S. Bernasconi
Clinica Pediatrica
Dipartimento dell’età evolutiva Università di Parma
Gli “Endocrine disrupters” :
realta’ o fantasia ?
Gli “Endocrine disrupters” : realta’ o fantasia ?
Definizione
Interesse per i pediatri
Esempio di possibile azione degli
endocrine disrupters: la sindrome del testicolo disgenetico
Una preoccupazione attuale : influenze sullo sviluppo puberale. Sicurezze e
dubbi.
Gli “Endocrine disrupters” : realta’ o fantasia ?
Definizione
Interesse per i pediatri
Esempio di possibile azione degli
endocrine disrupters: la sindrome del testicolo disgenetico
Una preoccupazione attuale : influenze sullo sviluppo puberale. Sicurezze e
dubbi.
Gli “Endocrine disrupters” : realta’ o fantasia ?
Definizione
Interesse per i pediatri
Esempio di possibile azione degli
endocrine disrupters: la sindrome del testicolo disgenetico
Una preoccupazione attuale : influenze sullo sviluppo puberale. Sicurezze e
dubbi
Arch. Dis. Child. 2006
Pediatrics 2008
Regulatory oversight of endocrine disrupting chemicals should be centralized such that regulations pass through a single office to ensure coordination among
agencies. Coordination is required for comprehensive and consistent regulations among all relevant federal agencies setting guidelines for acceptable exposure, manufacturing, sale, and human use of EDCs.
Policy should be based on comprehensive data covering both low-level and high- level exposures. Furthermore, tests and screens used to determine EDC activity of chemicals should be balanced between those that examine simple mechanisms and others that instead measure integrated biological outcomes, thereby
encompassing substances that have effects through several mechanisms, whether known or unknown.
• Policy should be developed and revised under the direction of a collaborative group comprising endocrinologists, toxicologists, epidemiologists, and
policymakers. The same group should identify knowledge gaps and recommend research directions to fill those gaps.
• Until such time as conclusive scientific evidence exists to either prove or disprove harmful effects of substances, a precautionary approach should be taken in the formulation of EDC policy.
• The federal government should develop a public awareness campaign to inform the public of the risks and potential risks related to the presence of EDCs in the environment and in the food supply.
• The federal government should support further research into EDCs, including the development of high-throughput assays that would allow the testing of many chemicals for EDC activity at a full range of concentrations
1 1 st st - - month breast milk content of month breast milk content of Mycoestrogens
Mycoestrogens in 47 health in 47 health primipara primipara women
women
0.00.0 0.50.5 1.01.0 1.5 1.5 2.0 2.0 2.52.5 3.03.0
00 55 1010 1515 2020 2525 3030 3535 4040 4545
Z E A Z E A c h e m ic a ls c h e m ic a ls (n g /m l) (n g /m l)
In 1
In 1
stst-month breast milk - month breast milk, , mean ZEA content mean ZEA content was was 1.1 1.1 ±0.4 ± 0.4 ng ng /ml /ml , corresponding to a Neapolitan , corresponding to a Neapolitan newborn TDI newborn TDI 1.4- 1.4 -1.6 1.6- -
told higher than 70
told higher than 70 - - kg adult limit for ZEA toxicity (i.e. 0.2 kg adult limit for ZEA toxicity (i.e. 0.2 µ µ g/kg/day g/kg/day ) ) . .
Massart
Massart etet al. Mineral. Miner PedPed 2008; 60: 1277-2008; 60: 1277-7878
1 2 3 4 5 6 7 8 9 10 11 12 13 14 0.0
0.1 0.2 0.3 0.4 0.5
ZEA (ppb)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0.00 0.25 0.50 2 3 3 4
αααα-ZOL (ppb)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0 5 10 15 20 25
ββββ-ZOL (ppb)
Italian infant formula milks Italian infant formula milks
28% of all infant formula milks (185 samples, 37 types) were 28% of all infant formula milks (185 samples, 37 types) were
contaminated by
contaminated by β β ZOL (6.76 ZOL (6.76 ± ± 14.17 14.17 ng ng /ml /ml ) ) , while 5% and 20% , while 5% and 20%
by by ZEA (0.02 ZEA (0.02 ± ± 0.11 0.11 ng ng /ml) /ml) and and α α ZOL ZOL (0.35 (0.35 ± ± 1.58 1.58 ng ng /ml) /ml) . . ppb=ng ppb=ng /ml /ml
Massart
Massart etet al. Hormal. Horm Res 2008; 70:21Res 2008; 70:21
Gli “Endocrine disrupters” : realta’ o fantasia ?
Definizione
Interesse per i pediatri
Esempio di possibile azione degli
endocrine disrupters: la sindrome del testicolo disgenetico
Una preoccupazione attuale : influenze sullo sviluppo puberale. Sicurezze e
dubbi
Gli “Endocrine disrupters” : realta’ o fantasia ?
testicular
testicular dysgenesis dysgenesis syndrome
syndrome (TDS) : (TDS) :
Criptorchidismo Criptorchidismo
Ipospadia Ipospadia
tumore testicolo tumore testicolo
infertilit infertilit à à
Geographic association between Geographic association between
abnormalities in male reproductive abnormalities in male reproductive
health health
Denmark Denmark
High incidence High incidence
of testicular of testicular
cancer cancer
Finland
Low incidence of
testicular cancer
Geographic association between Geographic association between
abnormalities in male reproductive abnormalities in male reproductive
health health
Denmark Denmark
High incidence of testicular High incidence of testicular cancer
cancer
High incidence of High incidence of cryptorchidism cryptorchidism
Finland
Low incidence of testicular cancer
Low incidence of
cryptorchidism
0 2 4 6 8 10
P e rc e n ta g e
FIN DK
Country
Incidence of cryptorchidism
(at birth)
Geographic association between Geographic association between
abnormalities in male reproductive abnormalities in male reproductive
health health
Denmark Denmark
High incidence of testicular High incidence of testicular cancer
cancer
High incidence of High incidence of cryptorchidism cryptorchidism
High incidence of High incidence of hypospadias
hypospadias
Finland
Low incidence of testicular cancer
Low incidence of cryptorchidism
Low incidence of
hypospadias
Birth rate of
Birth rate of hypospadias hypospadias 1997 1997 - - 2000 2000
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
R a te p e r 1 0 ,0 0 0 b ir th s
Finland
Denmark
Geographic association between Geographic association between
abnormalities in male reproductive abnormalities in male reproductive
health health
Denmark Denmark
High incidence of testicular High incidence of testicular cancer
cancer
High incidence of cryptorchidismHigh incidence of cryptorchidism
High incidence of hypospadiasHigh incidence of hypospadias
Low sperm counts Low sperm counts
Finland
Low incidence of testicular cancer
Low incidence of cryptorchidism
Low incidence of hypospadias
Normal sperm counts
0 20 40 60 80 100 120 140
1935-49 1950-59 1960-69 1970-75 1979-81
Year of birth Median sperm concentration mill per ml (25-75 percentiles)
Median sperm concentration and 25-75 percentiles according to year of birth from 10 Danish studies of men
born between 1935-75 (reconstructed from Bonde) and 708 men from the general Danish population born from
1979-81.
Skakkebaek
Skakkebaek N.E. N.E.
• • Time trends and geographical variations strongly Time trends and geographical variations strongly suggest environmental influence.
suggest environmental influence.
• • Epidemiological data suggests that the Epidemiological data suggests that the fetal
fetal/neonatal reproductive system may be the most /neonatal reproductive system may be the most vulnerable organism to environmental influences.
vulnerable organism to environmental influences.
• • Testicular cancer shares common risk factors and Testicular cancer shares common risk factors and geographic prevalence trends with other disorders geographic prevalence trends with other disorders of male reproductive health, and may be the most of male reproductive health, and may be the most severe symptom of a common entity: The testicular severe symptom of a common entity: The testicular dysgenesis
dysgenesis syndrome (TDS). syndrome (TDS).
• • Although some trends in male reproductive health Although some trends in male reproductive health problems can be explained from endocrine
problems can be explained from endocrine
disruption, genetic and life style factors should also disruption, genetic and life style factors should also be kept in mind.
be kept in mind.
Fertility and Sterility 2008
Gli “Endocrine disrupters” : realta’ o fantasia ?
Definizione
Interesse per i pediatri
Esempio di possibile azione degli
endocrine disrupters: la sindrome del testicolo disgenetico
Una preoccupazione attuale : influenze sullo sviluppo puberale. Sicurezze e
dubbi.
Gli “Endocrine disrupters” : realta’ o fantasia ?
Alterazioni Puberali Alterazioni Puberali
- - anticipo puberale soprattutto femminile anticipo puberale soprattutto femminile
6,7 27,2
14,7 48,3
38,2 77,4
67,9
94,6 88
98,4 96,8 100
0 25 50 75 100
7 8 9 10 11 12
White African- Americans
%
Age
Secular trend
Prevalence of breast and/or pubic hair development at Tanner stage 2 or greater (17,077 girls)
Herman – Giddens ME et al., Pediatrics,1997
Pediatrics 2005
Prevalenza dello sviluppo puberale M stadio ≥ 2 (con IC al 95%)
0,6% 0,3% 0,8% 0,9%
98,0% 99,8%
90,2%
72,6%
43,0%
15,5%
2,4% 5,9%
2 3 4 5 6 7 8 9 10 11 12 13
Telarca > 2 - - 2 2 DS DS media media + 2 + 2 DS DS
7.09
7.09 aa aa 9.73 aa 9.73 aa 12.36 aa 12.36 aa
Prevalenza del menarca (con IC al 95%)
0,0% 0,0% 0,0% 0,0% 0,0% 0,0% 0,2% 1,1% 5,8%
18,3%
52,2%
79,3%
2 3 4 5 6 7 8 9 10 11 12 13
Menarca
10.2410.2433°° c.lec.leaaaa 12.47 12.47 mediamediaaaaa 14.71 14.71 97°97° c.lec.leaaaa10 10 aaaa 12.45 12.45 aaaa 15 15 aaaa Figlie
Madri
international journal of andrology 2006
Pediatrics 2008;121;S192-S207
international journal of andrology 2006
Pediatrics 2007
international journal of andrology 2006
D. A Crain
Fertility and Sterility 2008
Teilmann et al
Gli “Endocrine disrupters” : realta’ o fantasia ?
1) evidenze sperimentali e tossicologiche 1) evidenze sperimentali e tossicologiche
2) Evidenze epidemiologiche 2) Evidenze epidemiologiche
a) pochi studi
a) pochi studi
International journal of andrology 2006
Gli “Endocrine disrupters” : realta’ o fantasia ?
1) evidenze sperimentali e tossicologiche 1) evidenze sperimentali e tossicologiche
2) 2) Evidenze epidemiologiche Evidenze epidemiologiche
a) pochi studi a) pochi studi
B) risultati in lin
B) risultati in linea con le ea con le aspettative co
aspettative co n qualche n qualche eccezione
eccezione
Endocrine Reviews 2003
Environ Health Perspect 2000
Phthalate esters were consistently detected at significant concentration
levels (ranging from tens of
parts per billion to units of
parts per million) in 28 of
41 (68%) serum samples
obtained from the thelarche
patients.
Massart
Massart et al. Gynecolet al. Gynecol EndocrEndocr 2005; 20:922005; 20:92
High incidence of precocious puberty in High incidence of precocious puberty in
a bounded area of northwest Tuscany a bounded area of northwest Tuscany
*
CPP prevalence in the five major health service areas (Livorno, Lucca, Massa, Pisa and Viareggio cities) of northwest Tuscany
Livorno 37332 7 12:1 18.7
Lucca 24630 5 10:1 20.3
Pisa 36420 9 7:2 24.7
Massa 22370 13 12:1 58.1*
Viareggio
Viareggio 19219 31 26:5 161.3* 161.3 *
*significant difference, P<0.05 Total number
of 0-14 yr-old children
CPP
cases ♀/♂
ratio
CPPs per 100000 children City
area
Massart
Massart et al. Gynecolet al. Gynecol EndocrEndocr 2005; 20:922005; 20:92
CPP case per 100,000 living children
CPP prevalence in 80
CPP prevalence in 80 - - km km 2 2 area next to area next to Viareggio is 25
Viareggio is 25 - - times higher than others times higher than others
α-α-ZearalenolZearalenol
1 2 3 4 5
6
β-β-ZearalenolZearalenol Zearalenone Zearalenone 00
200200 400400 600600 800 800 1,000 1,000 1,200 1,200
Mycoestrogens
Mycoestrogens are only HPLC are only HPLC - - detected detected in 6 CPP girls from Viareggio area
in 6 CPP girls from Viareggio area
Viareggio CPP
Viareggio CPP girlsgirls
Serum
Serum levels levels at CPP diagnosis at CPP diagnosis pg/ml pg /ml
17 CPP from Viareggio area 15 CPP not from Viareggio
vs.
15 Controls from Viareggio
16 Controls not from Viareggio
Massart
Massart et al. J Pediatret al. J Pediatr 2008; 152:6902008; 152:690-5-5
International journal of andrology 2006
Epidemiological research on the effects of endocrine disrupters on sexual maturation is hampered by numerous
pitfalls.
One major problem is the mixture of different
agents with potential oestrogenic, anti-oestrogenic and anti-androgenic activities in the environment.
Another important problem is the limited knowledge about the time lag between exposure and effect. For most effects,
the critical window of exposure has not yet been identified, so that it is not always clear whether to look at in
utero, lactational, pubertal or life-long exposure.
Additionally, epidemiological research in general may be
influenced by many factors such as selection of the study area, sample size, adjustment for confounders, choice of the
endpoints, etc.
International journal of andrology 2006
One of the reasons for the negative results on PCBs, is
that often total PCB concentrations in serum are measured,
while various PCB congeners may have different, sometimes
antagonistic, effects.
Gli “Endocrine disrupters” : realta’ o fantasia ?
1) evidenze sperimentali e tossicologiche 1) evidenze sperimentali e tossicologiche
2) Evidenze epidemiologiche 2) Evidenze epidemiologiche
a) pochi studi a) pochi studi
B) risultati in linea con le B) risultati in linea con le aspettative con qualche aspettative con qualche eccezione
eccezione
c) meccanismi
c) meccanismi
Arch. Dis. Child.
2006;91;633-641
Environ Health Perspect 2002
Molecular and Cellular Endocrinology 2006
Gli “Endocrine disrupters” : realta’ o fantasia ?
- They can interact at any step of the signalling pathway = receptor binding,
activation, nuclear transfert, transcriptional co-factor modulation, chromatin
modification, gene expression
- Environmental chemicals may play a role in programming or imprinting genes involved in cell differentiation and proliferation with a
risk of unknown long-term consequences.
Gli “Endocrine disrupters” : realta’ o fantasia ?
Conclusioni :
Gli “Endocrine disrupters” : realta’ o fantasia ?
International agencies (U.N, WHO, EPA, E.C.) should be deeply concerned by the emerging trends
Despite no direct proof that pesticides and other environmental chemicals cause
developmental abnormalities, the existing data suggest we need to take the threat of environmental chemical very seriously
