Disorders of Sex Development

Disorders of Sex Development

Division of Neonatology, Perrino Hospital, Brindisi, Italy;

2 Clinical Physiology Institute, National Research Council of

Italy (IFC-CNR); 3 Purdue University, Department of Industrial and Physical Pharmacy,575 Stadium Mall Dr., West

Lafayette, IN 47907; 4 Food and Veterinary Toxicology Unit, Dept. Veterinary Public Health and Food Safety, Istituto

Superiore di Sanità, Viale Regina Elena, 299 00161, Rome; 5 Department of Pediatrics, University of Chieti, via dei

Vestini 5, Chieti, Italy; 6 Department of Women’s and Children’s Health, Paediatric Endocrinology Unit, Karolinska

Institute and University Hospital, S-17176, Stockholm, Sweden

Abstract: Endocrine-disrupting chemicals (EDCs) are a group of diversely natural compounds or synthetic chemicals that

can interfere with the programming of normal endocrine-signalling pathways during pre- and neonatal life, thus leading to

adverse consequences later in life. In addition, early life exposure to EDCs may alter gene expression and consequently

transmit these effects to future generations.

Keywords: Endocrine-disruptors, environment, endocrine system, phthalates, pregnancy, neonate, fetal.


Endocrine-disrupting chemicals (EDCs) are a large and increasing group of diversely natural compounds or synthetic chemicals present in the environment that include persistent halogenated pollutants, such as polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and me- tabolites, industrial compounds, such as bisphenol A (BPA), alkylphenols and phthalate acid esters, as well as pharmaceu- ticals, pesticides, such as chlorpyrifos, fungicides including vinclozalin and phytoestrogens.

Man-made EDCs range across all continents and oceans. EDCs, which are typically present as complex mixtures and not as single substances, may mimic, block or modulate the synthesis, release, transport, binding, metabolism and/or elimination of natural endogenous hormones in wild animals and humans [1]. In particular, EDC may interfere with hor- monal signalling systems and alter feedback loops in the brain, pituitary, gonads, thyroid, and other components of the endocrine system.

Growing evidence shows that EDC may also modulate the activity/expression of steroidogenic enzymes and steroi- dogenic pathways [2-5].

In addition, EDC can also promote activation of meta- bolic sensors, such as the peroxisome proliferator-activated receptors (PPARs) [6]. As a consequence, there is an increas- ing concern worldwide on the potential adverse effects of ED on human health, although their impact on human be- ings’ health is not yet clear.

However, endocrine signalling pathways play an impor- tant role during prenatal differentiation; thus, developing organisms may be particularly sensitive to ED effects. In

*Address correspondence to this author at the Division of Neonatology,

Ospedale A. Perrino, s.s. 7 per Mesagne, 72100 Brindisi, Italy;

Tel: +39-0831-537471; Fax: +39-0831-537861; E-mail:gilatini@tin.it

fact, scientific evidence indicate that exposure to ED during critical periods of development can induce permanent changes in several organs, including molecular alterations, although the consequences of this disruption may not appear until later [7-11]. The mechanisms by which ED exert their action remain largely unclear; however, many ways have been identified by which ED can affect signal transduction systems [12].

Early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation, thus interfering with the germ-line. By contaminating the environment with ED hu- man race might be permanently affecting the health of sub- sequent generations [13-15]. Within the broad ED topic we have focussed on specific issues, selected since they are highly relevant to the up-to-date assessment of potential hu- man health risks from ED exposure.



Diet is a significant source of exposure to ED for the general population, as well as a source of concern for con- sumers’ health. One major issue is the “cocktail” effect: one cannot rule out additivity of different ED present in whole diet at low level, but hitting the same targets, e.g. nuclear receptors [16]. Furthermore, it is not just the daily dose that matters. Many ED can bioaccumulate in lipid fraction of tissues, originating a mixture “body burden” of contaminants of different origin that can include dioxins, polychlorinated biphenyls, chlorinated pesticides and their metabolites, as well as brominated flame retardants [17]. Other compounds may also concentrate in food chains, thus adding to the over- all ED burden, e.g., organotins [18]. However, the modern conception of food toxicology cannot consider diet just as an exposure source of external harmful substances. Contami- nants such as ED may interact with the same metabolic pathways as natural food components such as polyunsatu-

Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 847

rated fatty acids, trace elements, vitamins and other bioactive substances (e.g. polyphenols) that cannot be considered nu- trients as there is no recognized deficiency [19]. Dietary hab- its are related to socioeconomic status, cultural and religious factors, individual choices (e.g. vegetarianism/veganism); and dietary habits themselves may have the most important impact on the intake of both nutrients and contaminants. For instance, greater exposure to persistent ED is associated with the high consumption of fatty foods of animal origin [20, 21]. Thus, for specific food commodities a balanced evalua- tion is needed about contaminant-associated risks and nutri- tional benefits. A relevant example is represented by salmon- ids and other seafood, a useful source of nutrients such as polyunsaturated fatty acids as well as a major source of ED and other bioaccumulating contaminants, such as meth- ylmercury. Evidence might justify recommendations to in- crease as well as to reduce fish consumption, quite an uneasy situation for risk managers: decreasing fish consumption (and its nutritional benefits) may not be necessary in Europe, but monitoring of contaminants in edible fish should be con- tinued, as well as the development of novel aquaculture feeds, less liable to contamination [22].

Most important, effects of contaminants and natural food components may interact on the same pathways and targets. The outcomes of interactions may be complex, depending on dose and targets; e.g., phytoestrogens can protect against some hormone-dependent cancers, as well as postmeno- pausal osteoporosis, but may also interfere with receptor- mediated signal transduction (e.g. by inhibiting protein kinase) and DNA replication [23]. Up to date, scientific data available on interactions between xenobiotics and “natural” substances in food are still limited; below, some relevant examples are provided

Iodine and ED

Iodine is the main determinant of thyroid development and function; seafood and milk are the main dietary sources. Subclinical iodine deficiency is still a common problem in many areas, including Europe [24]; thyroid is also increas- ingly recognized as a major target for ED, including newly recognized ones, such as organpophopsphorus insecticides [25]. Yet, only a few papers target low iodine status in rela- tion to susceptibility to xenobiotics. Somewhat unexpectedly phthalates, the widespread plasticizers known mainly as antiandrogens, can modulate basal iodide uptake mediated by the sodium/iodide symporter in thyroid follicular cells in vitro: the effect was not shared by all phthalates and was independent from cytotoxicity [26]. Many phytoestrogens may interfere with iodination of thyroid hormones. Some (e.g., naringenin, and quercetin, which contain a resorcinol moiety) are direct and potent inhibitors of thyroid peroxi- dase, others (myricetin, naringin) show noncompetitive inhibition of tyrosine iodination with respect to iodine ion, whereas biochanin A may act as an alternate substrate for iodination [27]. A Czech biomonitoring study in children also indicated an adverse effect of genistein on thyroid func- tion [28]. The drinking-water contaminant perchlorate inhib- its thyroidal iodide uptake; however, iodine-deficient female rats were more resistent to the inhibition of iodine absorption from perchlorate exposure than normal rats [29]. Thus, the

interaction between iodine and some thyroid-targeting ED may be less straightforward than expected.

Phytoestrogens and the “xeno”ED

Due to their pleomorphic biological effects, phytoestro- gens are a sort of “natural ED”, whose overall dietary intake of phytoestrogens may be significant also in Europe [23, 30, 31]. Flavonoids (daidzein, genistein, quercetin, and luteolin) can at least partly antagonize the proliferation-stimulating activity of synthetic estrogenic ED in estrogen-dependent MCF-7 human breast cancer cells: thee ED included anionic detergent by-products alkylphenols, plastic additive bisphe- nol A, and the PCB 4-dihydroxybiphenyl [32, 33]. These findings suggest that phytoestrogens can compete with es- trogenic ED on shared biological targets, thus exerting a pro- tective action . In other models no interaction was observed: genistein did not modulate the effects on human astroglial cells by two persistent ED, the polybrominated flame retardant PBDE-99 and the PCB mixture Aroclor 1254 [34]. As it is sometimes the case, in vivo studies provide a more complex picture. Genistein and the estrogenic chlorinated insecticide methoxychlor had an additive impact on both immune function and immune functional development in rats; the developing thymus appeared as a sensitive target of combined exposure [35]. In estrogen reporter (ERE-tK- Luciferase) male mice genistein modulated the actions of both estradiol and persistent ED in liver and testis with tis- sue-specific features: the antiestrogenic action of beta- hexachlorocyclohexane in the testis and o,p’-DDT in the liver was antagonized, whereas genistein had an additive effect with the ER agonist p,p’-DDT in the liver [36]. Two predefined mixtures of phytoestrogens and synthesis ED were tested in the uterotrophic assay on prepubertal rats: the composition of each mixture (what chemicals and to what amount) was based on human exposure data. The phytoes- trogen mixture did elicit an uterotrophic response, whereas the synthetic one has no effect itself nor an additive effect with phytoestrogens, possibly because of exposure levels too low [37]. The combined exposure to estrogenic and antian- drogenic ED is suggested as a potential risk to male repro- ductive development. Genistein and the antiandrogenic fun- gicide vinclozolin, alone or in combination, were investi- gated concerning the induction of hypospadias in mice: the incidences were 25%,, 42% and 41% for genistein, vinclo- zolin and combined treatment, respectively, indicating a less than additive effect [38]. On the other hand, genistein, as well as the methyl donor folic acid, both antagonized the DNA hypomethylating effect of bisphenol A in mouse em- bryos [39]. The available data indicate that interactions be- tween phytoestrogens and ED can be important, but cannot simply explained in terms of additivity or antagonism; in- deed, additivity and antagonism may vary, depending on the chemicals, endpoints and lifestages.

ED and Vitamin A Pathways

Retinoic acid is the internal form of vitamin A interacting with the nuclear receptors RAR and RXR, whose natural ligands are all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoic acid pathways cross-talk with those of the aryl hydrocarbon receptor (AhR), the direct cell target for dioxins and dioxin-like compounds [40]. Dioxins are potent

848 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 Latini et al.
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