that the gynecological troubles which required hormonal prescription may have affected the course of pregnancy. Katz et al. reported a higher risk of psychosis after the mother took DES about four cases: DES doses varied from 7 to 12.8 g, but two pregnant women out of four also received progestatives (total dose of 1.950 mg of medroxyprogesterone to 3.600 mg of progesterone).

Therefore, a two factor model seems to be able to explain the onset of schizophrenia in which obstetrical complications may interact with a genetic liability and in which the consequences of hypoxic events may lie on a continuum ranging from cerebral palsy in some children to subtle cognitive and behavioural disturbances in others.

References

  • Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship?, European journal of obstetrics, gynecology, and reproductive biology, NCBI PubMed, PMID: 15140504, 2004.
  • Featured image wallpapercave.
DES DIETHYLSTILBESTROL RESOURCES

Gestational exposure to DES linked to maternal antibodies concentrations reduction

Perinatal exposure to low doses of PCB 153 and PCB 126 affects maternal and neonatal immunity in goat kids, 2006 Jan

Abstract

Pregnant does (10 goats/group) were dosed orally either with polychlorinated biphenyl (PCB) 153 (98 microg/kg body weight/d) or PCB 126 (ng/kg body weight/d) dissolved in corn oil or with corn oil only (control group) from gestation day (GD) 60 until delivery.

An additional group (n = 5) of pregnant does received the synthetic estrogen diethylstilbestrol (DES; 0.4 microg/kg body weight/d) by intramuscular injection using the same treatment schedule as for the PCB groups.

Blood samples for immune analysis were collected at wk 0, 1, 2, 4, 6, and 8 of age. The effects of perinatal PCB exposure on postnatal humoral immune responses were examined by assessing the levels of total immunoglobulin G (IgG) and immunoglobulins to specific microbes at wk 0, 1, 2, 4, 6, and 8 of age, and immune responses following immunization of kids at 2 wk of age.

PCB 153 exposure suppressed maternal and neonatal immunity, as demonstrated by reduced transfer of maternal IgG and specific antibodies to the environmental microbes Arcanobacterium pyogenes, Mannheimia haemolytica, and reovirus (REO-1). Furthermore, PCB 153 reduced the level of maternal antibodies to Mycobacterium avium paratuberculosis and equine influenza virus (EIV-1) in the newborn kids. The antibody response against EIV-1 was significantly higher in PCB 153-exposed kids 2 wk following immunization.

PCB 126 exposure reduced the levels of maternal antibodies to REO-1. In contrast, gestational exposure to PCB 126 increased the concentrations of maternal antibodies to tetanus toxoid. No differences from controls in plasma total IgG levels at birth or colostrum IgG concentrations were observed in the PCB 126-treated does. However, a significant reduction in IgG levels from GD 60 until delivery was found in this group.

Gestational exposure to DES reduced the concentrations of maternal antibodies against A. pyogenes, M. haemolytica, M. avium Paratuberculosis, and REO-1.

These results suggest that perinatal exposure to low doses of PCB 126 and PCB 153 affects the maternal immunity in kids. The difference in responses between PCB 126 and PCB 153 treatment groups may strengthen the hypothesis that PCBs mediate immunotoxic effects through both AhR-dependent and -independent mechanisms. The observation that the effects produced by PCB 153 resembled those produced by DES raises the question of whether this congener may modulate immunity by estrogenic mechanisms.

References

  • Perinatal exposure to low doses of PCB 153 and PCB 126 affects maternal and neonatal immunity in goat kids, Journal of toxicology and environmental health, NCBI PubMed, PMID: 16291567, 2006 Jan.
  • Featured image Terrie Schweitzer.
DES DIETHYLSTILBESTROL RESOURCES

Prenatal DES treatment alters two hepatic enzymes

Maternal exposure to low doses of DES altered mRNA expression of hepatic microsomal enzymes in male rat offspring, 2012

Abstract

Our previous studies demonstrated that prenatal diethylstilbestrol (DES) treatment disrupts steroidogenesis but induces high-level expression of androgen receptor (AR) mRNA to inhibit the disruption of spermatogenesis.

This study examined which prenatal DES treatment influenced hepatic microsomal enzymes, CYP3A1, CYP2B1/2, CYP2C11, UGT2B1 (UDP-glucuronosyltransferase 2B1), and IGF-1 (insulin-like growth factor-1), in male rat offspring.

DES treatment decreased the mRNA expression levels of CYP3A1 and CYP2B1/2, but did not alter the expression of CYP2C11.

At 6 weeks, DES treatment increasd the mRNA expression levels of UGT2B1 and IGF-1.

These results suggest that prenatal DES treatment alters two hepatic enzymes (CYP3A1 and CYP2B1/2) and IGF-1 mRNA expression levels to counteract the low level of testosterone, but this disrupted UGT2B1 mRNA expression reduces the testosterone level.

References

  • Maternal exposure to low doses of DES altered mRNA expression of hepatic microsomal enzymes in male rat offspring, The Journal of veterinary medical science, NCBI PubMed, PMID: 21959891, 2012 Feb.
  • Featured image hyperbiotics.
DES DIETHYLSTILBESTROL RESOURCES

DES exposure causes decreased testis weight and morphological demasculinization of males

Short-term study investigating the estrogenic potency of diethylstilbesterol in the fathead minnow (Pimephales promelas)

2012 Study Abstract

Diethylstilbestrol (DES) is a synthetic estrogen that has been “banned” for use in humans, but still is employed in livestock and aquaculture operations in some parts of the world.

Detectable concentrations of DES in effluent and surface waters have been reported to range from slightly below 1 to greater than 10 ng/L. Little is known, however, concerning the toxicological potency of DES in fish.

In this study, sexually mature fathead minnows (Pimephales promelas) of both sexes were exposed to 1, 10, or 100 ng of DES/L of water in a flow-through system. Tissue concentrations of DES and changes in a number of estrogen-responsive end points were measured in the fish at the end of a 4 d exposure and after a 4 d depuration/recovery period in clean water. Accumulation of DES was sex-dependent, with females exhibiting higher tissue residues than males after the 4 d exposure. The observed bioconcentration of DES in the fish was about 1 order of magnitude lower than that predicted on the basis of the octanol-water partition coefficient of the chemical, suggesting relatively efficient metabolic clearance by the fish. Exposure to 1, 10, or 100 ng of DES/L caused decreased testis weight and morphological demasculinization of males (regression of dorsal nuptial tubercles). Diethylstilbesterol induced plasma vitellogenin (VTG) in both sexes at water concentrations ≥10 ng/L; this response (especially in males) persisted through the end of the 4 d recovery period. Hepatic transcripts of VTG and estrogen receptor-α also were affected at DES concentrations ≥10 ng/L. Evaluation of transcript profiles in the liver of females using a 15K-gene fathead minnow microarray revealed a concentration-dependent change in gene expression, with mostly up-regulated transcripts after the exposure and substantial numbers of down-regulated gene products after depuration. Genes previously identified as vitellogenesis-related and regulated by 17β-estradiol were significantly enriched among those differentially expressed following exposure to DES.

Overall, our studies show that DES causes a range of responses in fish at water concentrations comparable to those reported in the environment and that in vivo potency of the estrogen is on par with that of the better-studied estrogenic contaminant 17α-ethinylestradiol.

References

  • Short-term study investigating the estrogenic potency of diethylstilbesterol in the fathead minnow (Pimephales promelas), Environmental science & technology, NCBI PubMed, PMID: 22708615, 2012 Jul.
  • Featured image situbiosciences.
DES DIETHYLSTILBESTROL RESOURCES

Neonatal DES exposure alters adult hepatic physiology

Hepatotoxicity induced by neonatal exposure to diethylstilbestrol is maintained throughout adulthood via the nuclear receptor SHP, 2014

Abstract

Background
Liver physiology is sensitive to estrogens, which suggests that the liver might be a target of estrogenic endocrine disrupters (EED). However, the long-term consequences of neonatal exposure to EED on liver physiology have rarely been studied. The nuclear receptor small heterodimer partner (SHP) mediates the deleterious effects of neonatal exposure to diethylstilbestrol (DES) on male fertility.

Objectives
As SHP is involved in liver homeostasis, we aimed to determine whether neonatal estrogenic exposure also affected adult liver physiology through SHP. Male mouse pups were exposed to DES in the first 5 days of life.

Results
DES exposure leads to alterations in the postnatal bile acid (BA) synthesis pathway. Neonatal DES-exposure affected adult liver BA metabolism and subsequently triglyceride (TG) homeostasis. The wild-type males neonatally exposed to DES exhibited increased liver weight and altered liver histology in the adult age. The use of deficient male mice revealed that SHP mediates the deleterious effects of DES treatment. These long-term effects of DES were associated with differently timed alterations in the expression of epigenetic factors.

Conclusions
However, the molecular mechanisms by which neonatal exposure persist to affect the adult liver physiology remain to be defined. In conclusion, we demonstrate that neonatal DES exposure alters adult hepatic physiology in an SHP-dependent manner.

Reference

  • Hepatotoxicity induced by neonatal exposure to diethylstilbestrol is maintained throughout adulthood via the nuclear receptor SHP, Expert opinion on therapeutic targets, NCBI PubMed, PMID: 6628266, 2014.
  • Featured image hepmag.
DES DIETHYLSTILBESTROL RESOURCES