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Heavy Metals in adolescents living in the Milazzo-Valle del Mela area

Francesco Squadrito, MD

The University of Messina, ITALY

The Sicilian Government (Decreto 4 september 2002) identified the Milazzo-

Valle del Mela Area at High Risk for Environmental Crisis

Oil Refinery – Milazzo Thermoelectric Plant “Edipower” - S. Filippo del Mela Ecological Scrap Industry (Recicle of exhausted batteries) – Pace del Mela Thermic Plant Milazzo s.r.l. - Milazzo TerNA – Electric - Milazzo ASI Consortium – production and processing of semi-finished materials

Major Heavy Metals

Mercury

Lead

Cadmium

Chromium

Aluminum

Arsenic

Nickel


Heavy metals are endocrine disruptors

– Cause oxidative stress and DNA damage

– Interfere with the reproductive system and the normal

development

Why?

– Produced by the emissions of industrial plants

– Taken up by the ecosystem and enter the food chain

– Children are more susceptible than adults

– They eat more food contaminants

– They are subjected to susceptible behavioural activities

– Active developmental activities

Ambient vs Biological Monitoring for health risk assessment

INDUSTRIAL AREA

MONTALBANO ELICONA

N=29

N=71

N=87

N=28

N=9

N=13

N=27

215 Adolescenti reclutati nell’area di Milazzo-Valle del Mela e 29 Controlli

Identification of the schools in the High Risk and Control

Areas

Meetings with school managers and parents to get

consent for analysis

Telephone calls and planning of the medical appointments

Medical examinations at the Milazzo Hospital (24 hrs

urine sampling; blood sampling; echographic evaluation of

ovaries and testis; quality of life questionnaires)

Heavy metal analysis in urine (Cadmium, Arsenic,

Chromium, Nickel and Vanadium) and blood (Lead)

Hormone levels analysis ( FSH, LH, Inhibin B,

Testosterone)

Data analysis

Study plan and activities

Heavy Metal Analysis

Every participant was provided with a 24-hour urine collection container at the time of enrollment.

The day of the medical examination the 24-hour urine was collected, total volume was recorded and 100 ml stored at -20°C with 10% nitric acid for heavy metals analysis (Arsenic, Cadmium, Chromium, Mercury, Nickel, Vanadium).

Heavy metals were determined by blinded technicians, on coded samples, by atomic absorption and graphite furnace. Lead was determined on blood samples obtained the day of the medical examination.

To avoid any metal contamination from the needle, the vial used for lead measurement was obtained after the withdrawal of 10ml of blood (later used for hormone assays, DNA and RNA extraction).

58%

61%

54% 75%

60% 69%

69% 88%

STRESS OSSIDATIVO:

una condizione patologica causata dalla rottura dell'equilibrio fisiologico, in un organismo vivente, fra la produzione e l'eliminazione, da parte dei

sistemi di difesa antiossidanti, di specie chimiche ossidanti.

Heavy Metals, ROS, DNA damage

Il DNA è probabilmente il bersaglio maggiormente più significativo dell’attacco ossidativo; Tra i markers utilizzati per identificare un danno ossidativo al DNA, abbiamo la formazione di 8-OHdG. L’8-OHdG è prodotto dal metabolismo cellulare ed è escreto con le urine; L’OGG1 è un gene che ripara il DNA E’ uno dei più rappresentativi sottoprodotti del danno ossidativo del DNA.

Addotti del DNA e 8-OHdG (8-hydroxydeoxyguanosine)

8-oxoguanine DNA glycosylase 1 (OGG1) is one of the

promising biomarker candidates of cancer susceptibility, there are also some controversial

results

ESPRESSIONE GENICA DI ENZIMI CHE RIPARANO IL DNA

Detoxification gene expression

Toxicity

mechanisms:

– binding to –SH groups

– competing with Zn and Se for

inclusion into metalloenzymes

– competing with calcium for binding

sites (calmodulin)‏

Kidney toxicity:

– free Cd binds to kidney glomerulus

– proximal tubule dysfunction

Detoxification genes:

- NQO1, ST13, MT1A

Oxidative stress and DNA damage in adolescents living in the Milazzo-Valle del Mela area

Conclusione n. 2

DANNO DEL DNA

Cadmium (Cd)‏: endocrine disruptor

Cadmium (Cd)‏

Cadmium (Cd)‏ Cadmium-induced testicular injury

From: Siu ER et al., Toxicol Appl Pharmacol 283(3):240-249, 2009

Cadmium delays pubertal onset in adolescents living in the Milazzo-Valle del Mela area

Tanner stages

Ritardo nell’inizio della pubertà

Conclusione n. 3


Continuous exposure at relatively low concentration of heavy metals is associated with increased oxidative DNA damage and impaired DNA repair and detoxification genes in adolescents

Increased Cd burden is associated with delayed onset of puberty in male adolescents and impaired testis growth

These results deserve particular attention by the local and regional government to initiate prevention programmes in this susceptible population

Oxidative Damage to Cell Membranes

Healthy Membrane Oxidative Stress Damage

Sources of Toxic Metals - Cadmium

Breathing contaminated air – Battery manufacturing

– Metal soldering or welding

Eating foods containing cadmium: – Shellfish, Liver, Kidney meats

Breathing cigarette smoke

Drinking contaminated water

Breathing contaminated air – Burning of fossil fuels, municipal waste

Global Chronic Low Level Metal Toxicity

Recognized by:

– US Environmental Protection Agency (EPA)‏

– Food & Drug Administration (FDA)‏

– Centers for Disease Control (CDC)‏

– State Health Departments

Treatment standards are needed

– Preventative measures

– Comprehensive medicine with proven results

– Reduction of crisis management

Cadmium (Cd)‏

Relatively new metal in terms

of humans

Sources:

– natural rock weathering

– copper, lead and zinc

smelting auto exhaust

– cigarette smoke (a

cigarette contains 1-2 ug

Cd)‏

Uses:

– metal plating

– nickel-cadmium batteries

– solders

– paint pigments (blue)‏

– plastic stabilizers

– photographic chemicals

– fungicides

readily absorbed and

accumulated in plants

Food as most common route

of exposure for general

population

Cadmium (Cd)‏

pharmacokinetics:

inhalation:

– smelters, cigarette smoke

– 15-50% absorbed

ingestion:

• main source is liver and

kidney of meats

• 6% absorbed, greater if

deficient in calcium, zinc or

iron

Cadmium (Cd)‏

pharmacokinetics:

distribution:

– bound to albumin in plasma and red blood cells

– transported to liver, pancreas, prostate and kidney, with eventual transfer to kidney

• 50-75% of total body Cd is found in liver and kidney

Metallothionein: protein rich in cysteine

– traps Cd esp. in kidney

• synthesis induced by Cd

Elimination: urine

– half-life in humans is 20 - 30 years

Metallothionein

Cadmium (Cd)‏

Toxicity

Lung toxicity:

– edema and emphysema by killing

lung macrophages

Skeletal effects:

– Osteoporosis and osteomalacia

(pseudofractures)‏

Cancer:

– carcinogenic in animal studies

– ~8% of lung cancers may be

attributable to Cd

Gonads:

- Hypothalamic-pituitary gonadal axis

- Pubertal onset and development

Cadmium (Cd)‏

Toxicity

mechanisms:

– binding to –SH groups

– competing with Zn and Se for

inclusion into metalloenzymes

– competing with calcium for binding

sites (calmodulin)‏

Kidney toxicity:

– free Cd binds to kidney glomerulus

– proximal tubule dysfunction

50

Heavy Metals

Heavy metals cause DNA damage

and cell membrane damage

through the production of free

radicals and oxidative stress.

Heavy Metals

Heavy metals cause DNA damage

and cell membrane damage

through the production of free

radicals and oxidative stress.

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