Advances in Autism Research
compiled by Teresa Binstock for
Autism Research Institute
April 2008

Endocrine Disruption

Endrocrine-disrupting chemicals

aka

EDCs

1: Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals

Kortenkamp A.
Environ Health Perspect. 2007 Dec;115 Suppl 1:98-105.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174407&blobtype=pdf

In the last 10 years, good evidence has become available to show that the combined effects of endocrine disruptors (EDs) belonging to the same category (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by using dose addition. This is true for a variety of end points representing a wide range of organizational levels and biological complexity. Combinations of EDs are able to produce significant effect, even when each chemical is present at low doses that individually do not induce observable effects. However, comparatively little is known about mixtures composed of chemicals from different classes of EDs. Nevertheless, I argue that the accumulated evidence seriously undermines continuation with the customary chemical-by-chemical approach to risk assessment for EDs. Instead, we should seriously consider group-wise regulation of classes of EDs. Great care should be taken to define such classes by using suitable similarity criteria. Criteria should focus on common effects, rather than common mechanisms. In this review I also highlight research needs and identify the lack of information about exposure scenarios as a knowledge gap that seriously hampers progress with ED risk assessment. Future research should focus on investigating the effects of combinations of EDs from different categories, with considerable emphasis on elucidating mechanisms. This strategy may lead to better-defined criteria for grouping EDs for regulatory purposes. Also, steps should be taken to develop dedicated mixtures exposure assessment for EDs.
    PMID: 18174957

2: Statistical power considerations show the endocrine disruptor low-dose issue in a new light

Scholze M, Kortenkamp A.
Environ Health Perspect. 2007 Dec;115 Suppl 1:84-90.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174415&blobtype=pdf

BACKGROUND: The endocrine disruptor field has been vexed by difficulties in reproducing various claims of effects at unusually low doses. In previous analyses, variations in control responses from experiment to experiment and problems with observing effects in positive controls have been identified as possible explanations of the resulting impasse. OBJECTIVE: In this article, we argue that both of these viewpoints fail to take sufficient account of the problems that exist in estimating low effects and low-effect doses. We have carried out post hoc power analyses on selected published data to illustrate that claims of low-dose effects (or their absence) are often compromised by insufficient statistical power of the chosen experimental design. CONCLUSIONS: We demonstrate that low-dose estimates such as the no observed adverse effect levels derived from statistical hypothesis-testing procedures are dependent on the specific experimental conditions used for testing. Thus, below the statistical detection limit of the experiment, the presence of effects can neither be proven nor ruled out. Common practice is to attempt to establish "doses without effect." However, low-dose estimations in the endocrine-disruptor field could be improved if decisions regarding the toxicologic effect size of relevance formed the starting point of testing procedures. Statistical power considerations could then reveal the resources necessary to demonstrate effect magnitudes of concern.
    PMID: 18174955

3: Endocrine-disrupting potential of bisphenol A, bisphenol A dimethacrylate, 4-n-nonylphenol, and 4-n-octylphenol in vitro: new data and a brief review

Bonefeld-Jørgensen EC, Long M, Hofmeister MV, Vinggaard AM.
Environ Health Perspect. 2007 Dec;115 Suppl 1:69-76.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174402&blobtype=pdf

BACKGROUND: An array of environmental compounds is known to possess endocrine disruption (ED) potentials. Bisphenol A (BPA) and bisphenol A dimethacrylate (BPA-DM) are monomers used to a high extent in the plastic industry and as dental sealants. Alkylphenols such as 4-n-nonylphenol (nNP) and 4-n-octylphenol (nOP) are widely used as surfactants. OBJECTIVES: We investigated the effect in vitro of these four compounds on four key cell mechanisms including transactivation of a) the human estrogen receptor (ER), b) the human androgen receptor (AR), c) the aryl hydrocarbon receptor (AhR), and d) aromatase activity. RESULTS: All four compounds inhibited aromatase activity and were agonists and antagonists of ER and AR, respectively. nNP increased AhR activity concentration-dependently and further increased the 2,3,7,8-tetrachlorodibenzo-p-dioxin AhR action. nOP caused dual responses with a weak increased and a decreased AhR activity at lower (10(-8) M) and higher concentrations (10(-5)-10(-4) M), respectively. AhR activity was inhibited with BPA (10(-5)-10(-4) M) and weakly increased with BPA-DM (10(-5) M), respectively. nNP showed the highest relative potency (REP) compared with the respective controls in the ER, AhR, and aromatase assays, whereas similar REP was observed for the four chemicals in the AR assay. CONCLUSION: Our in vitro data clearly indicate that the four industrial compounds have ED potentials and that the effects can be mediated via several cellular pathways, including the two sex steroid hormone receptors (ER and AR), aromatase activity converting testosterone to estrogen, and AhR; AhR is involved in syntheses of steroids and metabolism of steroids and xenobiotic compounds.
    PMID: 18174953

4: Effects of endocrine disruptors on dehydroepiandrosterone sulfotransferase and enzymes involved in PAPS synthesis: genomic and nongenomic pathways

Harris R et al.
Environ Health Perspect. 2007 Dec;115 Suppl 1:51-4.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174413&blobtype=pdf

BACKGROUND: Sulfation plays an important role both in detoxification and in the control of steroid activity. Studies in rodents have shown that the conversion of dehydroepiandrosterone (DHEA) to DHEA-sulfate is involved in learning and the memory process. METHODS: The effects of a range of plasticizers and related compounds commonly encountered in the environment were evaluated kinetically against human DHEA sulfotransferase (SULT 2A1) and by reverse transcriptase-polymerase chain reaction (RT-PCR) against several enzymes involved in the synthesis of the sulfotransferase cofactor adenosine 3'-phosphate 5'-phosphosulfate (PAPS). RESULTS: We found that several of the chemicals acted as competitive inhibitors of SULT 2A1 (K(i) for 4-tert-octylphenol is 2.8 microM). Additionally, after treatment of TE 671 cells with 0.005-0.5 microM 4-n-octylphenol, bis(2-ethylhexyl)phthalate, and diisodecyl phthalate, real-time RT-PCR showed dose-dependent decreases in the steady-state mRNA levels of cysteine dioxygenase type I, sulfite oxidase, and 3'-phosphate 5'-phosphosulfate synthase I. CONCLUSIONS: These data suggest that environmental contaminants may exert effects on neuronal function both by direct inhibition of sulfotransferase enzymes and by interrupting the supply of PAPS, which has wider implications for endocrine disruption and xenobiotic metabolism.
    PMID: 18174950

5: Human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested case-control study

Fernandez MF et al.
Environ Health Perspect. 2007 Dec;115 Suppl 1:8-14.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174399&blobtype=pdf

BACKGROUND: Exposure to xenoestrogens during pregnancy may disturb the development and function of male sexual organs. OBJECTIVE: In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. METHODS: In a case-control study, nested in a mother-child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10-7.24). More pesticides were detected in cases than in controls (9.34 +/- 3.19 vs. 6.97 +/- 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p'-DDT (OR = 2.25; 95% CI, 1.03-4.89), p,p'-DDT (OR = 2.63; 95% CI, 1.21-5.72), lindane (OR = 3.38; 95% CI, 1.36-8.38), mirex (OR = 2.85; 95% CI, 1.22-6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99-4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33-9.03), fathers' occupational exposure to xenoestrogens (OR = 2.98; 95% CI, 1.11-8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11-16.66) were also associated with risk of malformations. CONCLUSIONS: We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.
    PMID: 18174944

6: Impact of endocrine disruptor chemicals in gynaecology

Caserta D et al.
Hum Reprod Update. 2008 Jan-Feb;14(1):59-72.
http://humupd.oxfordjournals.org/cgi/content/full/14/1/59

The potential hazardous effects that estrogen- and androgen-like chemicals may have both on wildlife and human health have attracted much attention from the scientific community. Endocrine disruptors (EDCs) are chemicals that have the capacity to interfere with normal signalling systems. EDCs may mimic, block or modulate the synthesis, release, transport, metabolism and binding or elimination of natural hormones. Even though potential EDCs may be present in the environment at only very low levels, they may still cause harmful effects, especially when several different compounds act on one target. EDCs include persistent pollutants, agrochemicals and widespread industrial compounds. Not all EDCs are man-made compounds; many plants produce substances (phytoestrogens) that can have different endocrine effects either adverse or beneficial in certain circumstances. Natural substances such as sex hormones from urban or farm wastes can become concentrated in industrial, agricultural and urban areas; thus, such wastes may be considered potential 'EDCs' for humans and/or wildlife. Much attention has focussed on changing trends in male reproductive parameters in relation to EDC exposure; however, studies on the female reproductive system have been less comprehensive. We have focussed this article on four major aspects of female reproductive health: fertility and fecundability, endometriosis, precocious puberty and breast and endometrial cancer.
    PMID: 18070835

7: Introduction: endocrine disruptors-exposure assessment, novel end points, and low-dose and mixture effects

Kortenkamp A.
Environ Health Perspect. 2007 Dec;115 Suppl 1:7.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2174403&blobtype=pdf
    PMID: 18174943

8: Life style-related diseases of the digestive system: endocrine disruptors stimulate lipid accumulation in target cells related to metabolic syndrome

Wada K et al.
J Pharmacol Sci. 2007 Oct;105(2):133-7.
http://www.jstage.jst.go.jp/article/jphs/105/2/105_133/_article

Many reports indicated that endocrine disruptors (EDs) affect several hormonal functions in various living things. Here, we show the effect of EDs on lipid accumulation in target cells involved in the onset of metabolic syndrome. Treatment with nonylphenol and bisphenol A, typical EDs, stimulated the accumulation of triacylglycerol in differentiated adipocytes from 3T3-L1, preadipocytes, in time- and concentration-dependent manners. Up-regulation of gene expressions involved in lipid metabolism and metabolic syndrome were observed in adipocytes treated with EDs. Similarly, stimulatory effects of EDs were also observed on the human hepatoma cell line HuH-7. These observations indicate that exposure to EDs stimulates the lipid accumulation in target cells involved in the metabolic syndrome and may cause the dysfunction of those cells, resulting in induction of metabolic syndrome.
    PMID: 17928741

9: Developmental exposure to endocrine disruptors and the obesity epidemic

Newbold RR et al.
Reprod Toxicol. 2007 Apr-May;23(3):290-6. Epub 2007 Jan 17.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1931509&blobtype=pdf

Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed "the developmental origins of adult disease" and suggests new targets of abnormal programming by endocrine disrupting chemicals.
    PMID: 17321108

10: Endocrine disrupting chemicals: a new and emerging public health problem?

Acerini CL, Hughes IA.
Arch Dis Child. 2006 Aug;91(8):633-41.
http://adc.bmj.com/cgi/reprint/91/8/633
    PMID: 16861481

11: Late lessons from early warnings: Toward realism and precaution with endocrine-disrupting substances

Gee D.
Environ Health Perspect. 2006 Apr;114 Suppl 1:152-60.
http://www.ehponline.org/members/2005/8134/8134.html

    The histories of selected public and environmental hazards, from the first scientifically based early warnings about potential harm to the subsequent precautionary and preventive measures, have been reviewed by the European Environment Agency. This article relates the "late lessons" from these early warnings to the current debates on the application of the precautionary principle to the hazards posed by endocrine-disrupting substances (EDSs). Here, I summarize some of the definitional and interpretative issues that arise. These issues include the contingent nature of knowledge; the definitions of precaution, prevention, risk, uncertainty, and ignorance; the use of differential levels of proof; and the nature and main direction of the methodological and cultural biases within the environmental health sciences. It is argued that scientific methods need to reflect better the realities of multicausality, mixtures, timing of dose, and system dynamics, which characterize the exposures and impacts of EDSs. This improved science could provide a more robust basis for the wider and wise use of the precautionary principle in the assessment and management of the threats posed by EDSs. The evaluation of such scientific evidence requires assessments that also account for multicausal reality. Two of the often used, and sometimes misused, Bradford Hill "criteria," consistency and temporality, are critically reviewed in light of multicausality, thereby illustrating the need to review all of the criteria in light of 40 years of progress in science and policymaking.
    PMID: 16818262

12: The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals

Sanderson JT.
Toxicol Sci. 2006 Nov;94(1):3-21.
http://toxsci.oxfordjournals.org/cgi/content/full/94/1/3

Various chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms. Increasingly, the enzymes involved in the steroid biosynthesis pathway are being recognized as important targets for the actions of various endocrine-disrupting chemicals. Interferences with steroid biosynthesis may result in impaired reproduction, alterations in (sexual) differentiation, growth, and development and the development of certain cancers. Steroid hormone synthesis is controlled by the activity of several highly substrate-selective cytochrome P450 enzymes and a number of steroid dehydrogenases and reductases. Particularly aromatase (CYP19), the enzyme that converts androgens to estrogens, has been the subject of studies into the mechanisms by which chemicals interfere with sex steroid hormone homeostasis and function, often related to (de)feminization and (de)masculinazation processes. Studies in vivo and in vitro have focussed on ovarian and testicular function, with less attention given to other steroidogenic organs, such as the adrenal cortex. This review aims to provide a comprehensive overview of the state of knowledge regarding the mechanisms by which chemicals interfere with the function of steroidogenic enzymes in various tissues and organisms. The endocrine toxicities and mechanisms of action related to steroidogenesis of a number of classes of drugs and environmental contaminants are discussed. In addition, several potential in vitro bioassays are reviewed for their usefulness as screening tools for the detection of chemicals that can interfere with steroidogenesis. Analysis of the currently scattered state of knowledge indicates that still relatively little is known about the underlying mechanisms of interference of chemicals with steroidogenesis and their potential toxicity in steroidogenic tissues, neither in humans nor in wildlife. Considerably more detailed and systematic research in this area of (endocrine) toxicology is required for a better understanding of risks to humans and wildlife.
    PMID: 16807284

13: Epigenetic transgenerational actions of endocrine disruptors

Anway MD, Skinner MK.
Endocrinology. 2006 Jun;147(6 Suppl):S43-9.
http://endo.endojournals.org/cgi/content/full/147/6/s43

Endocrine disruptors have recently been shown to promote an epigenetic transgenerational phenotype involving a number of disease states (e.g. male infertility). The anti-androgenic fungicide vinclozolin was found to act transiently at the time of embryonic sex determination to promote in the F1 generation a spermatogenic cell defect and subfertility in the male. When the animals were allowed to age up to 1 yr, a number of other disease states developed. This phenotype was transferred through the male germ line to all subsequent generations analyzed (F1-F4). The ability of an environmental factor (i.e. endocrine disruptor) to promote an epigenetic transgenerational phenotype impacts the potential hazards of environmental toxins, mechanisms of disease etiology, and evolutionary biology. The biological importance of the epigenetic actions of environmental agents is reviewed in the context of the primordial germ cell and development of epigenetic transgenerational phenotypes.
    PMID: 16690803

14: Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function

Henley DV, Korach KS.
Endocrinology. 2006 Jun;147(6 Suppl):S25-32.
http://endo.endojournals.org/cgi/content/full/147/6/s25

The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals--diethylstilbestrol, genistein, di(n-butyl)phthalate, and methoxyacetic acid--to illustrate the diverse and complex nature of this class of compounds.
    PMID: 16690802

15: New modes of action for endocrine-disrupting chemicals

Tabb MM, Blumberg B.
Mol Endocrinol. 2006 Mar;20(3):475-82.
http://mend.endojournals.org/cgi/content/full/20/3/475

Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate." The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their coregulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Additional elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.
    PMID: 16037129

16. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age

Vreugdenhil HJ et al.
Environ Health Perspect. 2002 Oct;110(10):A593-8.
http://www.ehponline.org/members/2002/110pA593-A598vreugdenhil/vreugdenhil-full.html

Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic compounds that may modulate sex steroid hormones. Steroid hormones play a mediating role in brain development and may influence behaviors that show sex differences, such as childhood play behavior. In this study we evaluated the effects of perinatal exposure to environmental levels of PCBs and dioxins on childhood play behavior and whether the effects showed sex differences. As part of the follow-up to the Dutch PCB/dioxin study at school age, we used the Pre-School Activity Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n = 207). The PSAI assesses masculine or feminine play behavior scored on three subscales: masculine, feminine, and composite. Prenatal exposure to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord plasma and breast milk. For breast milk we measured additional PCBs as well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5 years +/- 0.4). Effects of prenatal exposure to PCBs, measured in maternal and cord plasma, on the masculine and composite scales were different for boys and girls (p <.05). In boys, higher prenatal PCB levels were related with less masculinized play, assessed by the masculine scale (p(maternal) =.042; p(cord) =.001) and composite scale (p(cord) =.011), whereas in girls higher PCB levels were associated with more masculinized play, assessed by the composite scale (p(PCBmilk) =.028). Higher prenatal dioxin levels were associated with more feminized play in boys as well as girls, assessed by the feminine scale (p =.048). These effects suggest prenatal steroid hormone imbalances caused by prenatal exposure to environmental levels of PCBs, dioxins, and other related organochlorine compounds.
    PMID: 12361940

17: Disrupting effects of hydroxy-polychlorinated biphenyl (PCB) congeners on neuronal development of cerebellar Purkinje cells: a possible causal factor for developmental brain disorders?

Kimura-Kuroda J et al.
Chemosphere. 2007 Apr;67(9):S412-20.

Polychlorinated biphenyls (PCBs) and hydroxy-PCB (OH-PCB) metabolites are widely distributed bioaccumulative environmental chemicals and have similar chemical structures to those of thyroid hormones (THs). Previously, we reported that THs are essential for neuronal development and the low doses of two OH-PCBs, namely, 4-OH-2',3,3',4',5'-pentachlorobiphenyl (4'-OH-PeCB-106) and 4-OH-2',3,3',4',5,5'-hexachlorobiphenyl (4'-OH-HxCB-159), inhibited the TH-dependent dendritic development of Purkinje cells in mouse cerebellar cultures using serum-free defined medium. To determine which type of OH-PCBs affect neuronal development, we further examined several OH-PCBs and other estrogenic chemicals using this simple and sensitive assay system. Two-way ANOVA was used to assess the effects of OH-PCBs and other chemicals on both factors of their concentrations and with/without T4 in the assay of TH-dependent dendritic development of Purkinje cells. Aside from the two OH-PCBs, 4-OH-2',3,4',5,6'-pentachlorobiphenyl (4'-OH-PeCB-121) and bisphenol A significantly inhibited the TH-dependent dendritic development of Purkinje cells, whereas 4-OH-2',3,3',5',6'-pentachlorobiphenyl (4'-OH-PeCB-112), 4-OH-2',3,3',5,5',6'-hexachlorobiphenyl (4'-OH-HxCB-165), 4-OH-2,2',3,4',5,5',6-heptachlorobiphenyl (4-OH-HpCB-187), progesterone and nonylphenol did not induce any inhibition, but significantly promoted the dendritic extension of Purkinje cells in the absence of THs. Other estrogenic chemicals, including beta-estradiol, diethyl stilbestrol and p-octylphenol did not show significant inhibitory or promoting effects. From these results, it is suggested that exposure to OH-PCBs and other environmental chemicals may disrupt normal neuronal development and cause some developmental brain disorders, such as LD, ADHD, and autism.
    PMID: 17223178

18:  Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain

Masuo Y et al.
Regul Pept. 2004 Dec 15;123(1-3):225-34.

Recent studies have revealed that the pituitary adenylate cyclase-activating polypeptide (PACAP) might act as a psychostimulant. Here we investigated the mechanisms underlying motor hyperactivity in patients with pervasive developmental disorders, such as autism, and attention-deficit hyperactivity disorder (ADHD). We studied the effects of intracisternal administration of 6-hydroxydopamine (6-OHDA) or endocrine disruptors (EDs) on spontaneous motor activity (SMA) and multiple gene expression in neonatal rats. Treatment with 6-OHDA caused significant hyperactivity during the dark phase in rats aged 4-5 weeks. Motor hyperactivities also were observed after treatment with endocrine disruptors, such as bisphenol A, nonylphenol, diethylhexyl phthalate and dibutyl phthalate, during both dark and light phases. Gene-expression profiles produced using cDNA macroarrays of 8-week-old rats with 6-OHDA lesions revealed the altered expression of several classes of gene, including the N-methyl-D-aspartate (NMDA) receptor 1, glutamate/aspartate transporter, gamma-aminobutyric-acid transporter, dopamine transporter 1, D4 receptor, and peptidergic elements such as the galanin receptor, arginine vasopressin receptor, neuropeptide Y and tachykinin 2. The changes in gene expression caused by treatment with endocrine disruptors differed from those induced by 6-OHDA. These results suggest that the mechanisms underlying the induction of motor hyperactivity and/or compensatory changes in young adult rats might differ between 6-OHDA and endocrine disruptors.
    PMID: 15518916

20. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration

Parent AS et al.
Endocr Rev. 2003 Oct;24(5):668-93.
http://edrv.endojournals.org/cgi/content/full/24/5/668

During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.
    PMID: 14570750

21. Early onset of puberty: tracking genetic and environmental factors

Parent AS et al.
Horm Res. 2005;64 Suppl 2:41-7.

Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. In pathological conditions, however, these variations can involve different genetic susceptibility and the interaction of environmental factors. The high incidence of precocious puberty in foreign children migrating to Belgium and the detection in their plasma of a long-lasting 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) residue suggest the potential role of environmental endocrine disrupting chemicals in the early onset of puberty. This hypothesis was confirmed by experimental data showing that temporary exposure of immature female rats to DDT in vivo results in early onset of puberty. We compared the gene expression profile of hypothalamic hamartoma associated or not with precocious puberty in order to identify gene networks responsible for both hamartoma-dependent sexual precocity and the onset of normal human puberty. In conclusion, pathological variations in the timing of puberty may provide unique information about the interactions of either environmental conditions or genetic susceptibility with the hypothalamic mechanism controlling the onset of sexual maturation, as shown by examples of precocious puberty following exposure to endocrine disrupters or due to hypothalamic hamartoma. (c) 2005 S. Karger AG, Basel.
   PMID: 16286770

22. Precocious puberty: a comprehensive review of literature

Cesario SK, Hughes LA.
J Obstet Gynecol Neonatal Nurs. 2007 May-Jun;36(3):263-74.

    CONTEXT: Precocious puberty currently affects 1 in 5,000 children and is 10 times more common in girls. Statistics indicate that girls in the United States are maturing at an earlier age than they did 30 years ago and the number of girls with diagnosed precocious puberty (the appearance of secondary sex characteristics before 8 years of age or the onset of menarche before age 9) is on the rise. A summary of the growing body of literature on this topic is necessary to inform nurses and other health care providers of the current trends and incidence of precocious puberty to better meet the physical and psychosocial needs of these girls and their families. METHODS: EBSCOhost Research Databases that included CINAHL Plus, Health Source: Nursing Edition, MEDLINE, PsycINFO, and Women's Studies International were searched for journal articles published in the past 10 years (1997-2006) that explicitly examined precocious puberty in females and proposed theories to describe the phenomenon. Search terms included precocious puberty, sexual maturation, menarche, and secondary sex characteristics. These terms were searched individually and in combination with proximate determinants such as endocrine disruptors, environmental toxins, phthalates, stress, skin care, genetics, age, ethnicity, obesity, and assisted reproduction. The search yielded 947 articles addressing this issue. RESULTS: Eighty-two studies or case reports met the criteria for inclusion in this literature review that captured six attributable causes of early sexual maturation in female children. These included genetic, ethnic, and pediatric obesity, as well as environmental toxins that disrupt endocrine function (chemicals, toxins, plasticizers, infant feeding methods, skin and hair products, assisted reproductive technologies), psychosocial stress, and early exposure to a sexualized society. The robustness of the reports varied and few of the studies were widely generalizable but did offer suggestions for assessment and nursing care. CONCLUSIONS: Precocious puberty has health and social implications that are complex and influenced by multiple factors. Further research is needed to expand and elucidate theoretical relationships between the early development of secondary sex characteristics in young girls and the proposed causative factors.
    PMID: 17489932

23. [An early clue]

Parental reproductive problems and gestational hormonal exposure in autistic and schizophrenic children

Funderburk SJ et al.
J Autism Dev Disord. 1983 Sep;13(3):325-32.

The incidence of infertility and two or more spontaneous abortions was significantly increased in the parents, compared to that reported for the general population, in this pilot survey of 61 patients evaluated for major childhood psychoses. In addition, 18% of our patients had a history of early gestational exposure to progesterone/estrogen compounds (9 patients) and to cortisone (2 patients). This frequency of gestational hormoné exposure was significantly increased over that in normal infants from three published surveys. However, in 5 of the 11 patients with gestational hormonal exposure, the medication was prescribed because of prior parental reproductive problems or bleeding during the current pregnancy. Therefore, it cannot be concluded that the gestational hormonal exposure was causally related to the psychoses present in these patients. In order to obtain more conclusive data, there will need to be continued monitoring of parental reproductive histories and gestational environmental exposures in autistic and schizophrenic children.
    PMID: 6643376

  see also:

Hormones and Heavy Metals in Autism
Hormones and Autism

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