Abnormal Development - Heavy Metals
|Embryology - 22 Jun 2018 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.
Asher Ornoy, Liza Weinstein-Fudim, Zivanit Ergaz Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD). Front Neurosci: 2016, 10;316 PubMed 27458336
Katarina Dathe, Evelin Beck, Christof Schaefer Pregnancy outcome after chelation therapy in Wilson disease. Evaluation of the German Embryotox Database. Reprod. Toxicol.: 2016; PubMed 27350316
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
Zivanit Ergaz, Liza Weinstein-Fudim, Asher Ornoy High sucrose low copper diet in pregnant diabetic rats induces transient oxidative stress, hypoxia, and apoptosis in the offspring's liver. Birth Defects Res: 2018; PubMed 29851303
Gideon Koren, Matitiahu Berkovitch, Asher Ornoy Dose-Dependent Teratology in Humans: Clinical Implications for Prevention. Paediatr Drugs: 2018; PubMed 29725877
Paul Merlob, Bracha Stahl, Gil Klinger For Debate: Does Cannabis Use by the Pregnant Mother Affect the Fetus and Newborn? Pediatr Endocrinol Rev: 2017, 15(1);4-7 PubMed 28845622
Abby A Li, Larry P Sheets, Kathleen Raffaele, Virginia Moser, Angela Hofstra, Alan Hoberman, Susan L Makris, Robert Garman, Brad Bolon, Wolfgang Kaufmann, Roland Auer, Edmund Lau, Thomas Vidmar, Wayne J Bowers Recommendations for harmonization of data collection and analysis of developmental neurotoxicity endpoints in regulatory guideline studies: Proceedings of workshops presented at Society of Toxicology and joint Teratology Society and Neurobehavioral Teratology Society meetings. Neurotoxicol Teratol: 2017; PubMed 28757310
|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."
- Liu W, Huang C, Cai J, Wang X, Zou Z & Sun C. (2018). Household environmental exposures during gestation and birth outcomes: A cross-sectional study in Shanghai, China. Sci. Total Environ. , 615, 1110-1118. PMID: 29751416 DOI.
- Lee DW, Oh SH, Park MK, Lim YH & Hong YC. (2018). Environmental cadmium exposure is associated with elevated risk of chronic otitis media in adults. Occup Environ Med , , . PMID: 29581150 DOI.
- Mancuso F, Arato I, Lilli C, Bellucci C, Bodo M, Calvitti M, Aglietti MC, dell'Omo M, Nastruzzi C, Calafiore R, Luca G & Marinucci L. (2018). Acute effects of lead on porcine neonatal Sertoli cells in vitro. Toxicol In Vitro , 48, 45-52. PMID: 29273543 DOI.
- Röllin HB, Kootbodien T, Channa K & Odland JØ. (2015). Prenatal Exposure to Cadmium, Placental Permeability and Birth Outcomes in Coastal Populations of South Africa. PLoS ONE , 10, e0142455. PMID: 26544567 DOI.
- Nekliudova LI, Tonkova-Iampol'skaia RV, Chertok TIa, Fedorova IuB & Gumennik AE. (1983). [Leukocyte function as one of the indices of resistance to influenza in children]. Vopr. Virusol. , , 160-2. PMID: 6306926
- Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL & Hoyo C. (2016). Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. Environ. Health Perspect. , 124, 666-73. PMID: 26115033 DOI.
- Al-Saleh I, Shinwari N, Mashhour A & Rabah A. (2014). Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population. Int J Hyg Environ Health , 217, 205-18. PMID: 23735463 DOI.
- Miranda ML, Edwards S & Maxson PJ. (2011). Mercury levels in an urban pregnant population in Durham County, North Carolina. Int J Environ Res Public Health , 8, 698-712. PMID: 21556174 DOI.
- Sztrum AA, D'Eramo JL & Herkovits J. (2011). Nickel toxicity in embryos and larvae of the South American toad: effects on cell differentiation, morphogenesis, and oxygen consumption. Environ. Toxicol. Chem. , 30, 1146-52. PMID: 21312246 DOI.
- Fan SF, Chao PL & Lin AM. (2010). Arsenite induces oxidative injury in rat brain: synergistic effect of iron. Ann. N. Y. Acad. Sci. , 1199, 27-35. PMID: 20633106 DOI.
- Cunningham G. (2007). Lead--toxicology and assessment in general practice. Aust Fam Physician , 36, 1011-3. PMID: 18075625
- Chuang HY, Schwartz J, Gonzales-Cossio T, Lugo MC, Palazuelos E, Aro A, Hu H & Hernandez-Avila M. (2001). 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. , 109, 527-32. PMID: 11401766
- Ettinger AS, Téllez-Rojo MM, Amarasiriwardena C, Bellinger D, Peterson K, Schwartz J, Hu H & Hernández-Avila M. (2004). Effect of breast milk lead on infant blood lead levels at 1 month of age. Environ. Health Perspect. , 112, 1381-5. PMID: 15471729
- Aruldhas MM, Subramanian S, Sekar P, Vengatesh G, Chandrahasan G, Govindarajulu P & Akbarsha MA. (2005). Chronic chromium exposure-induced changes in testicular histoarchitecture are associated with oxidative stress: study in a non-human primate (Macaca radiata Geoffroy). Hum. Reprod. , 20, 2801-13. PMID: 15980013 DOI.
- Cui Y & Freedman JH. (2009). Cadmium induces retinoic acid signaling by regulating retinoic acid metabolic gene expression. J. Biol. Chem. , 284, 24925-32. PMID: 19556237 DOI.
- Chen J, Han M, Manisastry SM, Trotta P, Serrano MC, Huhta JC & Linask KK. (2008). Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis. Birth Defects Res. Part A Clin. Mol. Teratol. , 82, 508-18. PMID: 18418887 DOI.
- Ungváry G, Szakmáry E, Tátrai E, Hudák A, Náray M & Morvai V. (2000). Embryotoxic and teratogenic effects of indium chloride in rats and rabbits. J. Toxicol. Environ. Health Part A , 59, 27-42. PMID: 10681097
Gulbis B, Jauniaux E, Decuyper J, Thiry P, Jurkovic D & Campbell S. (1994). Distribution of iron and iron-binding proteins in first-trimester human pregnancies. Obstet Gynecol , 84, 289-93. PMID: 8041549
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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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