Prenatal immunotoxicant exposure and postnatal autoimmune disease
Diethylstilbestrol : A Model Estrogen
The regulatory actions of estrogenic steroids on immune function in adult animals are well documented but remain poorly understood.
A role for endogenous estrogen and the development of autoimmune disease exists, as well as a correlation between increased serum estradiol levels (e.g., during pregnancy) and infections resulting from depression of cellmediated immunity.
Administration of pharmacologic or suprapharmacologic levels of steroidal and nonsteroidal estrogenic compounds further results in numerous alterations of immune function, particularly when administered perinatally during lymphoid organ organogenesis.
Effects of such administration in rodents include myelotoxicity, suppression of cell-mediated immunity, pronounced thymic atrophy, depressed activity of natural killer cells, and stimulation of the reticuloendothelial system. Studies of women exposed in utero to DES, a synthetic nonsteroidal compound possessing estrogenic activity, suggest possible adverse affects on the postnatal human immune system. For instance, altered function of T lymphocytes and natural killer cells in women exposed to DES in utero has been reported as well as an increased incidence of autoimmune diseases. Although it appears that estrogens mediate certain of their immune effects at the thymic level by altering thymic epithelium-dependent mechanisms, little is understood about mechanisms by which estrogenic chemicals may influence immune responses to foreign or self-antigens.
An altered prenatal hormonal environment has been associated with increased risk of developing autoimmune disease in mice. It has also been suggested that humans exposed in utero to DES may display a hyperreactive immune response. A retrospective study of DES-exposed (1,711 individuals) and unexposed (922 individuals) cohorts examined the possibility that prenatal DES may affect the prevalence of autoimmune disease and found a positive correlation when autoimmune diseases were grouped. Specifically, the overall frequency of any autoimmune disease among exposed women was 28.6 per 1,000 compared to 16.3 per 1,000 among the controls (significandy different at p = 0.02). Autoimmune diseases evaluated included systemic lupus erythematosus, scleroderma, Graves disease, Hashimoto thyroiditis, pernicious anemia, myasthenia gravis, thrombocytopenic purpura, rheumatoid arthritis, regional enteritis, chronic ulcerative colitis, multiple sclerosis, chronic lymphocytic thyroiditis, Reiter syndrome, and optic neuritis. When these autoimmune diseases were considered individually, however, only Hashimoto thyroiditis occurred significandy more often in the exposed women (p = 0.04). A similar evaluation of 1,173 humans exposed to DES during development (1,079 daughters and 94 sons) found increased asthma, arthritis, and diabetes mellitus compared to prevalence rates for these diseases in the general population. However, in a
more recent study evaluating rates of allergy, infection, and autoimmune disease in DESexposed sons and daughters (253 men and 296 women) matched with similar unexposed individuals (241 men and 246 women), no differences in disease occurrence were detected. These authors conduded that a larger sample was needed to evaluate DES-associated risk of autoimmunity, since autoimmune diseases are relatively rare in the human population.
Thus preliminary studies of humans exposed before birth to DES suggest the possibility of postnatal immune alterations, including increased autoimmune disease. Continued surveillance of DES sons and daughters will be required for more definitive statements but will become more difficult as this cohort ages and members are lost. Laboratory rodent studies will therefore be important to determine if prenatal exposure to chemicals such as DES may alter development of immune cells in such a way as to predispose an individual to expression of postnatal autoimmunity and to answer questions regarding specific immune cell targets and mechanisms of action.
Hybrid B6C3F1 (C57B1/6N x C3H) mice exposed to 8 pg/kg/day DES from days 10-16 of gestation displayed significant thymic hypocellularity in late gestation as well as limited but significant inhibition of thymocyte maturation. Thymic involution in these studies was related to a reduction by DES of fetal liver prothymocytes responsible for colonizing the fetal thymus. These authors also reported that fetal liver prothymocytes expressed estrogen receptors at about 290 fmol/100 pg DNA, a level approximately half that found in the uterus and sufficient to suggest an estrogenresponsive cell. These and other reports indicate the developing mouse immune system is sensitive to estrogen exposure, and that such exposure may contribute to postnatal immunosuppression. However, as with most of the well-established rodent developmental immunotoxicants, very limited information is available addressing possible relationships between gestational DES exposure and altered expression of postnatal autoimmune disease.
A single fetal exposure to DES in SNF1 mice induced autoimmune lupuslike nephritis in male offspring between 5 and 10 months of age. Female SNF1 mice develop this autoimmune syndrome spontaneously in their first year of life; however, male mice do not display significant autoimmunity before 1 year of age. These data suggest that pharmacologic exposure to DES may contribute to early expression of autoimmunity in genetically predisposed mice, and that autoimmune rodent models such as the SNF1 model may prove valuable for identification of biologic markers for human risk assessment. Because autoimmune diseases are multifactorial (genetic, environmental, hormonal, infectious), clearly, continued
research will be required to determine possible relationships between prenatal estrogen exposure and postnatal development of autoimmune disease.
Sources and more information
- Full text (free access) : Prenatal Immunotoxicant Exposure and Postnatal Autoimmune Disease, Environmental health perspectives, NCBI PubMed PMC1566248, 1999 Oct.
- Autoimmune Disease featured image credit nailsmag.
DES DIETHYLSTILBESTROL RESOURCES
- Source DES and autoimmune disease, immune-related diseases studies.
- Diethylstilbestrol DES studies by topics.