Developmental effects of endocrine-disrupting chemicals in human

Transgenerational exposure can result from DES exposure

1993 Study Abstrat

Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.

The DES Syndrome: A Model for Exposure to Estrogenic Chemicals in the Environment

Diethylstilbestrol (DES) is a synthetic estrogen that was used by physicians to prevent spontaneous abortions in women from 1948 until 1971, when its use for this purpose was banned. DES-exposed humans thus serve as a model for exposure during early life to any estrogenic chemical, induding pollutants in the environment that are estrogen agonists. The primary model for determining estrogenic activity of a chemical is the stimulation of mitotic activity in the tissues of the female genital tract in early ontogeny, during puberty, and in the adult, although estrogen also affects other tissues in females and males. Daughters whose mothers took DES (about 1 million or more between 1960 and 1970) suffer reproductive organ dysfunction, abnormal pregnancies, a reduction in fertility, immune system disorders, and periods of depression. As young adults these women also suffer increased rates of vaginal clear-cell adenocarcinomas ; this is a reproductive tract cancer found in women beginning in their fifties, but it is rare in women in their twenties. A major concern is that when women exposed in utero to estrogenic chemicals (DES and/or environmental pollutants that are estrogen agonists) reach the age at which the incidence of reproductive organ cancers normally increases, they will show a much higher incidence of cancer than unexposed individuals.

There is a substantial literature documenting the detrimental effects of exposure to DES during the critical period of organ differentiation in experimental studies using rodents. Animal models corroborate clinical studies in humans. For example, dysplastic changes in the rodent prostate are comparable to those seen in stillborn male offspring of women treated with DES. In female mice, DES exposure during early life leads to permanent cornification of the vaginal epithelium, which may be independent of effects on the brain-pituitary-ovarian axis. Significant impairment of immune function (particularly the T-cell system) has also been reported after exposure to DES during early life (as well as an increase in autoimmune diseases in women. These outcomes were typically not noticeable at birth and often not detected before maturity. For example, treatment of male rats with DES during the first month after birth [accessory reproductive organs are still developing] did not result in observable malignancies at 6-9 months of age, but by 20 months (old age), squamous cell cancer was detected with involvement of the dorsolateral prostate. In female mice treated during early life with DES, an increase in sensitivity of mammary glands to carcinogens has been reported.

A variety of agricultural and industrial chemicals produced today (either within or outside the United States) are capable of binding to intracellular estrogen receptors either directly, such as o,p’-DDT, or after in situ conversion to an active metabolite. For example, the pesticide methoxychlor is demethylated in situ to a more estrogenic bisphenolic compound. Pesticides such as o,p’-DDT, chlordecone, and components of plastics, such as nonylphenol, mimic the action of endogenous estrogens (and exogenous DES) both in laboratory animal models as well as in estrogen-sensitive cells in culture. A number of conditions in wildlife (reviewed earlier) parallel those reported in laboratory animals and humans exposed to DES during development.

It is worth noting that the estrogenicity of chlordecone was first detected in people working at a pesticide-producing plant, and although many effects of estrogenic chemicals may be primarily due to exposure during in utero development, chronic exposure throughout adulthood is also a concern. For example, in studies with male dogs, which show prostatic hyperplasia during aging, the disease only developed in castrated males treated with both androgen and estrogen, not androgen alone. Exposure of adult men to estrogen has been implicated in the etiology of prostate hyperplasia. Both prostate cancer and benign prostatic hyperplasia in men and cancers of estrogen-responsive tissues in women (vaginal, cervical, endometrial, and breast) represent major medical problems faced by older people.

It is now suspected that increases in the incidence of numerous pathologies in men and women may be related to exposure to pesticides and other endocrine-disrupting chemicals that can mimic DES and are thus estrogen agonists. The clinical and experimental findings with DES show that consideration must be given to the following facts:

  1. an increase in breast and prostatic cancer in the United States occurred between 1969 and 1986,
  2. a 400% increase in ectopic pregnancies occurred in the United States between 1970 and 1987
  3. a doubling of the incidence of cryptorchidism occurred in the United Kingdom between 1970 and 1987,
  4. and an approximate 50% decrease in sperm count worldwide over the last 50 years.

These trends may be a reflection of the increase from estrogenic pollutants in the environment. It has been suggested that the decrease in sperm count in men is the result of exposure during the fetal period of testicular differentiation to pollutants that have estrogenic activity. For example, an association between reduced sperm motility and PCBs in men with fertility problems has been reported; some PCBs are directly estrogenic while others become estrogenic after in vivo conversion, although the binding affinity of estrogen receptors for estrogenic PCBs is lower than that for estradiol.


  • Full text (free access) : Developmental Effects of Endocrine-Disrupting
    Chemicals in Wildlife and Humans, Environmental Health Perspectives, NCBI PubMed, PMC1519860, 1993 Oct.
  • Featured image credit Toni Cuenca.

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