The role of environmental estrogens and autoimmunity

doi:10.1016/j.autrev.2011.11.027

Autoimmunity Reviews

Volume 11, Issues 6–7, May 2012, Pages A493-A501

https://doi.org/10.1016/j.autrev.2011.11.027 Get rights and content

Abstract

The prevalence of autoimmune diseases has significantly increased over the recent years. It has been proposed that this epidemiological evidence could be in part attributable to environmental estrogens, compounds that display estrogen-like activity and are ubiquitously present in the environment.

Environmental estrogens can be found in a wide variety of foods: phytoestrogens occur in plants such as clover and soy, while mycoestrogens are food contaminants produced by fungi. Meat, eggs and dairy products from animals given exogenous hormones contain relatively high concentration of estrogens. Among xenoestrogens, industrial estrogens are synthetic chemicals produced for specific purposes (pesticides, plastics, surfactants and detergents) while metalloestrogens are found in heavy metals. Estrogens can be also administered through medications (contraceptive pill, hormone replacement therapy, genistein, cimetidine, creams).

There is a considerable burden of evidence in vitro and in animal models that these compounds may exert immunotoxic effects. However, to date there is no convincing data that exposure to environmental estrogens can be regarded as a risk for human health. In particular, there is no consensus whether prolonged exposure to relatively low concentrations of different estrogenic chemicals can affect the human immune system and induce clinically evident diseases in real-life scenario. Moreover, the effects on human health of the synergistic interactions between natural, medical, dietary and environmental estrogens have not been fully elucidated yet. Here we provide an extensive review of the in vivo and in vitro effects of environmental estrogens on the immune system, focusing on the evidences of association between exposure and autoimmune disorders.

Highlights

► Environmental estrogens are ubiquitously present in the environment. ► Environmental estrogens affect the immune system in several models. ► Whether or not environmental estrogens are health hazard is still a matter of research.

Introduction

Sex hormones display profound effects not only on the reproductive system but also on other cell types. In particular, they may affect the immune system by modulating cytokine production, their receptor expression and ultimately regulating the responses of different effector cells [1], [2].

Such an effect can be displayed on physiological immune responses against not only exogenous antigens but also self-components. This represents the rationale for the interference of sex hormones on autoimmunity and on its clinical manifestations [1], [2]. Autoimmune diseases are, in fact, a prototypical class of illness that displays high female-to-male (F/M) ratios. Although the reason of the F/M ratios in autoimmune diseases is still a matter of research, there is evidence for the influence of estrogenic hormones. Moreover, sex hormones, and in particular estrogens, may contribute to disease activity and to comorbidities influencing also the clinical management of the disease.

In addition to the endogenous source of estrogen (17β-estradiol, E2), the immune system can be targeted by different chemical molecules present in the environment and displaying an estrogen-like activity, the so called environmental estrogens [3].

The real impact of both endogenous and environmental estrogens on the immune system is still under investigation. The estrogens from exogenous sources may display a synergic/additive effect with that of endogenous molecules and theoretical may display sensitive effects on the immune responses. Because of the predominance of females in autoimmune diseases, it should also be taken into consideration the role of estrogens of therapeutic sources, i.e., oral contraceptives and hormone replacement therapy.

We will address the potential role of estrogens from exogenous sources and in particular from the environment after a schematic introduction of the potential effects of these hormonal molecules on the immune system.

Section snippets

Role of estrogens in the immune responses

There is evidence that estrogens may affect several effector cells of the immune system. Specific receptors for estrogens (ER) have been found on the immune cells, supporting a direct effect. Two kinds of estrogen receptors (ERs) have been identified in human beings, called ER-α and ER-β. The same estrogen can produce different effects depending on which receptor it binds and the ultimate effect of the hormones is closely related to the receptor subtype present on a given cell type. For

Role of estrogens in autoimmunity

The key role of estrogens in autoimmunity is illuminated by the example of systemic lupus erythematosus (SLE) [4], [5].

There are several indirect facts supporting a role for sex hormones in SLE pathogenesis. For example, the incidence of SLE increases after puberty and diminishes after menopause. The severity of the disease itself varies with physiological modifications of the estrogen levels such as during the menstrual cycle and with pregnancy. Both male and female patients with SLE display

Environmental estrogens

Environmental estrogens are ubiquitously present, being found in food, soil, air, water and household products. Therefore, environmental exposure to estrogenic chemicals can occur via oral, aerosol, dermal and subdermal routes. Many of these compounds can accumulate in adipose tissues, being released from body fat during starvation. They could also be passed on to the progeny during pregnancy and lactation.

Environmental estrogens can be of natural origin, being isolated from plants

Conclusions

Epidemiological evidence from Western countries indicates that the prevalence of autoimmune diseases is strongly increasing, being not merely attributable to improved diagnostics alone. Some authors have therefore postulated that this could be, at least, partially attributable to new or modified patterns of exposure to chemicals, including environmental estrogens.

However, despite the immunotoxic effects generated under experimental conditions, there is no convincing evidence that exposure to

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ReviewThe role of environmental estrogens and autoimmunity

Abstract

Highlights

Introduction

Section snippets

Role of estrogens in the immune responses

Role of estrogens in autoimmunity

Environmental estrogens

Conclusions

Toxicology

Immunol Lett

Sci Total Environ

Toxicology

Eur J Cancer

Fertili Ster

Toxicol Appl Pharmacol

Toxicol Appl Pharmacol

Front Neuroendocrinol

J Nutrition

Toxicol In Vitro

Toxicol Lett

J Endod

Toxicol Appl Pharmacol

Fundam Appl Toxicol

Toxicol Appl Pharmacol

Environ Res

Chemosphere

Clin Immunol Immunopathol

Int Immunopharmacol

Environ Res

Chemosphere

Reprod Toxicol

J Biol Chem

J Biol Chem

Mol Cell Endocrinol

Toxicology

Metabolism: Clin and Exp

Toxicol Lett

Toxicol Appl Pharmacol

Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment

Arthritis Res Ther

The complex role of estrogens in inflammation

Endocr Rev

The multi-faceted influences of estrogen on lymphocytes: toward novel immuno-interventions strategies for autoimmunity management

Clinic Rev All Immunol

The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants

Environ Health Perspect

Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women

N Engl J Med

Diethylstilboestrol. II: pharmacology, toxicology and carcinogenicity in experimental animals

Eur J Cancer

Washington

Long-term effects of exposure to diethylstilbestrol

West J Med

Gender and autoimmune diseases: possible role of estrogenic compounds

Environ Health Perspect

Effects of pesticide exposure on the human immune system

Human & Exp Toxicol

Enhancement of immune function in mice fed high doses of soy daidzein

Nutr Cancer

Mediators Inflamm

Suppression of dendritic cells' maturation and functions by daidzein, a phytoestrogen

Toxicol Appl Pharmacol

Effect of the mycotoxin zearalenone on the metabolism of membrane phospholipids of rat lymphocytes

Ukr Biokhim Zh

Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells

J Toxicol Environ Health

Possible health impact of animal oestrogens in food

Hum Reprod Update

Critical evaluation of key evidence on the human health hazards of exposure to bisphenol A

Crit Rev Toxicol

Molecular analysis of the inhibition of monocyte chemoattractant protein-1 gene expression by estrogens and xenoestrogens in MCF-7 cells

Endocrinology

Review
The role of environmental estrogens and autoimmunity