In recent years, a number of man-made chemicals have been shown to be able to mimic endogenous hormones, and it has been hypothesized that alterations in the normal pattern of reproductive development seen in some populations of wildlife are linked with exposure to these chemicals. Of particular importance are those compounds that mimic estrogens and androgens (and their antagonists), because of their central role in reproductive function. In fact, the evidence showing that such chemicals actually do mimic (or antagonize) the action of hormones in the intact animal is limited. In only a few cases have laboratory studies shown that chemicals that mimic hormones at the molecular level (in vitro) also cause reproductive dysfunction in vivo at environmentally relevant concentrations. In addition, the reported studies on wild populations of animals are limited to a very few animal species and they have often centered on localized 'hot-spots' of chemical discharges. Nevertheless, many of these xenobiotics are persistent and accumulate in the environment, and therefore a more widespread phenomenon of endocrine disruption in wildlife is possible. This article reviews the evidence, from both laboratory and field studies, that exposure to steroid hormone mimics may impair reproductive function and critically assesses the weight of evidence for endocrine disruption in wildlife.

Endocrine Disruption in Wildlife: A Critical Review of the Evidence

Two chemicals previously shown to have estrogenic activity, bisphenol A and octylphenol, were examined for their effects on accessory reproductive organs and daily sperm production in male offspring of mice fed these chemicals during pregnancy. These chemicals are used in the manufacture of plastics and other products, and have been detected in food and water consumed by animals and people. From gestation day 11-17 female mice were fed an average concentration (dissolved in oil) of bisphenol A or octylphenol of 2 ng/g body weight (2 ppb) and 20 ng/g (20 ppb). The 2 ppb dose of bisphenol A is lower than the amount reported to be swallowed during the first hour after application of a plastic dental sealant (up to 931 micrograms; 13.3 ppb in a 70 kg adult). We found that the 2 ng/g dose of bisphenol A permanently increased the size of the preputial glands, but reduced the size of the epididymides; these organs develop from different embryonic tissues. At 20 ng/g, bisphenol A significantly decreased efficiency of sperm production (daily sperm production per g testis) by 20% relative to control males. The only significant effect of octylphenol was a reduction in daily sperm production and efficiency of sperm production at the 2 ng/g dose. A new approach to studying physiologically relevant doses of environmental endocrine disruptors is discussed, particularly with regard to the development of the reproductive organs, the brain, and behavior.

A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and Behavior:

Several classes of environmental contaminants have been claimed or suggested to possess endocrine-disrupting potency, which may result in reproductive problems and developmental disorders. In this paper the focus is on the multiple and interactive mechanisms of interference of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites with the thyroid hormone system. Evidence suggests that pure congeners or mixtures of PHAHs directly interfere with the thyroid gland; with thyroid hormone metabolizing enzymes, such as uridine-diphosphate-glucuronyl transferases (UGTs), iodothyronine deiodinases (IDs), and sulfotransferases (SULTs) in liver and brain; and with the plasma transport system of thyroid hormones in experimental animals and their offspring. Changes in thyroid hormone levels in conjunction with high PHAH exposure was also observed in captive as well as free ranging wildlife species and in humans. Maternal exposure to PHAHs during pregnancy resulted in a considerable fetal transfer of hydroxylated PHAHs, which are known to compete with thyroxine (T4) for plasma transthyretin (TTR) binding sites, and thus may be transported to the fetus with those carrier proteins that normally mediate the delivery of T4 to the fetus. Concomitant changes in thyroid hormone concentrations in plasma and in brain tissue were observed in fetal and neonatal stages of development, when sufficient thyroid hormone levels are essential for normal brain development. Alterations in structural and functional neurochemical parameters, such as glial fibrillary acidic protein (GFAP), synaptophysin, calcineurin, and serotonergic neurotransmitters, were observed in the same offspring up to postnatal day 90. In addition, some changes in locomotor and cognitive indices of behavior were observed in rat offspring, following in utero and lactational exposure to PHAHs. Alterations in thyroid hormone levels and subtle changes in neurobehavioral performance were also observed in human infants exposed in utero and through lactation to relatively high levels of PHAHs. Overall these studies indicate that persistent PHAHs can disrupt the thyroid hormone system at a multitude of interaction sites, which may have a profound impact on normal brain development in experimental animals, wildlife species, and human infants.

Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health:

Synthetic chemicals are released into the environment by design (pesticides) or as a result of industrial activity. It is well known that natural environmental chemicals can cause goiter or thyroid imbalance. However, the effects of synthetic chemicals on thyroid function have received little attention, and there is much controversy over their potential clinical impact, because few studies have been conducted in humans. This article reviews the literature on possible thyroid disruption in wildlife, humans, and experimental animals and focuses on the most studied chemicals: the pesticides DDT, amitrole, and the thiocarbamate family, including ethylenethiourea, and the industrial chemicals polyhalogenated hydrocarbons, phenol derivatives, and phthalates. Wildlife observations in polluted areas clearly demonstrate a significant incidence of goiter and/or thyroid imbalance in several species. Experimental evidence in rodents, fish, and primates confirms the potentiality for thyroid disruption of several chemicals and illustrates the mechanisms involved. In adult humans, however, exposure to background levels of chemicals does not seem to have a significant negative effect on thyroid function, while exposure at higher levels, occupational or accidental, may produce mild thyroid changes. The impact of transgenerational, background exposure in utero on fetal neurodevelopment and later childhood cognitive function is now under scrutiny. There are several studies linking a lack of optimal neurological function in infants and children with high background levels of exposure to polychlorinated biphenyls (PCBs), dioxins, and/or co-contaminants, but it is unclear if the effects are caused by thyroid disruption in utero or direct neurotoxicity.

Effects of Environmental Synthetic Chemicals on Thyroid Function

Chemicals that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can induce reproductive malformations in humans and laboratory animals. Several environmental chemicals disrupt development in rats and/or rabbits at fetal concentrations at, or near, exposure levels seen in some segments of the human population. In rats, fetal tissues concentrations of 10-20 p.p.m. of the DDT metabolite, p,p'-DDE, are correlated with reproductive abnormalities in male offspring. These concentrations are similar to those measured in first-trimester human fetal tissues in the late 1960s. The pesticides vinclozolin, procymidone, linuron and DDT are AR antagonists. They reduce male rat anogenital distance, and induce areolas at relatively low dosages. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosages, while undescended testes and epididymal agenesis are seen in the highest doses. Phthalate esters (PE) inhibit testosterone synthesis during fetal life, but do not appear to be AR antagonists. Prenatal administration of a single low dose of dioxin (50-1,000 ng TCDD/kg) alters the differentiation of androgen-dependent tissues at p.p.t. concentrations, but the mechanism of action likely involves interaction with a hormone-like nuclear transcription factor, the hormone-like receptor AhR, rather than AR. p,p'-DDT and p,p'-DDE, vinclozolin and di-n-butyl phthalate affect reproductive function in rabbits when administered during prenatal and/or neonatal life. Cryptorchidism and carcinoma in situ-like (CIS) testicular lesions were seen in male rabbits treated during development with p,p'-DDT or p,p'-DDE. Extrapolation of effects from rodents to humans would be enhanced if future studies incorporate determination of tissue concentrations of the active metabolites. Knowledge of the tissue concentrations of the active toxicants also would provide an important link to in-vitro studies, which provide more useful mechanistic information when they are executed at relevant concentrations.

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Beverly M. Kulig

Papers

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants