Abnormal Development - Heavy Metals
|Embryology - 20 Feb 2017 Expand to Translate|
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The industrialization of the modern world has led to the proliferation in our environment of many different metal compounds. Some metals, such as zinc and iron are required in trace amounts for many biological functions. Other metals such as lead and mercury have had significant toxic effects on development.
There are historic examples of large scale disasters, for example the mercury poisoning of waterways in Japan (More? Mercury) Mercury poisoning (by methyl mercury) or Minamata disease had substantial neurological effects similar to Hunter Russell syndrome.
In addition to their direct toxic effects, the potential reduction in fetal growth and long-term effects should also be considered. Much of the basic research relies on studies in various animal models of development and we should also consider the ongoing development of new industrial products in the environment with unknown or untested effects upon development.
The specific effects of some metals are detailed in Safety and Data Sheets (SDSs), previously Material Safety and Data Sheets or MSDSs, available from an chemical index page that relate to developmental abnormalities. These sheets are now generally required to be supplied along with the chemical purchased from a supplier and give a standardised description of the chemical, its physical properties, handling and health effects/toxicity. There are also several internet sites that have searchable databases of SDS information. Note that handling chemical safety has previously varied from country to country. Recently the WHO has developed an internationally agreed-upon system Globally Harmonized System of Classification and Labeling of Chemicals (GHS) that will eventually standardise this information (see also Abnormal Development - Chemicals).
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Zivanit Ergaz, Meytal Neeman-Azulay, Liza Weinstein-Fudim, Sarah Weksler-Zangen, Dana Shoshani-Dror, Moshe Szyf, Asher Ornoy Diabetes in the Cohen Rat Intensifies the Fetal Pancreatic Damage Induced by the Diabetogenic High Sucrose Low Copper Diet. Birth Defects Res. B Dev. Reprod. Toxicol.: 2016; PubMed 26748987
Thijs R A Vandenbroucke, Poul Emsbo, Axel Munnecke, Nicolas Nuns, Ludovic Duponchel, Kevin Lepot, Melesio Quijada, Florentin Paris, Thomas Servais, Wolfgang Kiessling Metal-induced malformations in early Palaeozoic plankton are harbingers of mass extinction. Nat Commun: 2015, 6;7966 PubMed 26305681
A Ornoy, L Weinstein-Fudim, Z Ergaz Prenatal factors associated with Autism Spectrum Disorder (ASD). Reprod. Toxicol.: 2015; PubMed 26021712
Marc Oppermann, Cornelia Borisch, Christof Schaefer Hip arthroplasty with high chromium and cobalt blood levels-Case report of a patient followed during pregnancy and lactation period. Reprod. Toxicol.: 2015; PubMed 25828057
Edwin Trevathan Editorial brain malformation surveillance in the Zika era. Birth Defects Res. Part A Clin. Mol. Teratol.: 2016, 106(11);869-874 PubMed 27891785
Emma Brown, Elizabeth Hotham, Neil Hotham Pregnancy and lactation advice: How does Australian Product Information compare with established information resources? Obstet Med: 2016, 9(3);130-134 PubMed 27630750
Teresa Dodd-Butera, Penelope J E Quintana, Martha Ramirez-Zetina, Ana C Batista-Castro, Maria M Sierra, Carolyn Shaputnic, Maura Garcia-Castillo, Sonja Ingmanson, Stacy Hull Placental biomarkers of PAH exposure and glutathione-S-transferase biotransformation enzymes in an obstetric population from Tijuana, Baja California, Mexico. Environ. Res.: 2016; PubMed 27567517
Lin Ge, Kang-Shuai Li, Meng-Meng Li, Peng Xiao, Xu-Ben Hou, Xu Chen, Hong-da Liu, Amy Lin, Xiao Yu, Gui-Jie Ren, Hao Fang, Jin-Peng Sun Identification of a benzo imidazole thiazole derivative as the specific irreversible inhibitor of protein tyrosine phosphatase. Bioorg. Med. Chem. Lett.: 2016; PubMed 27554446
|Heavy Metals Toxicity (Table: U.S. GEOLOGICAL SURVEY CIRCULAR 1133, 1995)|
In another recent study using the sea urchin embryo, Japanese researchers have identified a hierarchy of toxic effects from different heavy metals.
"Interactive toxic effects between heavy metals were investigated using a sea urchin (Anthocidaris crassispina) bioassay. An effluent from an abandoned mine showed significant inhibitory effects on embryo development as well as producing specific malformations. The effects on the embryos were reproduced by synthetic polluted seawater consisting of eight metals (manganese, lead, cadmium, nickel, zinc, chromium, iron, and copper) at the concentrations detected in the mine effluent. This indicated that the heavy metals were responsible for the effects observed. Five heavy metals were ranked in decreasing order of toxicity as follows: Cu > Zn > Pb > Fe > Mn. Among these, zinc and manganese could cause malformation of the embryos. From bioassay results using 27 combinations of heavy metals, 16 combinations including zinc could produce specific malformations, such as radialized, exo-gastrulal, and spaceship Apollo-like gastrulal embryos. Zinc was one of the elements responsible for causing malformations and its effects were intensified by the presence of the other metals, such as manganese, lead, iron, and copper." Naomasa Kobayashia and Hideo Okamurab.
Metal in Water
A major dilemma is the biological difficulty of clearing heavy metals and the subsequent accumulation of these metals in the food chain mainly from the hydrologic environment.
Lead in the environment is postnatally toxic and prenatally teratogenic. Lead exposure can occur in industrial and mining and can also be derived from leaded petrol, old lead piping, historic paints, and other environmental sources).
For children aged less than 6 years of age the CDC (USA) has defined an elevated blood lead level (BLL) as >10 µg/dL, but also indicated that evidence exists for subtle effects at lower levels. (Links: CDC - Lead Poisoning Prevention Program | Blood Lead Levels in Young Children - United States and Selected States 1996-1999)
- Lead crosses the placental barrier readily.
- Fetal blood levels are directly proportional to maternal levels.
- Lead poisoning affects virtually every system in the body, and often occurs with no distinctive symptoms.
- Lead in our diet is mainly found in osseous (bone) structures.
- Lead can damage a child's central nervous system, kidneys, and reproductive system and, at higher levels, can cause coma, convulsions, and death.
- Even low levels of lead are harmful and are associated with decreased intelligence, impaired neurobehavioral development, decreased stature and growth, and impaired hearing acuity.
- CDC has established a national surveillance system for children with elevated blood lead levels.
- CDC helped to initiate federal activities to reduce lead in gasoline, which brought about declines in average blood lead levels in the U.S. population. Data from the most recent National Health and Nutrition Examination Survey (NHANES) show that the percentage of U.S. children with elevated blood lead levels has dropped from 88.2% in the late 1970s to 4.4% in the early 1990s. (NHANES Chart)
- Interrelations of lead levels in bone, venous blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in peripartum women
- Effect of breast milk lead on infant blood lead levels at 1 month of age
- Links: Normal Development - Milk | CDC - Childhood Lead Poisoning Publications | Global Alliance to Eliminate Lead Paint
Used traditionally in the felting of hats, hence "mad hatters", a more recent example of mercury's toxicity was shown in Japan.
|Japan Minamata disease map|
Japan had industrial mercury poisoning of waterways by methyl mercury causing Minamata disease, which had substantial neurological effects similar to Hunter Russell syndrome. For more information on mercury the chemical, see Mercury MSDS. There has also been a movie available "Medical Study of Minamata Disease".
Australia - Food Standards Australia New Zealand (FSANZ)
"FSANZ’s Chief Scientist, Dr Marion Healy, said ‘Our investigations show that the level of mercury in most fish caught and sold in Australia is low."
"The Australian Dietary Guidelines advise eating one or two fish meals per week for good health. The good news is that FSANZ has found it is safe for all population groups to eat 2-3 serves per week of most types of fish. There are only a few types of fish, which FSANZ recommends limiting in the diet – these are billfish (swordfish / broadbill and marlin ), shark/flake, orange roughy and catfish." FSANZ updates advice on mercury in fish (Australia only) 18 March 2004 see also 2 June 2011.
- Links: Diplomatic Conference for the Minamata Convention on Mercury 2013 | Minamata Convention on MercuryAustralia - food standards | NSW Food Authority | USA - federal register proposal 2011
Hexavalent chromium (CrVI) is used in more than 50 industries and is an important heavy metal pollutant. A recent study (2005) in monkeys (Macaca radiata) has demonstrated an effect on testicular spermatogenesis, possibly by inducing free radical toxicity. If these effects also occur in humans, then spermatazoa development could also be affected, the study further suggested a supplementation of antioxidant vitamins may be beneficial to the affected subjects.
- Links: Related References
Cadmium (Cd) is a heavy metal pollutant produced during the smelting of other metals. It has many industrial and domestic uses (some paints, plastics, fertilisers, metal plating) and is founds use in the environment cadmium is in nickel-cadmium (NiCad) rechargeable batteries used in many portable devices as well as being present in cigarette smoke.
An animal study has shown that cadmium can induce retinoic acid signaling by regulating retinoic acid metabolic gene expression, suggesting that cadmium-induced teratogenicity may be due to altering levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. Developmental Signals - Retinoid acid
A recent human study of coastal populations of South Africa'has identified associations between prenatal Cd exposure and birth anthropometry in female neonates but not in male neonates, suggesting a potential sex difference in the toxico-kinetics and toxico-dynamics of Cd.
- Links: Retinoic acid
Lithium (Li, atomic number 3) is a soft alkali metal found in the natural environment, in industrial products (lithium batteries, some glass and ceramic products) and also is used to treat people with bipolar disorder. Lithium used as a drug, in a salt form, acts on the central nervous system as an antimanic agent to treat episodes of mania (frenzied, abnormally excited mood) associated with bipolar disorders. Lithium has been associated with fetal cardiac teratogenicity possibly by affecting Wnt/beta-catenin signaling.
- Links: Abnormal Development - Drugs | MedlinePlus - Lithium | MedlinePlus - Lithium Toxicity | OTIS - Lithium and Pregnancy PDF
A therapeutic radioactive form of yttrium used in microspheres for the internal treatment of various liver cancers. As such it would be unlikely to be found in a human development situation.
A rare, malleable and easily fusible post-transition metal that is chemically similar to gallium and thallium, and also shows properties intermediate between these two elements. Currently used industrially in liquid crystal displays and touchscreens, and historically in thin-films to form lubricated layers. Medically used in a radioactive form (indium-111) in nuclear medicine tests and as a radio-tracker. Indium is not known to be used by any biological organism. There are some animal teratogenic studies that have looked at the effect of indium salts (indium chloride).
- Embryotoxic and teratogenic effects of indium chloride in rats and rabbits"Indium was found to cross the placenta and appeared in fetal blood in proportion to the metal concentration of the maternal blood. In the amniotic fluid, indium concentrations remained below the detection limit. ...In rats, the effects of indium chloride causing fetal retardation was found to be independent of exposure time. The teratogenic effects were the highest on d 11 and 12 of gestation, when indium chloride caused gross external malformations. Data suggest that the teratogenic effects of indium chloride can be attributed primarily to a direct cytotoxic action of indium resulting from placental transfer, but the effect is not a selective one, as it appears only in the presence of maternal toxic effects."
- Halina B Röllin, Tahira Kootbodien, Kalavati Channa, Jon Ø Odland Prenatal Exposure to Cadmium, Placental Permeability and Birth Outcomes in Coastal Populations of South Africa. PLoS ONE: 2015, 10(11);e0142455 PubMed 26544567 | PLoS One.
- L I Nekliudova, R V Tonkova-Iampol'skaia, T Ia Chertok, Iu B Fedorova, A E Gumennik [Leukocyte function as one of the indices of resistance to influenza in children]. [Funktsional'noe sostoianie leĭkotsitov kak odin iz pokazateleĭ rezistentnosyti deteĭ k grippu.] Vopr. Virusol.: 1983, (2);160-2 PubMed 6306926
- Yue Li, Changchun Xie, Susan K Murphy, David Skaar, Monica Nye, Adriana C Vidal, Kim M Cecil, Kim N Dietrich, Alvaro Puga, Randy L Jirtle, Cathrine Hoyo Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. Environ. Health Perspect.: 2015; PubMed 26115033
- Iman Al-Saleh, Neptune Shinwari, Abdullah Mashhour, Abdullah Rabah Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population. Int J Hyg Environ Health: 2014, 217(2-3);205-18 PubMed 23735463
- Marie Lynn Miranda, Sharon Edwards, Pamela J Maxson Mercury levels in an urban pregnant population in Durham County, North Carolina. Int J Environ Res Public Health: 2011, 8(3);698-712 PubMed 21556174
- Abelardo Andrés Sztrum, José Luis D'Eramo, Jorge Herkovits Nickel toxicity in embryos and larvae of the South American toad: effects on cell differentiation, morphogenesis, and oxygen consumption. Environ. Toxicol. Chem.: 2011, 30(5);1146-52 PubMed 21312246
- Su-Feng Fan, Pei-Ling Chao, Anya Maan-Yuh Lin Arsenite induces oxidative injury in rat brain: synergistic effect of iron. Ann. N. Y. Acad. Sci.: 2010, 1199;27-35 PubMed 20633106
- Greg Cunningham Lead--toxicology and assessment in general practice. Aust Fam Physician: 2007, 36(12);1011-3 PubMed 18075625 | AFP
- H Y Chuang, J Schwartz, T Gonzales-Cossio, M C Lugo, E Palazuelos, A Aro, H Hu, M Hernandez-Avila Interrelations of lead levels in bone, venous blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in peripartum women. Environ. Health Perspect.: 2001, 109(5);527-32 PubMed 11401766
- Adrienne S Ettinger, Martha María Téllez-Rojo, Chitra Amarasiriwardena, David Bellinger, Karen Peterson, Joel Schwartz, Howard Hu, Mauricio Hernández-Avila Effect of breast milk lead on infant blood lead levels at 1 month of age. Environ. Health Perspect.: 2004, 112(14);1381-5 PubMed 15471729
- M Michael Aruldhas, S Subramanian, P Sekar, G Vengatesh, Gowri Chandrahasan, P Govindarajulu, M A Akbarsha Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress: study in a non-human primate (Macaca radiata Geoffroy). Hum. Reprod.: 2005, 20(10);2801-13 PubMed 15980013
- Yuxia Cui, Jonathan H Freedman Cadmium induces retinoic acid signaling by regulating retinoic acid metabolic gene expression. J. Biol. Chem.: 2009, 284(37);24925-32 PubMed 19556237
- Jizhen Chen, Mingda Han, Shyam M Manisastry, Patrizia Trotta, Maria C Serrano, James C Huhta, Kersti K Linask Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis. Birth Defects Res. Part A Clin. Mol. Teratol.: 2008, 82(7);508-18 PubMed 18418887
- G Ungváry, E Szakmáry, E Tátrai, A Hudák, M Náray, V Morvai Embryotoxic and teratogenic effects of indium chloride in rats and rabbits. J. Toxicol. Environ. Health Part A: 2000, 59(1);27-42 PubMed 10681097
E D Weinberg Can iron be teratogenic? Biometals: 2010, 23(2);181-4 PubMed 20024603
Haobin Chen, Qingdong Ke, Thomas Kluz, Yan Yan, Max Costa Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol. Cell. Biol.: 2006, 26(10);3728-37 PubMed 16648469
Rita Hindin, Doug Brugge, Bindu Panikkar Teratogenicity of depleted uranium aerosols: a review from an epidemiological perspective. Environ Health: 2005, 4;17 PubMed 16124873
B Gulbis, E Jauniaux, J Decuyper, P Thiry, D Jurkovic, S Campbell Distribution of iron and iron-binding proteins in first-trimester human pregnancies. Obstet Gynecol: 1994, 84(2);289-93 PubMed 8041549
June 2010 "Heavy Metal Teratogen" All (744) Review (72) Free Full Text (86)
Search Pubmed: Heavy Metal Teratogen
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- Globally Harmonized System of Classification and Labeling of Chemicals (GHS) | Implementation | U.S. Department of Labor
- Center for Disease Control and Prevention Screening Young Children for Lead Poisoning: Guidance for State and Local Public Health Officials | CDC - Blood Lead Levels United States, 1999-2002 | CDC - Childhood Lead Poisoning Publications
- Global Alliance to Eliminate Lead Paint
- UK Information Sheet - Cadmium and you Working with cadmium - Are you at risk?
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