Comprehensive Assessment of Germline Chemical Toxicity Using the Nematode <em>Caenorhabditis elegans</em>

Identifying the reproductive toxicity of the thousands of chemicals present in our environment has been one of the most tantalizing challenges in the ...

University of California, Los Angeles

The objective of this study was to compare the expression of Col1a1, Col1a2, and procollagen I in the seminiferous tubules of immature and adult mice and to characterize the cellular expression pattern of procollagen I in germ cells during spermatogenesis in order to provide necessary groundwork for further functional studies in the process of spermatogenesis. Microarray analysis demonstrated that Col1a1 and Col1a2 were abundantly expressed in the seminiferous tubules of 6-day-old mice compared with 60-day-old mice, and the expression levels of Col1a1 and Col1a2 mRNA were validated using a semi-quantitative RT-PCR assay. Western blot analysis further confirmed that procollagen I was expressed at a higher level in the seminiferous tubules of 6-day-old mice compared with 60-day-old mice. Immunohistochemical analysis revealed that type A spermatogonia were positive for procollagen I in the testis of 6-day-old mice, whereas Sertoli cells were negative for this protein. The in vivo procollagen I staining in type A spermatogonia was corroborated in spermatogonia exhibiting a high potential for proliferation and the ability to form germ cell colonies in in vitro culture. Moreover, procollagen I was also detected in type A spermatogonia, intermediate spermatogonia, type B spermatogonia, and preleptotene spermatocytes in the adult mouse testes, but positive staining disappeared in more differentiated germ cell lineages detaching from the basement membrane, including leptotene spermatocytes, pachytene spermatocytes, round spermatids and elongated spermatids. These data suggest that Col1a1, Col1a2 and procollagen I are associated with type A spermatogonia and play a potential role in mediating the detachment and migration of germ cells during spermatogenesis.

Expression of Col1a1, Col1a2 and procollagen I in germ cells of immature and adult mouse testis.

To determine the prevalence of AZFc subdeletions in infertile Chilean men with severe spermatogenic impairment.

AZFc partial deletions in Chilean men with severe spermatogenic failure.

Cadmium is a heavy metal that is often referred to as the metal of the 20th century. It is widely used in industry principally in galvanizing and electroplating, in batteries, in electrical conductors, in the manufacture of alloys, pigments, and plastics, and in the stabilization of phosphate fertilizers. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. In the general population, exposure to cadmium occurs primarily through dietary sources, cigarette smoking, and, to a lesser degree, drinking water. Although the metal has no known physiological function, there is evidence to suggest that the cadmium is a potent metallohormone. This review summarizes the increasing evidence that cadmium mimics the function of steroid hormones, addresses our current understanding of the mechanism by which cadmium functions as a hormone, and discusses its potential role in development of the hormone dependent cancers.

Cadmium--a metallohormone?

Metalloestrogens son metales que activan el receptor del estr&oacute;geno en la ausencia de estradiol. Las metalloestrogens se dividen en dos subclases: metal/metaloide aniones y los metales bivalentes cati&oacute;nicos. Los aniones de metal/metaloide incluyen compuestos como arsenito, nitrito, selenita y vanadato mientras que los cationes bivalentes incluyen metales como el cadmio, calcio, cobalto, cobre, n&iacute;quel, cromo, plomo, mercurio y esta&ntilde;o. El metalloestrogen mejor estudiado es el cadmio. Es un metal pesado y un contaminante ambiental com&uacute;n con ninguna funci&oacute;n fisiol&oacute;gica conocida. Esta revisi&oacute;n dirige a nuestra actual comprensi&oacute;n del mecanismo por el cual cadmio y los metales bivalentes de cati&oacute;nicos activar&aacute;n del receptor de estr&oacute;geno-&alpha;. La revisi&oacute;n tambi&eacute;n resume las pruebas in vitro e in vivo que el cadmio funciona como un estr&oacute;geno y el papel potencial del cadmio en el c&aacute;ncer de mama.

Metales y c&aacute;ncer de mama.

Metalloestrogens &#x662F;&#x96CC;&#x4E8C;&#x9187;&#x7684;&#x6FC0;&#x6D3B;&#x4E2D;&#x7F3A;&#x4E4F;&#x96CC;&#x6FC0;&#x7D20;&#x53D7;&#x4F53;&#x7684;&#x91D1;&#x5C5E;&#x3002;Metalloestrogens &#x53EF;&#x5206;&#x4E3A;&#x4E24;&#x4E2A;&#x5B50;&#x7C7B;&#xFF1A; &#x91D1;&#x5C5E;/&#x975E;&#x91D1;&#x5C5E;&#x9634;&#x79BB;&#x5B50;&#x548C;&#x4E8C;&#x4EF7;&#x9633;&#x79BB;&#x5B50;&#x91D1;&#x5C5E;&#x3002;&#x91D1;&#x5C5E;/&#x975E;&#x91D1;&#x5C5E;&#x9634;&#x79BB;&#x5B50;&#x5305;&#x62EC;&#x7837;&#x3001; &#x4E9A;&#x785D;&#x9178;&#x76D0;&#x3001; &#x4E9A;&#x7852;&#x9178;&#x76D0;&#xFF0C;&#x9492;&#x9178;&#x7B49;&#x5316;&#x5408;&#x7269;&#xFF0C;&#x800C;&#x4E8C;&#x4EF7;&#x9633;&#x79BB;&#x5B50;&#x5305;&#x62EC;&#x9549;&#x3001; &#x9499;&#x3001; &#x94B4;&#x3001; &#x94DC;&#x3001; &#x954D;&#x3001; &#x94EC;&#x3001; &#x94C5;&#x3001; &#x6C5E;&#x3001; &#x9521;&#x7B49;&#x91D1;&#x5C5E;&#x3002;&#x6700;&#x4F73;&#x7684;&#x7814;&#x7A76;&#x7684; metalloestrogen &#x662F;&#x9549;&#x3002;&#x5B83;&#x662F;&#x91CD;&#x91D1;&#x5C5E;&#x548C;&#x666E;&#x904D;&#x7684;&#x73AF;&#x5883;&#x6C61;&#x67D3;&#x7269;&#xFF0C;&#x4E0E;&#x4EFB;&#x4F55;&#x5DF2;&#x77E5;&#x7684;&#x751F;&#x7406;&#x529F;&#x80FD;&#x3002;&#x6B64;&#x5BA1;&#x67E5;&#x5904;&#x7406;&#x6211;&#x4EEC;&#x5F53;&#x524D;&#x7406;&#x89E3;&#x5176;&#x4E2D;&#x9549;&#x548C;&#x4E8C;&#x4EF7;&#x9633;&#x79BB;&#x5B50;&#x91D1;&#x5C5E;&#x6FC0;&#x6D3B;&#x96CC;&#x6FC0;&#x7D20;&#x53D7;&#x4F53; &alpha; &#x7684;&#x673A;&#x5236;&#x3002;&#x5BA1;&#x67E5;&#x8FD8;&#x603B;&#x7ED3;&#x4E86;&#x9549;&#x4F5C;&#x4E3A;&#x96CC;&#x6FC0;&#x7D20;&#x548C;&#x9549;&#x5728;&#x4E73;&#x817A;&#x764C;&#x7EC4;&#x7EC7;&#x4E2D;&#x7684;&#x6F5C;&#x5728;&#x4F5C;&#x7528;&#x7684;&#x4F53;&#x5916;&#x548C;&#x4F53;&#x5185;&#x7684;&#x8BC1;&#x636E;&#x3002;

&#x91D1;&#x5C5E;&#x548C;&#x4E73;&#x817A;&#x764C;&#x3002;

Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-Î±. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer.

Metals and breast cancer.

Metalloestrogens sont les m&eacute;taux qui activent le r&eacute;cepteur des oestrog&egrave;nes en l&#39;absence d&#39;estradiol. Les metalloestrogens se r&eacute;partissent en deux sous-classes : les anions m&eacute;tal/m&eacute;tallo&iuml;de et m&eacute;taux cationiques bivalents. Les anions de m&eacute;tal/m&eacute;tallo&iuml;de comprennent des compos&eacute;s comme l&#39;ars&eacute;nite, nitrite, s&eacute;l&eacute;nite et vanadate tandis que les cations bivalentes comprennent des m&eacute;taux tels que le cadmium, calcium, cobalt, cuivre, nickel, chrome, plomb, mercure et d&#39;&eacute;tain. Le metalloestrogen les mieux &eacute;tudi&eacute;e est de cadmium. C&#39;est un m&eacute;tal lourd et un contaminant environnemental r&eacute;pandu sans fonction physiologiques connus. Cette revue traite de notre compr&eacute;hension actuelle du m&eacute;canisme par lequel le cadmium et les m&eacute;taux cationiques bivalents activent estrogen receptor-&alpha;. La synth&egrave;se r&eacute;sume aussi la preuve in vitro et in vivo que cadmium fonctionne comme un oestrog&egrave;ne et le r&ocirc;le potentiel du cadmium dans le cancer du sein.

Les m&eacute;taux et le cancer du sein.

Metalloestrogens sind Metalle, die der Estrogenrezeptor in Ermangelung von &Ouml;stradiol zu aktivieren. Die Metalloestrogens lassen sich in zwei Unterklassen: Metall/Halbmetalle Anionen und bivalenten kationische Metalle. Metall/Halbmetalle Anionen umfassen Verbindungen wie arsenit, Nitrit, Selenit und Vanadate, w&auml;hrend die zweiwertigem kationen Metalle wie Cadmium, Kalzium, Kobalt, Kupfer, Nickel, Chrom, Blei, Quecksilber und Zinn umfassen. Die am besten untersuchte Metalloestrogen ist Kadmium. Es ist ein Schwermetall und vorherrschende Umwelt Verunreinigung mit keine bekannte physiologische Funktion. Diese Bewertung richtet sich unser gegenw&auml;rtige Verst&auml;ndnis des Mechanismus, Cadmium und bivalenten kationische Metalle &Ouml;strogen-Rezeptor-&alpha; aktivieren. Die &Uuml;berpr&uuml;fung wird auch der in-vitro und in vivo Beweis, dass Kadmium als ein &Ouml;strogen und die potenzielle Rolle von Cadmium in Brustkrebs fungiert zusammengefasst.

Metalle und Brustkrebs.

Metalloestrogens sono i metalli che attivano il recettore estrogeno in assenza di estradiolo. Il metalloestrogens si dividono in due sottoclassi: metallo/metalloide anioni e metalli bivalenti cationici. Gli anioni metallo/metalloide includono composti quali arsenito, nitrito, selenite e vanadato mentre i cationi bivalenti includono metalli come cadmio, calcio, cobalto, rame, nichel, cromo, piombo, mercurio e stagno. Il metalloestrogen ha studiato meglio &egrave; cadmio. Esso &egrave; un metallo pesante e contaminanti ambientali prevalenti con alcuna funzione fisiologica conosciuta. Questa recensione si rivolge la nostra attuale comprensione del meccanismo mediante il quale cadmio e metalli bivalenti cationici attivano estrogeno recettore-&alpha;. La revisione inoltre riassume le prove in vitro e in vivo che cadmio funzioni come un estrogeno e il ruolo potenziale di cadmio nel cancro al seno.

Metalli e cancro al seno.

Metalloestrogens &#x30A8;&#x30B9;&#x30C8;&#x30E9;&#x30B8; &#x30AA;&#x30FC;&#x30EB;&#x306E;&#x30A8;&#x30B9;&#x30C8;&#x30ED;&#x30B2;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x3092;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306B;&#x3059;&#x308B;&#x91D1;&#x5C5E;&#x3067;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;2 &#x3064;&#x306E;&#x30B5;&#x30D6;&#x30AF;&#x30E9;&#x30B9;&#x306B;&#x306F; metalloestrogens &#x306B;&#x843D;&#x3061;&#x308B;: &#x91D1;&#x5C5E;/&#x30E1;&#x30BF;&#x30ED;&#x30A4;&#x30C9;&#x9670;&#x30A4;&#x30AA;&#x30F3;&#x3068; 2&#x4FA1;&#x967D;&#x30A4;&#x30AA;&#x30F3;&#x6027;&#x91D1;&#x5C5E;&#x3002;&#x4E8C;&#x4FA1;&#x306E;&#x967D;&#x30A4;&#x30AA;&#x30F3;&#x91D1;&#x5C5E;&#x30AB;&#x30C9;&#x30DF;&#x30A6;&#x30E0;&#x3001;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x3001;&#x30B3;&#x30D0;&#x30EB;&#x30C8;&#x3001;&#x9285;&#x3001;&#x30CB;&#x30C3;&#x30B1;&#x30EB;&#x3001;&#x30AF;&#x30ED;&#x30E0;&#x3001;&#x925B;&#x3001;&#x6C34;&#x9280;&#x3001;&#x304A;&#x3088;&#x3073;&#x30B9;&#x30BA;&#x306A;&#x3069;&#x304C;&#x91D1;&#x5C5E;/&#x30E1;&#x30BF;&#x30ED;&#x30A4;&#x30C9;&#x9670;&#x30A4;&#x30AA;&#x30F3;&#x306B;&#x306F;&#x4E9C;&#x30D2;&#x9178;&#x3001;&#x4E9C;&#x785D;&#x9178;&#x3001;&#x4E9C;&#x30BB;&#x30EC;&#x30F3;&#x9178;&#x3001;&#x304A;&#x3088;&#x3073;&#x30D0;&#x30CA;&#x30B8;&#x30F3;&#x9178;&#x5869;&#x306A;&#x3069;&#x306E;&#x5316;&#x5408;&#x7269;&#x304C;&#x542B;&#x307E;&#x308C;&#x307E;&#x3059;&#x3002;&#x6700;&#x9AD8;&#x306E;&#x7814;&#x7A76; metalloestrogen &#x30AB;&#x30C9;&#x30DF;&#x30A6;&#x30E0;&#x3067;&#x3059;&#x3002;&#x91CD;&#x91D1;&#x5C5E;&#x3068;&#x3001;&#x6D41;&#x884C;&#x3057;&#x3066;&#x3044;&#x308B;&#x74B0;&#x5883;&#x6C5A;&#x67D3;&#x7269;&#x8CEA;&#x306E;&#x306A;&#x3044;&#x65E2;&#x77E5;&#x306E;&#x751F;&#x7406;&#x6A5F;&#x80FD;&#x3068;&#x3067;&#x3059;&#x3002;&#x3053;&#x306E;&#x30EC;&#x30D3;&#x30E5;&#x30FC; &#x30AB;&#x30C9;&#x30DF;&#x30A6;&#x30E0;&#x3068; 2&#x4FA1;&#x967D;&#x30A4;&#x30AA;&#x30F3;&#x6027;&#x91D1;&#x5C5E;&#x30A8;&#x30B9;&#x30C8;&#x30ED;&#x30B2;&#x30F3;&#x53D7;&#x5BB9;&#x4F53; &alpha; &#x30E9;&#x30A4;&#x30BB;&#x30F3;&#x30B9;&#x8A8D;&#x8A3C;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306E;&#x73FE;&#x5728;&#x306E;&#x7406;&#x89E3;&#x306F;&#x79C1;&#x305F;&#x3061;&#x306B;&#x5BFE;&#x51E6;&#x3057;&#x307E;&#x3059;&#x3002;&#x30EC;&#x30D3;&#x30E5;&#x30FC;&#x3082;&#x30AB;&#x30C9;&#x30DF;&#x30A6;&#x30E0;&#x3001;&#x30A8;&#x30B9;&#x30C8;&#x30ED;&#x30B2;&#x30F3;&#x3001;&#x4E73;&#x764C;&#x306B;&#x304A;&#x3051;&#x308B;&#x30AB;&#x30C9;&#x30DF;&#x30A6;&#x30E0;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x5F79;&#x5272;&#x3068;&#x3057;&#x3066;&#x6A5F;&#x80FD;&#x3057;&#x3066;&#x3044;&#x308B; in vitro &#x304A;&#x3088;&#x3073; in vivo &#x3067;&#x306E;&#x8A3C;&#x62E0;&#x3092;&#x307E;&#x3068;&#x3081;&#x305F;&#x3082;&#x306E;&#x3067;&#x3059;&#x3002;

&#x91D1;&#x5C5E;&#x3068;&#x4E73;&#x304C;&#x3093;&#x3002;

Metalloestrogens&#xB294; &#xAE08;&#xC18D; estradiol&#xC758; &#xBD80;&#xC7AC;&#xC5D0; &#xC2A4; &#xD2B8;&#xB85C; &#xAC90; &#xC218;&#xC6A9; &#xCCB4;&#xB97C; &#xD65C;&#xC131;&#xD654; &#xD558;&#xB294;. &#xB450; &#xAC1C;&#xC758; &#xD558;&#xC704; &#xD074;&#xB798;&#xC2A4;&#xC5D0;&#xB294; metalloestrogens&#xAC00;&#xC744;: &#xAE08;&#xC18D;/&#xC900;&#xAE08;&#xC18D; &#xC74C;&#xC774;&#xC628;&#xACFC; &#xC591;&#xC774;&#xC628; &#xAE08;&#xC18D; &#xB0B8;&#xB2E4;. &#xAE08;&#xC18D;/&#xC900;&#xAE08;&#xC18D; &#xC74C;&#xC774;&#xC628;&#xC774; &#xC591;&#xC774;&#xC628; &#xAE08;&#xC18D; &#xCE74;&#xB4DC;&#xBBB4;, &#xCE7C;&#xC298;, &#xCF54;&#xBC1C;&#xD2B8;, &#xAD6C;&#xB9AC;, &#xB2C8;&#xCF08;, &#xD06C;&#xB86C;, &#xB0A9;, &#xC218;&#xC740;, &#xADF8;&#xB9AC;&#xACE0; &#xC8FC;&#xC11D; &#xB4F1;&#xC744; &#xD3EC;&#xD568; &#xD558;&#xB294; &#xB3D9;&#xC548; arsenite, &#xC544; &#xC9C8;&#xC0B0;&#xC5FC;, selenite, &#xBC14; &#xB4F1; &#xD654;&#xD569;&#xBB3C;&#xC744; &#xD3EC;&#xD568;. &#xCD5C;&#xACE0;&#xC758; &#xACF5;&#xBD80; metalloestrogen &#xCE74;&#xB4DC;&#xBBB4;&#xC740;. &#xC911; &#xAE08;&#xC18D; &#xBC0F; &#xC544;&#xBB34; &#xC54C;&#xB824;&#xC9C4;&#xB41C; &#xC0DD;&#xB9AC; &#xC801; &#xAE30;&#xB2A5;&#xC744; &#xAC00;&#xC9C4; &#xC720;&#xD589; &#xD658;&#xACBD; &#xC624;&#xC5FC; &#xBB3C;&#xC9C8; &#xC774;&#xB2E4;. &#xC774; &#xAC80;&#xD1A0;&#xB294; &#xCE74;&#xB4DC;&#xBBB4;&#xACFC;&#xAC00; &#xC591;&#xC774;&#xC628; &#xAE08;&#xC18D; &#xC5D0;&#xC2A4;&#xD2B8;&#xB85C;&#xAC90; &#xC218;&#xC6A9; &#xCCB4;-&alpha;&#xB97C; &#xD65C;&#xC131;&#xD654; &#xD558;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC5D0; &#xB300; &#xD55C; &#xC6B0;&#xB9AC;&#xC758; &#xD604;&#xC7AC; &#xC774;&#xD574;&#xB97C; &#xD574;&#xACB0; &#xD569;&#xB2C8;&#xB2E4;. &#xAC80;&#xD1A0;&#xC5D0;&#xB294; &#xCE74;&#xB4DC;&#xBBB4;&#xC73C;&#xB85C;&#xB294; &#xC5D0;&#xC2A4;&#xD2B8;&#xB85C;&#xAC90;&#xACFC; &#xC720;&#xBC29;&#xC554;&#xC5D0; &#xCE74;&#xB4DC;&#xBBB4;&#xC758; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC5ED;&#xD560; &#xAE30;&#xB2A5; &#xC0DD;&#xCCB4; &#xC678; &#xBC0F; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; &#xC99D;&#xAC70; &#xC694;&#xC57D; &#xB418;&#xC5B4; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xAE08;&#xC18D; &#xBC0F; &#xC720; &#xBC29; &#xC554;&#xC785;&#xB2C8;&#xB2E4;.

Early life exposure to estrogens and estrogen like contaminants in the environment is thought to contribute to the early onset of puberty and consequently increases the risk of developing breast cancer in the exposed female. The results of this study show that in utero exposure to the metalloestrogen arsenite altered mammary gland development prior to its effect on puberty onset. In the prepubertal gland, in utero exposure resulted in an increase in the number of mammosphere-forming cells and an increase in branching, epithelial cells, and density. In the postpubertal gland, in utero exposure resulted in the overexpression of estrogen receptor-alpha (ERα) that was due to the increased and altered response of the ERα transcripts derived from exons O and OT to estradiol. These results suggest that, in addition to advancing puberty onset, in utero exposure to arsenite alters the pre- and postpubertal development of the mammary gland and possibly, the risk of developing breast cancer.

Daniela A. Parodi

Institute for Society and Genetics

University of California, Los Angeles

Comprehensive Assessment of Germline Chemical Toxicity Using the Nematode Caenorhabditis elegans

Daniela A. Parodi

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Institute for Society and Genetics

University of California, Los Angeles

Comprehensive Assessment of Germline Chemical Toxicity Using the Nematode Caenorhabditis elegans

Institute for Society and Genetics