Thyroid hormone is essential for normal brain development. However, little is known about the molecular and cellular mechanisms that mediate thyroid hormone action on the developing brain or the developmental events selectively affected. Consequently, although a large number of environmental chemicals interfere with the thyroid system, there are few neurodevelopmental end points to recruit for toxicological studies. Therefore, my goal here is to review what is known about the relative timing of normal brain construction and thyroid system development, with special focus on the period of in utero development in humans and the comparable developmental period in laboratory rats. These data are presented as a timeline to aid in the identification of thyroid-sensitive end points in brain development and to highlight important data gaps. I discuss the known influence of certain synthetic chemicals on the thyroid system and include a brief review of the effects of developmental exposure to chemicals on thyroid system function. The relationship between the thyroid hormone and retinoic acid systems, as well as the thyroid hormone sensitivity of the developing cochlea, is also discussed.

A model of the development of the brain as a construct of the thyroid system.

There has been increasing concern about the impact of environmental compounds with hormone-like action on human development and reproductive health over the past decades. An alternative but neglected source of hormone action that may be considered in this connection is hormone residues in meat from husbandry animals treated with sex steroid hormones for growth promotion. Treatment of cattle with naturally occurring or synthetic sex hormones may enhance lean muscle growth and improve feed efficiency and is therefore a very cost effective procedure for cattle producers who have used it for decades in some Western countries, including the USA and Canada. The Joint Food and Agricultural Organisation/World Health Organisation (FAO/WHO) expert committee on food additives (JECFA) and the US Food and Drug Administration (FDA) considered, in 1988, that the residues found in meat from treated animals were safe for the consumers. We have re-evaluated the JECFA conclusions regarding the safety of estradiol residues in meat in the light of recent scientific data, with special emphasis on estradiol levels in prepubertal children. These levels are needed for estimates of the normal daily production rates of estradiol in children, who may be particularly sensitive to low levels of estradiol. In our opinion, the conclusions by JECFA concerning the safety of hormone residues in meat seem to be based on uncertain assumptions and inadequate scientific data. Our concerns can be summarized as follows. 1) The data on residue levels in meat were based on studies performed in the 1970 s and 1980 s using radioimmunoassay (RIA) methods available at the time. The sensitivity of the methods was generally inadequate to measure precisely the low levels found in animal tissues, and considerable variation between different RIA methods for measuring steroids exists. Therefore the reported residue levels may be subject to considerable uncertainty. 2) Only limited information on the levels of the various metabolites of the steroids was given despite the fact that metabolites also may have biological activity. 3) Reliable data on daily production rates of steroid hormones were and are still lacking in healthy prepubertal children. This lack is crucial as previous guidelines regarding acceptable levels of steroid residues in edible animal tissues have been based on very questionable estimates of production rates in children. Thus, even today the US FDA bases its guidelines on the presumably highly overestimated production rates in prepubertal children given in the JECFA 1988 report. 4) The possible biological significance of very low levels of estradiol is neglected. In conclusion, based on our current knowledge possible adverse effects on human health by consumption of meat from hormone-treated animals cannot be excluded.

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Exposure to exogenous estrogens in food : possible impact on human development and health

A large number of chemical pollutants including phthalates, alkylphenolic compounds, polychlorinated biphenyls and polychlorinated dibenzodioxins, organochlorine pesticides, bisphenol A, and metals including lead, mercury, and cadmium have the ability to disrupt endocrine function in animals. Some of these same chemicals have been shown to alter cognitive function in animals and humans. Because hormonally mediated events play a central role in central nervous system development and function, a number of researchers have speculated that the changes in cognitive function are mediated by the endocrine-like actions of these chemicals. In this paper we review the evidence that cognitive effects of chemicals classified as environmental endocrine disruptors are mediated by changes in hormonal function. We begin by briefly reviewing the role of gonadal steroids, thyroid hormones, and glucocorticoids in brain development and brain function. We then review the endocrine changes and cognitive effects that have been reported for selected endocrine-disrupting chemicals, discuss the evidence for causal relationships between endocrine disruption and cognitive effects, and suggest directions for future research.

Cognitive effects of endocrine-disrupting chemicals in animals.

Polycyclic Aromatic Hydrocarbons (PAHs) are a group of chemicals that are formed during the incomplete burning of coal, oil, gas, wood, garbage, or other organic substances, such as tobacco and charbroiled meat. There are more than 100 PAHs. PAHs generally occur as complex mixtures (for example, as part of products such as soot), not as single compounds. PAHs are found throughout the environment in the air, water, and soil. As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals, including PAHs (ATSDR, 1995), found at facilities on the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). These profiles include information on health effects of chemicals from different routes and durations of exposure, their potential for exposure, regulations and advisories, and the adequacy of the existing database. Assessing the health effects of PAHs is a major challenge because environmental exposures to these chemicals are usually to complex mixtures of PAHs with other chemicals. The biological consequences of human exposure to mixtures of PAHs depend on the toxicity, carcinogenic and noncarcinogenic, of the individual components of the mixture, the types of interactions among them, and confounding factors that are not thoroughly understood. Also identified are components of exposure and health effects research needed on PAHs that will allow estimation of realistic human health risks posed by exposures to PAHs. The exposure assessment component of research should focus on (1) development of reliable analytical methods for the determination of bioavailable PAHs following ingestion, (2) estimation of bioavailable PAHs from environmental media, particularly the determination of particle-bound PAHs, (3) data on ambient levels of PAHs metabolites in tissues/fluids of control populations, and (4) the need for a critical evaluation of current levels of PAHs found in environmental media including data from hazardous waste sites. The health effects component should focus on obtaining information on (1) the health effects of mixtures of PAHs particularly their noncarcinogenic effects in humans, and (2) their toxicokinetics. This report provides excerpts from the toxicological profile of PAHs (ATSDR, 1995) that contains more detailed information.

Atsdr Evaluation of Health Effects of Chemicals. Iv. Polycyclic Aromatic Hydrocarbons (PAHs): Understanding a Complex Problem:

Publisher Summary This chapter focuses on the origin and development of hormone receptors. Studies of evolution show that there are no unique signal molecules, only those which are selected to be hormones and which are more suitable than others to perform the hormone function. It is also probable that there are no unique hormone receptors, only those structures which are able to recognize the environment. These structures develop into receptors following an encounter with a molecule suitable for signal transmission. Hormonal imprinting occurs at the first encounter of the prospective hormone and the prospective receptor. This results in more specific receptors and more numerous receptors being produced by the cell. The receptors are transmitted to the offspring generations. The hormonal imprinting that occurs at the beginning of the evolutionary sequence retains its role in the higher organisms and influences the maturation of receptors around the period of birth. Imprinting is necessary to complete the program of receptor formation. Imprinting is not age-dependent but depends on the stage of development; it can be developed also in immature, differentiating cells in adults. The recognition system of cells is universal but there are several ways it can be expressed. In each method there are receptors and ligands.

Phylogeny and Ontogeny of Chemical Signaling: Origin and Development of Hormone Receptors

Neonatal treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accounted for a considerable decrease in the number of thymic glucocorticoid receptors in both male and female rats, as assessed at 6 weeks of age. TCDD also gave rise to a marked and prolonged increase in microsomal enzyme activity in the female rats but had practically no such effect on the males. These experimental observations attract attention on to the lasting microsomal inducer effect of the herbicide contaminant dioxin which damages foreign receptors and substantiate the chemical imprinting potential of aromatic hydrocarbons.

Persistent influence of neonatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment on glucocorticoid receptors and on the microsomal enzyme system.

1. 1. Rats exposed to benzpyrene in utero at 19 days of pre-natal life showed a relative decrease in the number of thymic glucocorticoid receptors at 6 weeks of age. 2. 2. Primary exposure to benzpyrene at 6 weeks of age had a similar effect on females 4 weeks later, but did not change the glucocorticoid receptor number of males. 3. 3. In utero exposure accounted for an increase in the fetal cytochrome P 450 level within 1 day, whereas exposure at 6 weeks of age did not change it within 4 weeks. 4. 4. It appears that exposure to benzpyrene gives rise to a faulty imprinting of the thymic glucocorticoid receptor in both fetal and growing age, to judge from a lasting change in the receptor number.

Lasting impact of a single benzpyrene treatment in pre-natal and growing age on the thymic glucocorticoid receptors of rats.

A single neonatal exposure to methylcholanthrene or benzo(a)-pyrene altered the hepatic microsomal enzyme activity of rats for a long time. Methylcholanthrene depressed, whereas benzo(a)pyrene enhanced the activity of the microsomal enzyme system. The former had a greater influence on males than on females, whereas the latter acted practically uniformly on both sexes.

A single neonatal treatment with methylcholanthrene or benzo(a)pyrene alters microsomal enzyme activity for life.

Healthy and neonatally castrated male rats were treated with testosterone twice perinatally, while other groups were treated with testosterone also in adulthood or received testosterone only in adulthood. Castration resulted in a moderate (but in some instances significant) decrease of PSMO (polysubstrate monooxygenase) level measured in adulthood. The decrease could partially be compensated by perinatal testosterone treatment. Further testosterone treatment administered in adulthood did not result in further alteration when compared either with the controls or with the neonatally treated animals. However, since in the controls the second testosterone treatment (following the neonatal one), had a decreasing effect, therefore the testosterone treatment administered in adulthood was responsible for the disappearance of the difference between the castrated animals and the controls treated both perinatally and in adulthood. On the basis of these findings it seems likely that the perinatal presence of testosterone plays a major role in the development of enzymatic imprinting and thus, in securing the capability of the liver to split testosterone in adulthood. Since testosterone influences the glycocorticoid receptors of the thymus (presumably by its overlapping effect), so the amount of free glycocorticoid receptors is always higher in the animals castrated neonatally than in the controls. Conversely, neonatal testosterone treatment somewhat increases the number of receptors detectable in adulthood.

Effect of the absence of neonatal testosterone imprinting on the activity of the microsomal enzyme system and on the dexamethasone binding of the thymus in adulthood.

A single neonatal treatment of rats with a steroid (allylestrenol or diethylstilbestrol) did not alter the later activity of the hepatic microsomal (cytochrome P-450) enzyme system, but inhibited the inducer action of another steroid (testosterone) administered at the age of six weeks. This suggests that a hormonal imprinting-like mechanism also operates in the case of enzymes.

Szeberényi S

Papers

Persistent influence of neonatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment on glucocorticoid receptors and on the microsomal enzyme system.

Lasting impact of a single benzpyrene treatment in pre-natal and growing age on the thymic glucocorticoid receptors of rats.

A single neonatal treatment with methylcholanthrene or benzo(a)pyrene alters microsomal enzyme activity for life.

Effect of the absence of neonatal testosterone imprinting on the activity of the microsomal enzyme system and on the dexamethasone binding of the thymus in adulthood.

Influence of single neonatal treatment with allylestrenol or diethylstilbestrol on microsomal enzyme activity of rat liver in adulthood.