**2. Behavioral disorders demonstrated in animals (rats) exposed in utero**

Animal studies (on mice and rats) have demonstrated the toxicity of these synthetic estrogens on the offspring, including the cause of behavioral disorders [3–8]. Palanza et al. [3] demonstrated in particular that prenatal exposure to three different synthetic chemicals, DES and two pesticides, DDT and methoxychlor, and its analog, affects the behavior of young suckling mice, showing increased aggression in males (increased numbers of attacks and decreased reaction time before the attack) (**Figure 1**). Doses of DES were 1000 times less than those of DDT and caused much larger aggression responses, demonstrating the considerable effect of DES at very low doses. The treatment period for rodent mothers from day 11 to day 17 of pregnancy was also critical because it represents a key period in the differentiation of the reproductive system and brain development in these rodents in the early stages of pregnancy.

Moreover, injection of 17-alpha-estradiol (EE) in pregnant rats causes not only many abortions in mothers but also anxiety and depression disorders in offspring [4, 5], the synthetic hormone having been administered at the same relative doses as in humans (15 g/kg, 1 per day, versus 19 g/kg, 1 per day). At the cytological level of the brain, an alteration of the anterior part of the hippocampus in young rats exposed to EE in utero has been demonstrated in 2004 [6]. The hippocampus is indeed a part of the brain that contains many estrogen receptors during the prenatal period. Ogiue-Ikeda et al. [7] showed in 2008 that synaptic plasticity can

#### **Figure 1.**

*Psychopathology - An International and Interdisciplinary Perspective*

schizophrenia and severe depression associated with suicide attempts. He observed also the relationship with the fact that in all three cases, his wife received medical treatment consisting of a synthetic hormone cocktail: diethylstilbestrol (DES), ethinyl estradiol (EE), plus synthetic progestin delay during her three pregnancies after a previous miscarriage. He conducted research in the world literature on the subject and came to the conclusion that not only was one of these products, diethylstilbestrol (DES), already known for its misdeeds but that it continued to be administered in France until 1977/1982. The product, inexpensive to make, was not patented and was manufactured and distributed by many pharmaceutical laboratories. The same goes for EE, which was banned for pregnant women in 1980 but remains the best-selling estrogen in the world because it is part of the contra-

In 1998, one of us (MOS-G), concerned by the same kind of problems in her two children who were exposed in utero to the same cocktail of synthetic estrogens, lost her two children after psychiatric illnesses. Following the reading of a "Call to Families" printed in a newspaper, she met Mr. RA, who had gathered around him about 20 French families concerned with their in utero-exposed children suffering from psychiatric illnesses. He wanted to expose his observations and the results of his bibliographic researches at a meeting of patient families collecting observations on the genital malformations of girls exposed in utero to DES. Alas, he was condemned, rejected, and disclaimed by doctors, mostly gynecologists and psychiatrists as well as by associative members. They denied the existence of psychiatric disorders in exposed boys and girls. Discouraged, Mr. RA died shortly afterward. In order to continue his work and regroup the families concerned by the origin of the heavy psychiatric pathologies of their children and despite the taboo surrounding such diseases as psychoses, we gathered several mothers concerned and created the Association of Patients Halt to Artificial Hormones for Pregnancies (HHORAGES), in 2002. This Association which collected more than 1300 French spontaneous testimonies is now registered with the Epidemiology Portal of French National Institute for Medical Research

Despite various alerts published in the 1940s, after work on animals proving in particular its carcinogenic effect, and despite the work of Dieckman et al. [1], initiated as early as 1953, demonstrating in a large cohort of pregnant women given diethylstilbetrol (DES), a synthetic estrogen, *versus placebo* that the drug was inefficient in preventing miscarriages or premature births, this product has been widely distributed around the world, sowing a long list of misdeeds. After the discovery of cervicovaginal cancers called "clear cells adenoma (CCAD)" [2] in the "DES girls," DES was banned in the United States for pregnant women in 1971 but only in 1977 in France, where this recommendation disappeared from the "French Vidal book," but DES continued to be prescribed sporadically until 1982. Meanwhile another synthetic estrogen, steroidal, also synthesized on 1938, 17-alpha-ethinyl estradiol (EE), was often added to DES as a cocktail or later as a replacement, sometimes with the addition of synthetic-delay progestin. The idea that prevailed at the time was that women had a hormonal deficit that triggered a miscarriage, whereas now we know that the miscarriage itself causes this deficiency. These products were prescribed not only to women who had miscarriages but also in comfort ("to have beautiful babies," according to an advertising) or even as a "morning after pill" or to cut milk after childbirth. DES and 17-alpha-EE, although belonging to different estrogenic and degrading categories, are, however, bound to the same ER beta-

**8**

estrogen receptors.

ceptive pill.

(INSERM) as a French Health Database.

*Measurement of aggressiveness in young male mice after prenatal exposure to diethylstilbestrol (DES) (0.02 and 0.2 μg/kg) [in gray], DDT [20 and 200 μg/kg] [in black], with a control without DES [in white]. There is an increase in the number of attacks and a decrease of the reaction time before the attack although the doses of DES are 1000 times less than those of DDT. According to Palanza et al. [3], with the permission of Elsevier (License No: 2514671323242).*

be upset by estrogens or other endocrine disruptors (EDs). Later and unequivocally, Newbold demonstrated the validity of the rodent model transposed to humans [8].
