**Acknowledgements**

Mr. René Alexandre, Dr. Henri Pézerat, Pfr. Jean Caston, Mr. Michel Datry, and Dr. Charles Zelwer worked tirelessly to demonstrate the harmful role of the endocrine disruptors and in particular of synthetic hormones; before passing away: we shall never forget their efficient help. This work could not continue without the daily ongoing support of the HHORAGES board especially Mrs. Geneviève A., Mauricette P., Yette B., Annie R., Aimée I., Sylvette C., Denise H., Marie-Noelle P., and Pierre D. We acknowledge Mr. André Cicolella, president of the French Environment-Health network (RES), for his constant support. We are very grateful to Pfr. Michael Dolan, professor at the University of Massachusetts, Amherst (USA), for his help and critical reading during the preparation of the manuscript.

#### **Notes**

*Psychopathology - An International and Interdisciplinary Perspective*

exposure of the children suffering from these illnesses [29, 30].

be taken with regard to the use of these progestins during pregnancy and even outside these periods (contraception or hormone replacement therapy).

The brain is a very vulnerable organ because its development covers a very broad period extending from the early prenatal stage (third week of pregnancy) to end around the age of 20. During its development, there are times when its vulnerability is even greater than others; these periods are called "shooting windows," during which the environment can impact the normal process of development. Abdolmaleky et al. [41] as early as 2005 had developed the hypothesis that geneenvironment modulations could be performed via DNA methylations. Krebs' team put forward the hypothesis that DES-induced changes in epigenetic background and alteration of DNA functioning (methylations) could be significant factors to demonstrate a possible origin of psychotic disorders and a link with in utero DES

Numerous studies have shown that, for example, in the rat, early maternal separation or the fact of causing significant stress to the mother changes the methylation signals of certain genes of the rat directly related to the regulation of anxiety. It has also been discovered that the proper environment for changing the methylation signals may be chemical. This is the case of DES recognized by the scientific community as an endocrine disruptor and banned for pregnant women. This change in the level of methylation caused in utero by DES has been demonstrated for urogenital malformations of girls and boys as well as for cancers. On 2015, Harlid et al. published in a pioneer work the first study for evaluation of possible effects of in utero DES exposure on genome-wide DNA methylation in humans [42]. They studied whole blood DNA methylation in 100 40–59-year-old women reporting in utero exposure, compared to 100 unexposed women. They did not find any differential methylation, but the DMR approach was not used in their recent work (2015). On the other hand, in 2017 Rivollier et al. [30] described specific differential methylated regions (DMR) on two genes implicated in neurodevelopment (ZFP57 and ADAMTS9). Surprisingly, they cautiously claim that these DMR are "supposedly" associated with prenatal exposure to DES in young psychotic patients in utero exposed to DES/ EE. Nevertheless, these modifications of methylation are really specific because they do not exist in the methylome of young psychotic patients not exposed to DES [28] in which global methylation of the genome was observed. Moreover authors have compared exposed subjects to their unexposed siblings which do not present these specific methylations although they shared environmental and genetic factors.

The citizen work carried out between the French HHORAGES Patient Association

and two major medical research laboratories has provided convincing scientific results: (1) on the detection and confirmation of the existence of psychiatric disorders (accompanied or not of somatic disorders) in children exposed in utero to synthetic hormones and (2) on the mechanisms of action of these synthetic hormones administered to pregnant mothers on the brain of their offspring. The effects of these endocrine disruptors in humans through what is becoming a public health scandal, denied for a long time by doctors, especially psychiatrists, scientists, and specialized journalists, are thus better known. The fact that these synthetic products do not degrade in the human body in the same way as the natural hormones [13] and act on the functioning of genes implicated in neurodevelopment during the fetal life, following an epigenetic mechanism, is a real time bomb. Indeed, this mechanism induces a transgenerational effect already partially demonstrated in the HHORAGES cohort at the third-generation level for hypospadias, a specific genital malformation. So far, only a few third-generation children suffering psychiatric illness are documented in the HHORAGES testimonies. This is understandable because third-generation exposed children are still too young (excepted in some cases) to present psychiatric disorders as schizophrenia which is not the case for hypospadias that are detectable

**16**

Association HHORAGES-France is registered on the Epidemiological Portal of French Health Databases INSERM (French National Institute for Medical Research) and AVIESAN (National Alliance for Life Sciences and Health) (epidemiologiefrance.aviesan.fr).

### **Disclaimer**

The authors declare they have no competitive financial interests; the finances of HHORAGES-France association come exclusively from the donations of families and of sympathetic individuals.

#### **Author Biography**

*Marie-Odile Soyer-Gobillard:* National Center for Scientific Research (CNRS), Sorbonne University, P. and M. Curie University, Paris 6, and HHORAGES Association (Halt to Artificial Hormones for Pregnancies), The Priory of Baillon, F-95270 Asnieres sur Oise, France. Email: elido66@orange.fr. Doctor of Science (Cell Biology), Honorary Emeritus Research Director at CNRS, laureate of several scientific awards, and author of more than 150 publications in peer-reviewed scientific journals. Former Director of the Department of Cellular and Molecular Biology (UMR 796 "Models in Cell and Evolutive Biology") at the Arago Laboratory (Paris 6 University) and expert at the National Agency for Research (ANR). National president of HHORAGES, France (Stop to Artificial Hormones for Pregnancy) and president of its Scientific Council. Member of the Clinical Projects Reviewers Committee, INSERM, Paris.

*Charles Sultan:* Unité d'endocrinologie et gynécologie pédiatrique, Hôpital Arnaud-de-Villeneuve, CHU de Montpellier, 34295 Montpellier Cedex 5, France. Email: c-sultan@chu-montpellier.fr

*Laura Gaspari:* Unité d'endocrinologie et gynécologie pédiatrique, Hôpital Arnaud-de-Villeneuve, CHU de Montpellier, 34295 Montpellier Cedex 5, France. Email: dr.lauragaspari@gmail.com
