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Endocrine disruptors exposure and risk of male congenital malformations N.Olea Hospital Clínico University of Granada Granada, Spain June 2005 Kos, Greece. Environment and Childhood: The INMA Spanish Study. Study cohorts. Exposures and other determinants. Background - PowerPoint PPT Presentation
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Endocrine disruptors exposure and risk of male congenital malformations
N.OleaHospital Clínico University of GranadaGranada, Spain
June 2005Kos, Greece
Environment and Childhood: The INMA Spanish Study
Population Inclusion
year Target number of
infants
Ribera de l’Ebre 1997/99 100
Menorca 1997/98 500
Granada 2001/02 700
Valencia 2003/04 1300
Asturias 2003/04 500
Sabadell 2004 800
Study cohorts
Exposures and other determinants
Prenatal period Postnatal period
12 weeks 20 weeks 32 weeks Birth 1 year 4 years
Exposures
PAHS, PMs, Ozone, VOCs, and NO2
Outdoor
Outdoor Indoor (VOCs,
NO2) Questionnaire
Questionnaire
GIS Questionnaire
GIS
Hydroxypyrene Maternal urine Child urine
Trihalomethanes Outdoor Indoor
Questionnaire Questionnaire Questionnaire
Organochlorines, Policromates, Polybrominates,
Ftalates, Phenols and Polyphenols
Maternal serum Questionnaire Cord serum Mecomium1 Child serum
Other endocrine disrupters Questionnaire Placenta
Lead Cord blood Child blood
Arsenic Maternal nail Child nail
Mercury Newborn hair Child hair
Maternal occupation Questionnaire
Other determinants
Diet Questionnaire Questionnaire Questionnaire Questionnaire
Antioxidants Maternal serum Child serum
Folate Maternal serum
Fatty acids Maternal plasma Maternal milk2
Cord blood Child plasma
Genetic study Maternal blood Cord blood
Paternal psicoaffectivity Questionnaire
Background
An previous ecological study*
searching for geographical variations
in male reproductive health and its
relationships with the exposure to
pesticides suggested that:
The incidence of cryptorchidism
(orchidopexy rates) in south-eastern
Spain was higher in areas with
greater use of pesticides.
García-Rodriguez et al., EHP 104:1090-5, 1996
GR GRAlong the
Mediterranean
coast,
extensive
areas are
devoted to
intensive
farming in
plastic
greenhouses.
Study findings
270 criptorchidic boys <16 y.o.
The frequency of orchidopexy increases in parallel with the degree of pesticide use
OR = 2.32, 95%IC: 1.26-4.29 (level 0 to level 3)
Analysis limited to rural areas, excluding municipal areas
OR = 2.35, 95%IC: 1.39-3.99
*García-Rodriguez et al., EHP 104:1090-5, 1996
Study limitations
Ecologic fallacy
the failure of ecologic effect estimates to reflect the biologic effect al individual level
...... among other limitations
*Vidaeff & Sever, Reproductive Toxicology, 20:5-20, 2005
Ecologic studies are good generating hypothesis
• Background: Male sexual differentiation and reproductive functioning are critically dependent on a balance androgen/estrogen ratio.
• The exposure of the developing foetus to environmental pollutants (xenohormones) may be responsible for anomalies of sexual maturation and reproductive function in adult life.
Some difficulties
The xenohormone hypothesis should be extended to encompass the multitude of weakly “estrogenic” agents:
........but
• how to assess exposure?
• what kind of epidemiology design?
How these points have been addressed?
Chemical uses• Pesticide sales• Machinery as pesticide sprayers
Questionnaires• Parent occupation• Mother exposure during pregnancy
Biologic samples• Determination of selected chemicals
Biomarkers of exposure/effect• Hormone/Xenohormone activity
1. Restrepo et al., Scan J Work Environ Health 16:239-46, 1990
Colombia: Offspring 8867 floriculture workers
Nested case-control: cryptorchidism (16/222 congenital malformations)
Controls: 443 boys
Pesticide exposure: Questionnaire
OR: 1.3 95%CI 0.7-2.4 (Cryptorchidism)OR: 1.2 95%CI 0.6-2.4 (Hypospadias)
2. García-Rodriguez et al., EHP 104:1090-5, 1996
3. Kristensen et al., Epidemiology 8:537-44,1997
Norway: register of newborn 192,417 births
Retrospective cohort: cryptorchidism (251) and hypospadias (270)
Pesticide purchaseTractor pesticide spraying equipment
OR: 1.70 95%CI 1.16-2.50 (Pesticide purchase)OR: 2.32 95%CI 1.34-4.01 (Vegetable farming)
4. Weidner et al., Environ Health Perspect 106:793-6, 1998
Denmark: Register of newborn malformations
Register based case-control: cryptorchidism (6177) and hypospadias (1345)
Controls: 23,273 boys
Parent occupation in farming and gardening (year of conception: 1983-1992)
OR: 1.38 95%CI 1.10-1.73 (Mother in farming/gardening)OR: 1.67 95%CI 1.14-2.47 (Mother in gardening)
5. Longnecker, et al. Am J Epidemiol 155:313-22, 2002
USA: Cohort of newborn 1959-1966
Nested case-control: cryptorchidism (219) and hypospadias (199)
Controls: 599 boys
Pesticide measurements: DDE in mother blood, third trimester of pregnancy
OR: 1.3 95%CI 0.7-2.4 (Cryptorchidism)OR: 1.2 95%CI 0.6-2.4 (Hypospadias)
Some problems detected in these publications regarding misclassification of exposure*.......
• The ecologic fallacy
• The use of registries and census
• The use of proxies instead of direct determinations
• The choice of a single reference exposure (DDE)
*Vidaeff & Sever, Reproductive Toxicology, 20:5-20, 2005
5 papers!
.........that’s all?
Working hypothesis
• Recent animal and human data suggest that exposure to pesticides during pregnancy may play a role in the development of some male sexual disorders, such as cryptorchidism and hypospadias.
• Pesticides as endocrine disruptors (EDs), include some organochlorine compounds with oestrogen or anti-androgen properties.
- Some (few) methods have been proposed by Soto and coworkers (1995) and Kortenkamp and coworkers (1999) to overcome the unpredictability of xenoestrogen interactions.
Exposure scenario
- Low level exposure to large numbers of chemicals.
- Synergetic, additive, and/or antagonistic interactions between chemicals and hormones should be considered.
1. To identify the main risk factors for cryptorchidism and hypospadias in south-eastern Spain, and their possible association with environmental factors, with special emphasis on exposure to environmental chemicals with estrogenic activity (xenoestrogens).
2. To determine whether the combined effect of environmental estrogens measured as the total effective xenoestrogen burden (TEXB) is a risk factor for cryptorchidism and hypospadias.
Cryptorchidism and hypospadias: A case-control studyin South eastern Spain
Objectives
Case
Boys born at the University Granada hospital, who are diagnosed with cryptorchidism (one or both testes) or hypospadias at birth
Control
Boys born at the University Granada hospital, selected from the cohort, without cryptorchidism or hypospadias, matched with cases
• for gestational age ( 7 days)• day of birth ( 15 days) • parity (primiparous/multiparous)
Questionnaire: conducted by trained interviewers, at the hospital, and developed for the prospective multi-centre study
Biomarker of exposure to mixtures of xenoestrogens: Total effective xenoestrogen burden (TEXB)
Chemicals quantified in placentas: Bioaccumulative organochlorine compounds/xenohormones p-p´ DDT, aldrin, o-p´ DDT, dieldrin, mirex, p-p´ DDE, endrin, lindane, o-p´DDD, chlordane, methoxychlor, endosulfan y , endosulfan diol, endosulfan sulfate, endosulfan ether, endosulfan lactone
Cohort (n=702) Cases Controls
Eligible population 50 (100) 118 (100)
Decline to participate 2 (4) 4 (3)
Final population 48 (96) 114 (97)
Recruitment period ~2 years
Subjects (%)
Results
- Mean age of mothers was 29.5 yrs (range, 17-43 yrs)
- 57% had low educational level (similar to that of fathers)
- 40% were multiparous
- 19.25% had preterm delivery
- 21% of deliveries were by Caesarian
Risk of cryptorchidism and hypospadias increased with:
- lower birth weight (p= 0.03)
- the professional exposure of fathers to chemicals (OR= 2.98, 95%CI= 1.11-8.01, p for trend= 0.03)
- work of mothers in agriculture (OR= 3.47, 95%CI= 1.33-9.03)
Results
Risk cryptorchidism and hypospadias decreased with:
- mother age (p=0.09)
- lower increase in maternal weight during pregnancy (p= 0.008)
Results
TEXB was positive in:
- 72% of the alpha fractions (mean 3.21 ± 9.26 pM estradiol/g of placenta)
- 86% of the beta fractions (mean 8.61±2.88 pM estradiol/g of placenta).
Higher TEXB alpha and beta levels were found in cases than in paired controls.
Results
Conditional logistical regression analysis, adjusted for mother’s age at delivery and weight of newborn,
........showed that TEXB of the alpha fractions is a risk factor for cryptorchidism........
(OR = 2.82, 95% CI: 1.10-7.24; p= 0.031)
Results
DDT and metabolites, endosulfan and metabolites, lindane, aldrin/dieldrin/endrin, hexachlorobenzene, methoxychlor and mirex were found in placentas.
The most frequent pesticides detected were p,p’DDE (84%), followed by lindane (61%).
The number of residues found in placenta samples was significantly higher in cases (p= 0.002).
Results
Conditional logistical regression analysis, adjusted for mother’s age at delivery and weight of newborn, showed a higher risk of cryptorchidism/hypospadias with the presence of:
Lindane, DDTs, Endosulfan I, Mirex.
This risk was also associated with higher concentrations of lindane (p = 0.007) and dieldrin (p = 0.052).
Results
The estrogenicity of placenta tissue extracts due to bioaccumulated environmental estrogens,
.......measured as the total effective xenoestrogen burden of the alpha fraction (TEXB-alpha) .....
.......is a risk factor for genital tract malformations.
TEXB: goes beyond the quantification of environmental estrogens. It measures the biological activity resulting from mixture of xenoestrogens
Conclusions
The optimal information regarding harmful effects of xenoestrogens in human should come from epidemiologic studies
It would be irresponsible to postpone the monitoring and regulatory measures until all the necessary evidence is available
Recomendations
Information Knowledge Concern Awareness Decision Making
The precautionary principle (Spanish version)
ANA
MARGA
PATRICIA
JUANPEDRO
ROSA
RAMON