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Gemma Calamandrei, Laura Ricceri

Reparto di Neurotossicologia e neuroendocrinologia

Dipartimento di Biologia cellulare e Neurosceinze

ISTITUTO SUPERIORE DI SANITA’

Roma, 02/07/2014 SAPIEXPO

Nutrients in fish: placental transfer of omega3 and fetal brain development

Eicosapentanoic acid (EPA)

Docosahexaenoic acid (DHA)

Arachidonic acid..

Iodine, vitamin D

Improved neural transmission, ion channel activity, improved neuropsychological performances


Risks...??? Presence of contaminants in fishes and protection of vulnerable

population groups


Types of mercury Elemental

Liquid, volatile at room temperature

Example: dental filling

Ionic Forms Salts with widely varying solubility

Combustion emissions

Organic Methyl mercury: ingested through diet


Organic Mercury Routes of exposure

Ingestion/ inhalation: >90% absorption

Dermal: well absorbed; % depends on contact time

Sources of exposure

Primarily via ingestion of methyl mercury from fish

Occupational exposures to other forms

Some via inhalation

Key Toxicities

CNS; neurodevelopmental



EPA Reference Dose for

Chronic Oral Exposure

(RfD):

0.1 mg/kg/bw

Calculated on the basis of

neuropsychological

effects in 7-year children

following prenatal

exposure (maternal blood

and hair)

http://en.wikipedia.org/wiki/Mercury_in_fish

http://en.wikipedia.org/wiki/Mercury_in_fish

Health effects of mercury depend on: the chemical form of mercury;

the dose;

the age of the person exposed (the fetus is the most susceptible);

the duration of exposure;

the route of exposure -- inhalation, ingestion, dermal contact, etc.; and

the health of the person exposed.


Neurological Symptoms of Mercury Poisoning Irritability and moodiness

Peripheral vision affected

Tingling sensations, numbness

Lack of coordination of movements

Impaired speech, hearing

Muscle weakness

Memory loss

Mental disturbance


Key Data on Mercury NeurobehaviouralToxicity

Hundreds of research papers demonstrating toxicity

Epidemic poisonings:

Minamata

Iraq

Key epidemiological studies:

Faroe Islands;

Seychelles Islands;

New Zealand


Minamata and Nigata Bay Poisonings

1953-1960s

High level exposures to

methyl mercury in fish from

industrial waste

Symptoms: slurred speech;

behavioral effects; serious

brain damage

>2,000 severe cases; many

deaths.

Children born from parents

apparently unaffected had

severe neuropsychological

and motor deficits


Hg developmental neurotoxicity

In the nineties, the effects on intellectual function in children prenatally exposed to MeHg via maternal fish consumption have been the subject of two on-going major, prospective, longitudinal studies in the Seychelles and the Faroe Islands

These large epidemiological studies and their results gave the way to a strong debate on the pros and cons of eating fish in pregnancy


Faroe Study Study Overview

>900 children

Battery of neurodevelopmental/behaviour tests at several ages (18 months to 12 years)

Mercury exposure from whale and fish Levels ranged from < 0.1- over 2 ppm

Exposure measured by cord blood and hair Hair= 4.3 ppm


Faroe Study main resultsDeficits in several neurodevelopmental endpoints

observed: Effects subtle but significant

Cognitive function; neonatal neurological status; All indicative of brain toxicity in utero

Cardiovascular; post natal effects

Observed at several ages

Co-exposure to other chemicals: PCBs Effect still observed when controlled for


Seichelles study Study overview

>700 children, to 9 years of age

Mercury in fish ranged from < 0.1 ppm- about 2 ppm, with average about 0.3 ppm

Somewhat different battery of tests used: language; memory; motor; cognitive; behavioral

Measure of exposure: maternal hair: 6 ppm


Seichelles Study main results

“No evidence of neurodevelopmental risk from prenatal methylmercury exposure”.

• Differences from the Faroe study explained on the basis of: • absence of other contaminants’ exposure• different nutritional factors• life style


Nutritional factors: the protective role of PUFA in the Seichelles studyAssociations of maternal long chain polyunsaturated fatty acids,methyl mercury, and infant development in the Seychelles ChildDevelopment Nutrition StudyNeurotoxicology 2008

J.J. Strain1, Philip W. Davidson2, Maxine P. Bonham1, Emeir M. Duffy1, Abbie Stokes-Riner2, Sally W. Thurston2, Julie M.W. Wallace1, Paula J. Robson1, Conrad F. Shamlaye3,Lesley A. Georger2, Jean Sloane-Reeves2, Elsa Cernichiari2, Richard L. Canfield4,Christopher Cox5, Li Shan Huang2, Joanne Janciuras2, Gary J. Myers2, and Thomas W.Clarkson21University of Ulster2University of Rochester School of Medicine and Dentistry3Ministry of Health, Republic of Seychelles4Cornell University5The Johns Hopkins Bloomberg School of Public Health

AbstractFish consumption during gestation can provide the fetus with long chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles ChildDevelopment Nutrition Study (SCDNS). These data support the potential importance to child development of prenatal availability of Ω-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHgexposure in longitudinal observational studies.


Recent evidence on genetic susceptibility to Hg


Genetic polimorphism (Single nucleotid Polymorphism, SNP)

Hg source Size of the study Reference

ABC (ATP Binding Cassette) transporter genes

Environmentalexposure (fish diet)

1651(birth cohorts) Llop et al. 2014

PON-1, Progesteron Receptor,Trasferrin,

Brain Derved Neurotrophic Factor(BDNF)

Not known(Avon longitudinal

study of parents and children)

1135Cord blood +

neuropsychologicalassessment at 8y

Julvez et al. 2013

MetallothioneinDental amalgalm

tooth filling

505/330(8-12 y) Woods et al. 2013

Glutathione-related genes Environmentalexposure (fish diet)

400(adults) Barcelos et al. 2013

Apolipoprotein E (APOE) Environmentalexposure (fish diet)

180(0-2y) Ng et al. 2013

Catechol -O- methyltransferase(COMT)

Dental amalgalmtooth filling

505/330(8-12 y) Woods et al. 2014

Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review

Mary C Sheehan a, Thomas A Burke b, Ana Navas-Acien c, Patrick N Breysse c, John McGready d & Mary A Fox b

a. Risk Sciences and Public Policy Institute, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, United States of America (USA).b. Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.c. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.d. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.

Correspondence to Mary C Sheehan (e-mail: [email protected]).(Submitted: 05 December 2012 – Revised version received: 15 October 2013 – Accepted: 12 November 2013 – Published online: 10 January 2014.)Bulletin of the World Health Organization 2014;92:254-269F. doi: http://dx.doi.org/10.2471/BLT.12.116152


mailto:[email protected]

http://dx.doi.org/10.2471/BLT.12.116152

Category/subcategory Predominant Hg pathway to seafood

Predominant seafood type Seafood intake range (kg per month)b

Residential context

Locally self-caught seafood is important share of diet

Arctic– Traditional diet– Mixed diet

Unique polar meteorology and Hg deposition/mobilization, Arctic food-chain (marine mammals as apex predators)

Traditional: marine fish and marine mammalsMixed: marine fish and non-seafood protein sources, few if any marine mammals

0.6–7.1 Far northern Arctic, where people rely on apex Hg-contaminated marine mammals and fish

Gold mining– Rural riverine– Urban

Artisanal and small-scale gold mining, soil lixiviation, forest fires releasing Hg emissions

Rural: high share of locally-caught freshwater fishUrban: mixed diet including non-seafood protein, low share of locally-caught freshwater fish

0.6–14.9 Rural and urban tropical areas near artisanal and small-scale gold mining, where the diet includes fish from rivers contaminated by gold mining activity

Fishing Local and general global transport of Hg emissions

Marine and freshwater fish and shellfish

0.1–3.8 Recreational or subsistence fishing areas near rivers, reservoirs or lakes without a particular Hg contamination source

Industry Local Hg-emitting industry (chloralkali, power generation, mining other than gold mining)


0.2–5.8 Recreational or subsistence fishing areas near water bodies with active or disused industrial facilities

Seafood consumed is mostly from commercial sources (i.e. non-self-caught)c

Coastal– Atlantic– Mediterraneand

– Pacific

Local and general global transport of Hg emissions in all three regions; natural Hg emission sources in the Mediterranean


0.3–5.6 Atlantic, Mediterranean or Pacific coastal areas where seafood intake is frequent

Inland Local and general global transport of Hg emissions


Very little–2.0 Inland areas where seafood intake is low

Methylmercury exposure categories for women and infants from seafood-consuming populations


Table 1Annual numbers of births and numbers exceeding three cut-off limits, as indicated by hair-mercury analyses (in μg/g) in population samples in European countries

Countrya

Annual number of births (2008)

Number of samplesb Above 0.58 μg/g Above 1.0 μg/g Above 2.5 μg/g

Proportion in sample (%)

Estimated number of births





Austria 77,800 NA (6.7) 5,213 (0.8) 622 (0) 0

Belgium 127,200129 28.7 36,506 9.3 11,830 0

0242c 23.2 29,510 7.2 9,158 0

Bulgaria 77,700 NA (4.2) 3,263 (1.2) 932 (0.8) 622Croatia 43,800 234d 52.0 22,776 22.0 9,636 4.7 2,059Cyprus 9,200 60 36.7 3,376 18.3 1,684 3.3 304Czech Republic 119,600 120 5.0 5,980 0.8 957 0 0Denmark 65,000 145 36.6 23,790 13.1 8515 0.7 455Estonia 16,000 NA (10.0) 1,600 (2.0) 320 (0) 0Faroe Islands 675 505e 62.6 423 30.2 204 5.3 36Finland 59,500 NA (10.0) 5,950 (2.0) 1,190 (0) 0France 829,300 126f 44.0 364,892 14.51 120,331 0.61 5,059

Germany 682,500 120 6.7 45,728 0.8 5,460 0 0

Greece 118,300 454d 78 92,274 57 67,431 14 16,562Hungary 99,100 120 0.83 823 0 0 0 0Ireland 74,000 120 10.8 7,992 2.5 1,850 0 0Italy 576,700 891d + 115g (65.6) 378,315 (36.8) 212,226 (5.7) 32,872Latvia 23,834 NA (10.0) 2,383 (2.0) 477 (0) 0Lithuania 35,100 NA (10.0) 3,510 (2.0) 702 (0) 0Luxembourg 5,600 55 32.7 1,831 18.2 1,019 0 0Malta 4,100 NA (65.6) 2,690 (36.8) 1,509 (5.7) 234Netherlands 184,600 NA (23.2) 42,827 (7.2) 13,291 (0) 0Norway 60,500 119h 27.7 16,759 5.9 3,570 0 0Poland 414,500 120 1.7 7047 0 0 0 0Portugal 104,600 120 90.8 94,977 57.5 60,145 8.3 8,682Romania 221,900 120 4.2 9,320 1.2 2,663 0.8 1,775Slovakia 57,400 129 5.43 3,117 0.8 459 0 0Slovenia 21,800 156 22.0 4,796 7.7 1,679 1.9 414Spain 519,800 120 88.5 460,023 74.2 385,692 31.7 164,777Sweden 109,300 100 10.0 10,930 2.0 2,186 0 0Switzerland 76,700 120 5.0 3,835 2.1 1,611 0 0United Kingdom 794,400 4134h 31.0 246,264 5.1 40,200 0 0Total EU (27) 5,400,000 1,865,416 903,169 231,754Roma, 02/07/2014 SAPIEXPO

HUMAN MERCURY EXPOSURE AND EFFECTS IN EUROPEANA MIKLAVCIC VIŠNJEVEC, DAVID KOCMAN, and MILENA HORVAT*Department of Environmental Sciences, “Jožef Stefan” Institute, Ljubljana, Slovenia

Environmental Toxicology and Chemistry, Vol. 33, No. 6, pp. 1259–1270, 2014


What’s a health-conscious fish eater to do?


Harvard University Study: Babies’ performance on visual recognition memory tests increased a significant four points with each additional weekly serving of fish that the mother ate while pregnant.But the researchers also measured mercury levels in the mothers’ hair, and found that infants whose mothers had very high levels of mercury scored lower than the others, for a drop of 7.5 points for every one part per million increase in mercury.

The babies who scored highest were those whose mothers were among the top fish and seafood consumers, eating it at least twice a week, but who also had lower mercury levels.

http://www.crome-life.eu/

Cross-Mediterranean Environment and Health Network

CROME–LIFE Prof. Denis Sarigiannis – Project manager, Thessaloniki University, Greece

Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC) – Spain –Principal investigator: Prof. Joan Grimalt

Istituto Superiore di Sanità (ISS) – Italy - Principal investigator: Dr. GemmaCalamandrei

Jožef Stefan Institute (JSI) – Slovenia - Principal investigator: Prof. Milena Horvat

CROME - Main objectives and strategyThe project will build a prototype methodology for linking environmental, biological and

health status monitoring data to draw comprehensive and robust associations

between environmental stress and human health.

Main diseases targeted: cancer, neurodegenerative and neurodevelopmental disorders, diabetes

• 1. Data collection and revision in the four different countries• 2. Identification of gap in knowledge in at-risk areas• 3. Building local networks (health authorities, NGO, citizen, etc.) on the problem• 4. New biomonitoring campaigns• 5. Demonstration and dissemination

The methodological framework of CROME-LIFE will be demonstrated in four

different Countries in EU namely Greece, Slovenia, Italy and Spain.

Targeted biomonitoring campaign: assessing potential relationship between exposure to MeHg in fish and

neuropsycological scores at 6-7 years in Friuli-Venezia Giulia Region


CROME biomonitoring campaign starting in September 2014 A large mother/child cohort (N =6200) born in the area of

Trieste Gulf were enrolled in 2007. Exposure to Hg and other neurotoxic metals was assessed during pregnancy and in cord blood. Children were scored as for neuropsychological and motor development at 18 and 40 months of age. Results lacked to identify a link between exposure levels and neurodevelopment.

CROME will now support the follow up of these same children at 6-7 years, with new biomonitoring of Hg and other contaminants, and evaluation of cognitive, language and motor skills. Dietary factors and genetic susceptibility will be also measured.


Previous results from the Friuli Venezia Giulia cohort


Neurodevelopmental Effects of Low-level Prenatal Mercury Exposure From Maternal Fish Consumption in a Mediterranean Cohort: Study Rationale and Design Francesca Valent1,2, Milena Horvat3, Aikaterini Sofianou-Katsoulis4, Zdravko Spiric5, Darja Mazej3,D ’Anna Little1, Alexia Prasouli4, Marika Mariuz1, Giorgio Tamburlini6, Sheena Nakou4, and Fabio Barbone1,21Institute of Hygiene and Epidemiology, Department of Medical and Biological Sciences (DSMB), University of Udine, Udine, Italy 2Institute of Hygiene and Clinical Epidemiology, University Hospital of Udine, Udine, Italy 3Jozef Stefan Institute, Ljubljana, Slovenia 4Institute of Child Health, Athens, Greece 5OIKON Ltd, Institute for Applied Ecology, Zagreb, Croatia 6Institute forMaternal and Child Health-IRCCS Burlo Garofolo, Trieste, ItalyReceived February 23, 2012; accepted September 9, 2012; released online December 22, 2012, Journal of Epidemiology 2013

Newborns from this Mediterranean area presented detectable levels of T-Hg in cord blood. Higher concentrations of T-Hg were related to maternal fish intake, particularly in the case of large oily fish species

Neuropsychological assessment does not evidence to date signficant deficits at 18 months. In some cases Hg is positively correlated with neuropsychological performances: protective role of Selenium?

Expected results Crome will produce new data, relating prenatal and

actual exposure to Hg and other metals, nutrients present in daily diet, to learning, attention and motor performances at 6-7 years.

For the first time different gene polymorphisms will be also assessed and possibly associated with neuropsychological scores.

This multidimensional approach will hopefully give information on the link between dietary exposure to contaminants and neurobehavioural maturation, balancing risk and benefit of fish consumption


Acknowledgements The CROME partners (Slovenia, Spain, and Greece)

University of Udine and IRCCS Burlo Garofolo of Trieste

Department of Environment and Primary Prevention of the ISS (Dr. Alessandro Alimonti, Dr Anna Pino, Dr. Beatrice Bocca)

Dr. Flavia Chiarotti, Dr. Maria Luisa Scattoni, Dr. Aldina Venerosi, Dr. Alessia De Felice, Unit of Neurotoxicology and neuroendocrinology, Dept Cell Biology and Neurosciences, ISS.


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