Abnormal Development - Heavy Metals

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Metal contamination.jpg

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).

Environmental Links: Introduction | Low Folic Acid | Iodine Deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | Thalidomide | Herbal Drugs | Illegal Drugs | Smoking | Fetal Alcohol Syndrome | TORCH Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Maternal Diabetes | Maternal Hyperthermia | Maternal Inflammation | Maternal Obesity | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis

Some Recent Findings

Lead campaign poster 2013
  • Prenatal Exposure to Cadmium, Placental Permeability and Birth Outcomes in Coastal Populations of South Africa[1] "The impact of prenatal exposure to cadmium (Cd) on birth outcomes is an area of concern. This study aimed to assess an impact of prenatal Cd exposure on birth outcomes in distinct coastal populations of South Africa. ...Significant inverse associations between prenatal Cd exposure and birth anthropometry were found in female neonates but not in male neonates, suggesting potential sex differences in the toxico-kinetics and toxico-dynamics of Cd."
  • Maternal-infant biomarkers of prenatal exposure to arsenic and manganese[2] "Because arsenic (As) and manganese (Mn) are able to pass the placenta, infants among exposed populations may be exposed to considerable levels in utero. The main objective of this paper is to evaluate infant toenails, hair, and cord blood as biomarkers of prenatal exposure to As and Mn and determine the relationship between maternal and infant As and Mn concentrations in these biomarkers. ...Toenails and cord blood appear to be valid biomarkers of maternal-fetal transfer of As and Mn, whereas hair may not be a suitable biomarker for in utero exposure to Mn."
  • Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood[3] "The objective of this study was to determine if maternal, postnatal and early childhood lead exposure alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth and development. ...The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS: Our findings provide evidence for early childhood lead exposure resulting in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19 and PLAGL1/HYMAI in adulthood." Epigenetics
More recent papers
Mark Hill.jpg
This table shows an automated computer PubMed search using the listed sub-heading term.
  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

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.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Heavy Metal Teratology Denise S Hill, Robert Cabrera, Deeann Wallis Schultz, Huiping Zhu, Wei Lu, Richard H Finnell, Bogdan J Wlodarczyk Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model. Behav Neurol: 2015, 2015;426263 PubMed 26586927

M V Belousov, O S Mashkina [CYTOGENETIC RESPONSE OF SCOTS PINE (PINUS SYLVESTRIS L.) TO CADMIUM AND NICKEL]. Tsitologiia: 2015, 57(6);459-64 PubMed 26495713

Suchismita Das, Shamim Sultana Choudhury Analysis of heavy metals from water, sediment, and tissues of Labeo angra (Hamilton, 1822), from an Ox-box lake- an wetland site from Assam, India. J Environ Sci Health A Tox Hazard Subst Environ Eng: 2015;1-13 PubMed 26422176

S Ould Hamouda, J Perrin, V Achard, B Courbière, J-M Grillo, I Sari-Minodier [Association between sperm abnormalities and occupational environment among male consulting for couple infertility]. [Association entre anomalies spermatiques et environnement professionnel chez les hommes consultant pour infertilité de couple.] J Gynecol Obstet Biol Reprod (Paris): 2015; PubMed 26387599

Tatiana Zotina, Marina Medvedeva, Elena Trofimova, Yuliyana Alexandrova, Dmitry Dementyev, Alexander Bolsunovsky Chromosomal abnormalities in roots of aquatic plant Elodea canadensis as a tool for testing genotoxicity of bottom sediments. Ecotoxicol. Environ. Saf.: 2015, 122;384-391 PubMed 26342689

Search term: Lead Teratology Erica B Sherry, Phil Lee, In-Young Choi In Vivo NMR Studies of the Brain with Hereditary or Acquired Metabolic Disorders. Neurochem. Res.: 2015; PubMed 26610379

Jihye Park, Robert S Welner, Mei-Yee Chan, Logan Troppito, Philipp B Staber, Daniel G Tenen, Catherine T Yan The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining. J. Immunol.: 2015; PubMed 26608917

Telma Mary Nakata, Naoya Matsuura, Hideki Kaji, Miki Shimizu, Ryuji Fukushima, Noboru Machida, Ryou Tanaka Sequential radial and circumferential strain and oxidative stress assessment in dogs with tachycardia-induced cardiac dysfunction. Int J Cardiovasc Imaging: 2015; PubMed 26608802

Ruben C Gur, Raquel E Gur Social cognition as an RDoC domain. Am. J. Med. Genet. B Neuropsychiatr. Genet.: 2015; PubMed 26607670

N W M Ramnath, L J A C Hawinkels, P M van Heijningen, L Te Riet, M Paauwe, M Vermeij, A H J Danser, R Kanaar, P Ten Dijke, J Essers Fibulin-4 deficiency increases TGF-β signalling in aortic smooth muscle cells due to elevated TGF-β2 levels. Sci Rep: 2015, 5;16872 PubMed 26607280

Older Publications
  • Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population[4] "This cross-sectional study was conducted to assess the association between exposure to heavy metals (lead, cadmium and mercury) during pregnancy and birth outcomes in 1578 women aged 16-50 years who delivered in Al-Kharj hospital, Saudi Arabia, in 2005 and 2006. The levels of lead, cadmium and mercury were measured in umbilical cord blood, maternal blood and the placenta. ... Cadmium, despite its partial passage through the placenta had the most prominent effect on several measures of birth outcome.""
  • International Lead Poisoning Awareness Week (20 - 26 October 2013) "Despite what is known about the health risks arising from lead paint, such paints are still widely available and used in many countries for decorating the interiors and exteriors of homes. It can also be found in paint in public buildings such as schools and hospitals, as well as on toys, toy jewellery, glazes, furniture, and playground equipment."
  • Meeting Diplomatic Conference for the Minamata Convention on Mercury 2013 | Minamata Convention on Mercury
  • Mercury levels in an urban pregnant population in Durham County, North Carolina[5] "The adverse effects of prenatal mercury exposure, most commonly resulting from maternal fish consumption, have been detected at very low exposure levels. The omega-3 fatty acids found in fish, however, have been shown to support fetal brain and vision development. Using data from a prospective, cohort study of pregnant women from an inland area in the US South, we sought to understand the fish consumption habits and associated mercury levels across subpopulations. Over 30% of women had at least 1 μg/L of mercury in their blood, and about 2% had blood mercury levels above the level of concern during pregnancy (≥ 3.5 μg/L). Mercury levels were higher among Asian/Pacific Islander, older, higher educated, and married women."
  • Nickel toxicity in embryos and larvae of the South American toad: effects on cell differentiation, morphogenesis, and oxygen consumption[6] "Nickel, a widely distributed heavy metal in the biosphere, produces systemic, carcinogenic, and teratogenic effects. The objectives of the present study are to report the acute, short-term chronic, and chronic toxicity of Ni in Rhinella arenarum embryos as well as the stage-dependent susceptibility to this heavy metal, including oxygen consumption, teratogenesis, and adverse effects on cell differentiation processes. ...The main teratogenic effects were retarded growth and development, extremely severe axis incurvations, persistent yolk plug, asymmetry, microcephaly and mouth and gill agenesia, and limited neuromuscular activity. Ciliated cells were not functional."
  • Arsenite induces oxidative injury in rat brain: synergistic effect of iron[7] "Sodium arsenite (arsenite)-induced neurotoxicity and its interaction with ferrous citrate (iron) was investigated in rat brain. In vitro data showed that arsenite (1-10 micromol/L) concentration dependently increased lipid peroxidation and the potency of arsenite was less than that of iron. ...Taken together, our study demonstrates that arsenite was less potent than iron in inducing oxidative stress. Furthermore, concomitant arsenite and iron potentiated oxidative injury in the nigrostriatal dopaminergic system, indicating that interaction of metals plays a more clinically-relevant role in pathophysiology of central nervous system neurodegeneration."

Metal Toxicity

Heavy metals toxicity.gif
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.

Heavy metals water.gif


Lead pipe
CDC - Screening young children for lead poisoning

Lead in the environment is postnatally toxic and prenatally teratogenic.[8] 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)

Related References

  • Interrelations of lead levels in bone, venous blood, and umbilical cord blood with exogenous lead exposure through maternal plasma lead in peripartum women[9]
  • Effect of breast milk lead on infant blood lead levels at 1 month of age[10]

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.

Minamata disease map.gif
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.[11]

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,[12] 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'[1]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.[13]

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[14]"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."


  1. 1.0 1.1 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.
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Greg Cunningham Lead--toxicology and assessment in general practice. Aust Fam Physician: 2007, 36(12);1011-3 PubMed 18075625 | AFP
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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

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June 2010 "Heavy Metal Teratogen" All (744) Review (72) Free Full Text (86)

Search Pubmed: Heavy Metal Teratogen

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Cite this page: Hill, M.A. (2015) Embryology Abnormal Development - Heavy Metals. Retrieved November 30, 2015, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Heavy_Metals

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