Endocrine disruptors

The endocrine system, one of the three major communication systems of the organisms.

Chemical communication is the basis of all information exchange within organisms, organism-organism interactions and organism-environment interactions.

Relatively early in evolution, three main communication systems have been developed in animals: the nervous system, the immune system and the endocrine system. The endocrine system is composed of organs involved in the synthesis and secretion of hormones (endocrine glands). Hormones are chemical messengers carried by the blood to the cells on which they act. Hormone-sensitive cells and organs are usually referred as target cells or organs. The functions that are regulated by the endocrine system are as varied as primordial: development, osmotic regulation, metabolism, reproduction, behavior ...

What is an endocrine disruptor?

An endocrine disruptor (ED) is an exogenous substance or mixture that alters the functions of the endocrine system and thus induces undesirable effects on the health of an organism, its descendants or (sub) populations "(OMS, 2002, 2012). EDs can interfere with the endogenous endocrine system function through three mechanisms:
  • the synthesis, transport, metabolism and excretion of the hormone, thereby impairing its concentration
  • by antagonism of the hormone binding to its receptor in the target cells
  • by mimicking the action of the endogenous hormone, thus inducing effects similar to those of the endogenous hormone, but in a deregulated manner

Nature of endocrine disruptors

EDs can be natural compounds secreted by animals or plants (phyto-oestrogens) or synthetic hormones (contraceptives, hormone of substitution). However, in the vast majority of cases they are chemical compounds released into the environment by human activities. These compounds, when they are persistent, can be transported over very great distances so that these days all the continents including the poles are contaminated. EDs can be classified according to their use by humans or their structural properties. We find :
  • pesticides (DDT, lindane, atrazine ...)
  • dioxins (TCDD)
  • plasticisers (bisphenol A, phthalates, etc.)
  • detergents (alkylphenols and their derivatives)
  • care products (triclosan)
  • flame retardants and insulators (polychlorobiphenyls and polybromorobiphenyls)

Questionning of Paracelse principle and linearity

Paracelse, a Swiss physician of the sixteenth century, and commonly considered as a founding father of toxicology, is particularly associated with the famous maxim “all things are poison, and nothing is without poison; only the dose determines what is not a poison.”

Thus, for several centuries, it was considered that the response of an organism to a chemical compound was described by a more or less linear monotonic numerical function. A monotonic function is an invariable numerical function as for its direction of variation, in other words a function that always remains either increasing or decreasing. Even today in toxicology and ecotoxicology, the safety of a chemical is usually fixed at the dose at which the effects observed at higher doses are no longer found. At this no observed effect level (NOEL), safety factors are applied taking into account the differences observed when extrapolating data from experimental studies, most often conducted in animals compared to a real exposure situation in humans (Figure 1A).

In fact, in addition to the usual monotonic dose-response curves, EDs occasionally describe non-monotonic dose-response curves that are generally U-shaped (with the maximum responses of the measured effect observed at low doses and at high doses) or inverted U-shape (with maximal responses observed at intermediate doses). In toxicology this mechanism is called hormesis.

Therefore, the extrapolation of low-level contaminant effects from threshold values obtained with high concentrations is difficult to apply in the case of endocrine disruptors as they are part of a paradigm different from that of Paracelse (Figure 1B).
Schéma - Une remise en cause du principe de Paracelse et de linéarité
Figure 1: The dose-response curve in toxicology. A. Case of a nonlinear monotonic dose-response curve. High doses are tested to obtain the maximum tolerated dose, and the no observed effect level (NOEL). Several safety factors are then applied to calculate the reference dose, i.e. the dose at which exposures are presumed to be safe. B. Case of a non-monotonic dose-response curve. When chemical contaminants or hormones are involved in hormesis phenomena, undesirable effects can be observed at or below the reference dose.

Endocrine disruptors and metabolic disruption

Although EDs can target the entire hormonal systems, a very large number of observations have revealed disruptions in development and sexual differentiation as well as in embryonic development and puberty. These observations have directed the majority of research on EDs toward interference with sexual steroid hormones.

The current prevalence of metabolic syndromes, type-2 diabetes and obesity is unprecedented. In 2014, on a worldwide scale, 422 million of adults had type-2 diabetes as compared to 108 million in 1980. In 2012, it was estimated that 1.5 million deaths were directly due to diabetes and 2.2 million more deaths were due to hyperglycemia.
In 2030, current estimations suggest that diabetes will be the 7th leading cause of death in the world. So far, the reasons for the rapid rise in cases of diabetes and obesity remain unclear. Excessive calorie intake and sedentary lifestyle are undoubtedly key factors. However, an increase in the average weight of laboratory animals has also been noted in recent decades, with no change in dietary habits or physical activity, suggesting that other factors may be involved. It is clear that the increase in the prevalence of metabolic diseases is concomitant with an increase in the exposure of populations to pollutants such as endocrine disruptors.
This hypothesis is now supported by epidemiological data showing that several metabolic pathologies can be directly attributed to exposures to very low doses of EDs, independently of a poor diet or low physical activity.

Endocrine disruptors, transgenerational and epigenetic effects

The actions of an ED producing an altered phenotype or diseases can be caused by direct exposure of somatic cells. On the other hand, if germ cells (oocytes, sperm cell) are affected, a transgenerational phenomenon can occur. In the majority of cases, exposure of pregnant women to EDs can lead to exposure of multiple generations (themselves, their direct descendants and grandchildren that are so far in the form of sexual cells forming in the foetus). This is then called a multigenerational effect.

A classic example of a multigenerational effect of EDs has been demonstrated with the pharmaceutical agent diethylstilbestrol (DES) which has an estrogen-mimetic effect. Prescribed from 1940 to 1970 to pregnant women undergoing spontaneous abortions, DES led to abnormalities of the genital tract and gonad dysfunction in their sons and daughters and abnormalities of the genital tract in their grand-child girls.

A transgenerational effect involves the transmission of sexual cell damage over generations. These transgenerational effects then appear without any direct exposure of individuals. One of the pilot studies that showed a transgenerational epigenetic effect concerns the effect of vinclosine (fungicide) on male germ cells. Exposure of pregnant rats to vinclosine then had effects on male reproductive function up to the next 4 generations.

Highlighting and understanding the multi- or transgenerational metabolic effects of EDs and the implication of epigenetic modifications in associated pathologies is today a challenge that the Symer project aims to address