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Endocrine Disruptors: Endocrine Disruptors:
Child healthsChild healths
Vichit Supornsilchai, MD, PhDVichit Supornsilchai, MD, PhD
Endocrine Unit, Department of Pediatric,Endocrine Unit, Department of Pediatric,
Faculty of Medicine, Faculty of Medicine,
King Chulalongkorn MemorKing Chulalongkorn Memoriaial Hospitall Hospital
Overview Background animal experiences evidences in human Definition and classification of EDs Routes of human exposure The effects of EDs on the reproductive systems The effects of Bisphenol A (BPA) on PP and
obesity in Thai’s children and adolescents
Background: Animal experiences
Outbreak of infertility in Australian sheep (1940s) Outbreak of infertility in Australian sheep (1940s) ingestion of large amount of subterranean clover ingestion of large amount of subterranean clover estrogenic effects of phytoestrogens in the Clover estrogenic effects of phytoestrogens in the Clover
(Clover disease)(Clover disease)
Reproductive dysfunction in the bald eagle Reproductive dysfunction in the bald eagle and other wild birdsand other wild birds exposure of high doses of DDT and other chemicalsexposure of high doses of DDT and other chemicals development of thin-shelled, nonviable eggs development of thin-shelled, nonviable eggs
Murkies AL et al., J Cli Endocrinol Metab, 1998, 83, 297-303Murkies AL et al., J Cli Endocrinol Metab, 1998, 83, 297-303
Garcelon DK et al., J Wildl Dis, 1997, 33, 299-303Garcelon DK et al., J Wildl Dis, 1997, 33, 299-303
BackgroundBackground: : Animal experiencesAnimal experiences
Edwards TM et al., International Journal of Andrology 2006, 29, 109-121
Reproductive dysfunction in Reproductive dysfunction in young male alligators in Lake young male alligators in Lake Apopka, Florida (1970s) Apopka, Florida (1970s)
small phallus sizesmall phallus size decreased serum testosterone decreased serum testosterone
levelslevels abnormal gonadal morphologyabnormal gonadal morphologyAssociate with elevated level of Associate with elevated level of
DDT metabolitesDDT metabolites Guillette LT et al., Environ Health Perspect, 1994, 102, 680-688Guillette LT et al., Environ Health Perspect, 1994, 102, 680-688
Background: Background: Evidences in humansEvidences in humans
DiethylstilbestrolDiethylstilbestrol (DES)(DES) is a prototype in is a prototype in humanhuman
exposed exposed male male offspringoffspring hypospadiashypospadias micropenismicropenis cryptorchidismcryptorchidism decreased fertilitydecreased fertility
exposed exposed femalefemale offspring offspring reproductive organ dysfunctionreproductive organ dysfunction decreased pregnancy ratedecreased pregnancy rate decreased fertility decreased fertility
Bibbo M et al., Obstet Gynecol, 1997, 49, 1-7
Background: Background: Epidemiological evidences in humansEpidemiological evidences in humans
Fisher JS, Reproduction 2004, 127, 305-315 Fisher JS, Reproduction 2004, 127, 305-315
Carlsen et al., Environ Health Perspect 1995, 103, 137-139Carlsen et al., Environ Health Perspect 1995, 103, 137-139
Sperm countSperm count
Paulozzi, Environ Healthe Perspect 1999, 107, 297-302Paulozzi, Environ Healthe Perspect 1999, 107, 297-302
Definition of EDs
An exogenous substance, either anthropogenic or natural, that can alter endocrine functions by
a variety of different mechanisms; By acting as either agonists or antagonists By altering the synthesis, transport and/or
catabolism of endogenous hormones By modifying the levels of expression
and/or functioning of hormone receptors
ClassificationClassification
Estrogenic activity: Estrogenic activity: Dichlorodiphenyltrichloroethane (DDT)Dichlorodiphenyltrichloroethane (DDT) Phytoestrogens (at high concs)Phytoestrogens (at high concs) Polychlorinated biphenyls (PCBs)Polychlorinated biphenyls (PCBs) Bisphenol ABisphenol AAnti-androgenic activity: Anti-androgenic activity: AR antagonist:AR antagonist: vinclozolin, procymidone, vinclozolin, procymidone,
linuron, pp’ DDElinuron, pp’ DDE Reduce androgen synthesis:Reduce androgen synthesis: phthalate phthalate
estersesters
Classification Classification
Anti-estrogenic activity:Anti-estrogenic activity: dioxin (TCDD), dioxin (TCDD), PCBs, phytoestrogens (at low concs)PCBs, phytoestrogens (at low concs)
Androgenic activity: Androgenic activity: Testosterone, Testosterone, Trembolone acetate Trembolone acetate
Thyroid hormonal effectsThyroid hormonal effects
Evidences were mostly from animal experimentsEvidences were mostly from animal experiments
Identified EDs are just a tip of icebergIdentified EDs are just a tip of iceberg
Other mechanismsOther mechanisms
nonnuclear steroid hormone receptor nonnuclear steroid hormone receptor i.e.i.e. membrane receptormembrane receptor
nonsteroid receptors nonsteroid receptors i.e.i.e. neurotransmitter receptors neurotransmitter receptors (serotonin receptor, dopamine (serotonin receptor, dopamine receptor)receptor)
orphan receptor orphan receptor i.e.i.e. Aryl-hydrocarbon receptor (AhR) Aryl-hydrocarbon receptor (AhR)
direct effect on the enzymes in steroidogenesisdirect effect on the enzymes in steroidogenesis
Routes of human exposureRoutes of human exposure
Timing of exposure is critical !
Factors of endocrine Factors of endocrine disruption of EDsdisruption of EDs
Age at exposureAge at exposure Latency from exposureLatency from exposure Importance of mixturesImportance of mixtures Nontraditional dose-response dynamicsNontraditional dose-response dynamics Transgenerational epigenetic effectsTransgenerational epigenetic effects
Evanthia DK et.al. Endocrine Review 2009; 30: 293-342Evanthia DK et.al. Endocrine Review 2009; 30: 293-342
The effects of EDs on reproductive systems
Male reproductive system Genital malformations and the TDS
(Testicular dysgenesis syndrome)
Female reproductive system Early and precocious puberty
Asklund C, BJU international 2004, 93, 6-11Asklund C, BJU international 2004, 93, 6-11
First introduced by Skakkebaek (Denmark) First introduced by Skakkebaek (Denmark)
Genital malformations and the TDS Genital malformations and the TDS (Testicular (Testicular dysgenesis syndrome)dysgenesis syndrome)
Reproductive disease in adult men may result from disruptionReproductive disease in adult men may result from disruption of embryonic programming and fetal gonadal developmentof embryonic programming and fetal gonadal development
Early and precocious pubertyEarly and precocious puberty
The onset of puberty trend to be earlier, The onset of puberty trend to be earlier, particularly in girlparticularly in girl
The precise trigger for the onset of The precise trigger for the onset of puberty is not known, but it is believed to puberty is not known, but it is believed to be a complex interaction between be a complex interaction between genetics, hormones, and environmental genetics, hormones, and environmental influences influences
EDs may play an important role in timing EDs may play an important role in timing and disturbance of normal pubertyand disturbance of normal puberty
Exposure-outcome relationshipExposure-outcome relationship ExposureExposure ReferencesReferences
Advanced pubertyAdvanced puberty
Earlier menarche and pubarcheEarlier menarche and pubarche PBBPBB Blanck et al., 2000Blanck et al., 2000
Earlier thelarcheEarlier thelarche pesticides, pesticides, phthalatesphthalates
Colon et al., 2000Colon et al., 2000
Earlier menarcheEarlier menarche DDEDDE Vasiliu et al., 2004Vasiliu et al., 2004
Central precocious pubertyCentral precocious puberty DDEDDE Krstevska-Konstantinova Krstevska-Konstantinova et al., 2001et al., 2001
Earlier age at menarcheEarlier age at menarche DDTDDT Ouyang et al., 2005Ouyang et al., 2005
PBBs: Polybrominated biphenyls; DDE: Dichlorodiphenyldichloroethylene; DDT: Dichlorodiphenyltrichloroethane; PCBs: Polychlorinated biphenyls; PCDFs: Polychlorinated dibenzofurans; PCDDs: Polychlorinated dibenzodioxins)
The literatures: outbreaks of The literatures: outbreaks of early puberty in sub-populationearly puberty in sub-population
Related to exposure to exogenous Related to exposure to exogenous hormones or hormone-like chemicalshormones or hormone-like chemicals
High frequency of CPP in a region with High frequency of CPP in a region with high exposure to the estrogenic high exposure to the estrogenic mycotoxin zearalenone mycotoxin zearalenone (Massart et.al., J Pediatr 2008; 152: 690-95)(Massart et.al., J Pediatr 2008; 152: 690-95)
Premature thelarche in 4 pre-pubertal Premature thelarche in 4 pre-pubertal girls after consumption of tea containing girls after consumption of tea containing a phytoestrogen (a phytoestrogen (Foeniculum vulgareFoeniculum vulgare) ) (Turkyilmaz et.al., J Peddiatr Surg 2008; 43: 2109-11)(Turkyilmaz et.al., J Peddiatr Surg 2008; 43: 2109-11)
Evidences of PP and poultryEvidences of PP and poultry
An epidemic outburst of premature An epidemic outburst of premature breast development and ovarian cyst breast development and ovarian cyst in 2716 girls from Peurto Rico (1990-in 2716 girls from Peurto Rico (1990-1995) with unknown cause, 1995) with unknown cause, environmental factors (EDs: soy-environmental factors (EDs: soy-based formula, meat products) were based formula, meat products) were suspected. suspected. (Larriuz-Serrano et.al., P R Health Sci J 2001; 20:13-18)(Larriuz-Serrano et.al., P R Health Sci J 2001; 20:13-18)
Evidences of PP and poultryEvidences of PP and poultry US Department of Agriculture and Puerto US Department of Agriculture and Puerto
Rico Department of Health reported that Rico Department of Health reported that there was no abnormal levels of the there was no abnormal levels of the suspected chemicals found in the suspected chemicals found in the approximately 800 samples of meat and approximately 800 samples of meat and dairy products that were analysed dairy products that were analysed (unpublished data)(unpublished data)
Early breast development in both sexes Early breast development in both sexes in Northern Italy due to estrogen in Northern Italy due to estrogen exposure through poultry and beef from exposure through poultry and beef from school cafeteria school cafeteria (Scaglioni et.al. Lancet 1978; 1: 551-2) (Scaglioni et.al. Lancet 1978; 1: 551-2)
Neuroendocrine systemNeuroendocrine system
Hypothalamus (GnRH neurons)-pituitary-Hypothalamus (GnRH neurons)-pituitary-target organtarget organ
Highly complexHighly complex HPG axis: GnRH neurons express steroid HPG axis: GnRH neurons express steroid
hormone receptorshormone receptors Other cells in the brain also express steroid Other cells in the brain also express steroid
hormone receptors and can regulate GnRH hormone receptors and can regulate GnRH i.e. neurotransmitters (Noradrenergic, i.e. neurotransmitters (Noradrenergic, serotonergic, dopaminergic etc.) serotonergic, dopaminergic etc.)
Bisphenol A (BPA)Bisphenol A (BPA)
synthetic estrogen (Xenoestrogen)synthetic estrogen (Xenoestrogen)
Dose-dependent effectsDose-dependent effects Low dose: interacts with both ERLow dose: interacts with both ER and and
ERERββ Higher dose: antiandrogenic activity Higher dose: antiandrogenic activity
Chemical structureChemical structure
Bisphenol A
Estrogen
phenol group: bind to ER
One of the hightest volume chemicals One of the hightest volume chemicals produced worldwideproduced worldwide
Epoxy resins and polycarbonate plastic Epoxy resins and polycarbonate plastic containers (hard, clean plastic)containers (hard, clean plastic)
Plastic use Plastic use considerationsconsiderations
Plastic use Plastic use considerationsconsiderations
Sources of BPA exposureSources of BPA exposure
Canned
products
Polycarbonate plastics
Thermal paper products
Food Most plastics with recycling code 07
Sales receipts
Soda Intravenous tubing and medical equipments
Lottery tickets
Liquid infant formula (versus powder, which typically has no detectable BPA)
Bottles, toys, pacifier shields, dental sealants
Fax paper, recycling paper products (paper
towels, toilet paper, pizza boxes)
Factors that increase BPA
migration from containers
Increased temperature
Damaged surfaces (scratches)
Increased acidity
Polycarbonate plasticsPolycarbonate plastics
Canned Canned productsproducts
Thermal paper Thermal paper productsproducts
BPA-free productsBPA-free products
Routes of exposureRoutes of exposure
Dietary:Dietary: majority (99%) majority (99%) Monomers of BPA: hydrolyse and leach Monomers of BPA: hydrolyse and leach
from epoxy resins and polycarbonate from epoxy resins and polycarbonate plastics into food and liquids in contact plastics into food and liquids in contact
with the containerwith the container Factors: thermal, acidic and basic Factors: thermal, acidic and basic
conditionsconditions
The primary source of BPA exposure in The primary source of BPA exposure in - - children age and adult: children age and adult:
oral intake from canned foodoral intake from canned food
- - infant: infant:
breastmilk and polycarbonate feeding bottlesbreastmilk and polycarbonate feeding bottles Young children have higher urinary BPA Young children have higher urinary BPA
concentration than adults: reflect higher food concentration than adults: reflect higher food intake per kilogram of body massintake per kilogram of body mass
Nondietary exposureNondietary exposure Cashiers (Cashiers (occupational exposure)occupational exposure), industries , industries
using BPA Human exposure to BPA is using BPA Human exposure to BPA is widespread, small adverse effects of BPA widespread, small adverse effects of BPA could have large public health implicationscould have large public health implications
Infants in NICU have higher BPA exposure Infants in NICU have higher BPA exposure than the general poppulation due to intensive than the general poppulation due to intensive medical interventions and proceduresmedical interventions and procedures
ประเทศแคนาดาออกกฎหมายห�ามการผลิ�ตแลิะประเทศแคนาดาออกกฎหมายห�ามการผลิ�ตแลิะจำ�าหน�ายผลิ�ตภั�ณฑ์�ท� ม�สาร จำ�าหน�ายผลิ�ตภั�ณฑ์�ท� ม�สาร BPA BPA ม�ผลิต�#งแต� ม�ผลิต�#งแต� 19 19 เมษายน เมษายน 2551 2551 เป&นต�นไปเป&นต�นไป
ประเทศสหร�ฐอเมร�กาออกกฎหมายห�ามการผลิ�ตประเทศสหร�ฐอเมร�กาออกกฎหมายห�ามการผลิ�ตแลิะจำ�าหน�ายผลิ�ตภั�ณฑ์�ท� ม�สาร แลิะจำ�าหน�ายผลิ�ตภั�ณฑ์�ท� ม�สาร BPA BPA ท� ใช้�ส�าหร�บท� ใช้�ส�าหร�บเด,ก ม�ผลิต�#งแต� เด,ก ม�ผลิต�#งแต� 1 1 ธั�นวาคม ธั�นวาคม 2553 2553 เป&นต�นไปเป&นต�นไป
กระทรวงสาธัารณส/ขจำ�น ประกาศห�ามใช้�สาร กระทรวงสาธัารณส/ขจำ�น ประกาศห�ามใช้�สาร BPA BPA ในการผลิ�ตขวดนมส�าหร�บเด,ก ม�ผลิต�#งแต� ในการผลิ�ตขวดนมส�าหร�บเด,ก ม�ผลิต�#งแต� 1 1 ม�ถุ/นายน ม�ถุ/นายน 2554 2554 เป&นต�นไป เป&นต�นไป
BPA regulationsBPA regulations
BPA exposure in childrenBPA exposure in children
In the US population, in the 2003-2004 National Health and Nutrition Examination Survey (NHANES) data, •92.6% Age > 6 years expose BPA (Urine BPA mean 2.6 ug/g.cr, P10 0.9ug/g cr, P95 11.2ug/g cr).•High level BPA in female, young age (6-11yrs), low annual household income (<$20,000), Mexican American
Environ Health. 2012 Oct 19;11:79.
Country Sample size(male/female)
Age (yr)
Sampling date
(year)
Detectionfrequency
Ur BPA level(ng/mL)
U.S. 314715
6-11 12-19
2003-2004 92.6% for all GM 3.5GM 3.7
U.S. 356702
6-1112-19
2005-2006 92.9% for all GM 2.9GM 2.5
Canada 1031(524/507) 945(489/456)
6-1112-19
2007-2009 93.20%93.80%
GM 1.30GM 1.50
German 599 3-14 2003-2006 98.60% GM 2.66
Spanish 30 boys 4 2005-2006 96.70% Median 4.2
China 17(10/7) ≤19 2010 94.3% for all GM 1.65
Egypt 57 girls 10-13 2009 79% GM 0.84
Thai (adults) 2340 18-94 2011 52.8% Median 0.33
Thai (children) 376 4-18 2013 75.3% Mean 0.68
Effect of BPAEffect of BPA
Current Opinion in Pediatrics 2011 ;23: 233-9Endocr Rev 2009 ;30: 75-95
Mutat Res. 2012 ;743: 83-90
Effect of BPA
Human
Cancer Breast cancer had higher median serum BPA than without breast cancer
Metabolic Cardiovascular disease, T2DM
Pubertal development
No significant association
Neurodevelopment
Externalizing behaviors (aggression and hyperactivity)
Reproductive system
semen quality, increased sperm DNA damage serum E2, oocyte in women undergoing in-vitro fertilization (IVF)
BPA and obesityBPA and obesity
Authors Country Year N Age(yr)
Method
LOD(ng/mL)
BPA(ng/mL)
Obesity (%)
OW(%)
ResultBPA (ng/mL) and
obesity
P-value
2012: Trasande L, et al
USA 2003-2008
2838 6-19 LCMS
0.3 2.8(median)
17.8 34.1 1st Q (BPA ≤1.5)2nd Q (1.5-2.7)3rd Q (2.8-5.5)4th Q (>5.6)OR 2.08-2.57
< 0.001
2012:Bhandari R, et al
USA
2003-2008
2200
6-18 LCMS
0.3 4.8 17.7
16.7 1st Q (BPA ≤1.5)2nd Q (1.5-2.7)3rd Q (2.8-5.4)4th Q (>5.4)OR 1.78-2.55
0.002
2012:Wang H, et al
China 2011 259 8-15 LCMS
0.07 0.45 GM
31.7 20.4 Normal BPA 0.33Obesity BPA
0.57
0.018
2013:Li D, et al
China 2011 1,326 4-12 HPL/FD
0.31 NA 18.3 Girl: associated with overweight
Significant, 95%CI
Thai children
Thailand
2013-2014
376 3-18 LCMS
0.05 0.68(median)
11.3 9.0 OR 3.42 (NL vs. obese)
0.02
LOD: Lower limit of detection, OR: Odds ratio, LCMS: Liquid chromatography mass spectrometry
BMIUrine BPA
(ng/mL)Urine adjusted BPA (ug/g Cr.)
Estimated daily intake (ug/day)
Median (IQR) Median (IQR) Median (IQR)
Normal weightOverweightObesity
0.67 (0-1.48)0.62 (0-1.13)
0.87 (0.39-1.70)
0.51 (0-1.09)0.36 (0-0.76)
0.71 (0.20-1.16)
0.50 (0-1.32)0.45 (0-1.03)
0.65 (0.30-2.04)
IQR: Interquatile range
BMI OR 95% Confident interval for OR P-value
Normal weight Overweight Obesity
1.001.123.42
0.48-2.621.18 -9.95
1.000.790.02*
OR: Odds ratio
BPA and pubertyBPA and puberty
15/04/23Vichit Supornsilchai, MD 41
Integration of timing of Integration of timing of puberty influenced by both puberty influenced by both genetic and environmental genetic and environmental factorsfactors
BPA and pubertal onsetBPA and pubertal onset
Pubertal developmentPubertal development No association between urine BPA conc No association between urine BPA conc
at 6-8 yrs of age and breast or pubic hair at 6-8 yrs of age and breast or pubic hair development 1 yr later (Wolff et al): development 1 yr later (Wolff et al): prospective cohort study, n= 1151prospective cohort study, n= 1151
No association between urine BPA and No association between urine BPA and pubertal develpoment (Wolff et al): cross pubertal develpoment (Wolff et al): cross sectional study, n= 192sectional study, n= 192
Study Year Country Number
patients/
control
Specimen/
Analysis
method
BPA
Statistic
significant
patients control
Sun Woo
Lee et al
2009 Korea 30/30 Serum/
GCMS
11.2 ± 10.3 16.2 ± 12.5 No
Yunje Kim
et al
2013 Korea 150/90 Serum/
GCMS
7.56 ± 5.6
(N.D.-29.53)
ng/mL
3.53 ± 4.11
(0.39-26.16)
ng/mL
no
Cai D et al 2010 China 110/100 Serum/
HPLC
40.9% 2% yes
Durmaz
et al
2014 Turkey 28 Urine/
HPLC
8.34
(median;
0.84-67.35)
µg/g Cr
1.62
(median;
0.3-25.79)
µg/g Cr
OR 8.68
95% CI:
2.03-32.72
Thai 2014 Thailand 29a/12b/43c
a:precocious
puberty,
b:early puberty
c:control
Urine/
LCMSMS
1.62 (0.68, 3)/
0.54 (0, 1.22)
(median)
µg/g Cr
0.59 (0, 0.97)
(median) µg/g
Cr
yes
BPA and precocious pubertyBPA and precocious puberty
Kiss1 neuron
Kiss1 neuron
Kiss1 neuron
“Kiss network”
GnRH neuron
RFRP3 neuron
TTF1
EAP1
YY1 AVP/PeN
ARC
MeAPituitary
FSH, LH
Puberty
++
GnRH
stimulator
inhibitor
?
+
+
GPR54
GPR14
7/G
PR74
+
-
-
-
-
--
BPA
BPABPA
How to reduce the endocrine How to reduce the endocrine
disruptors exposuredisruptors exposure Eliminate any pesticide, herbicide and Eliminate any pesticide, herbicide and
insecticide use (recommend organic insecticide use (recommend organic products)products)
Wash non-organic fruits and vegetablesWash non-organic fruits and vegetables Make as much of your diet organic as Make as much of your diet organic as
possible. This will eliminate the toxic, possible. This will eliminate the toxic, hormone-disrupting chemicals that are hormone-disrupting chemicals that are sprayed on fruits and vegetables. sprayed on fruits and vegetables.
15/04/23Vichit Supornsilchai, MD 47
How to reduce the endocrine How to reduce the endocrine disruptors exposuredisruptors exposure
Use organic personal care products Use organic personal care products (shampoos, sunscreens, skin (shampoos, sunscreens, skin care, body care)care, body care)
How to reduce the endocrine How to reduce the endocrine disruptors exposuredisruptors exposure
Teach your children to wash their hands Teach your children to wash their hands frequently and not to lick their fingers or frequently and not to lick their fingers or bite their nails. bite their nails.
Avoid buying canned foods or foods Avoid buying canned foods or foods wrapped in plastic. Make sure you wrapped in plastic. Make sure you remove foods from packaging as soon as remove foods from packaging as soon as possible. Use glassware for oven cooking possible. Use glassware for oven cooking
How to reduce the endocrine How to reduce the endocrine disruptors exposuredisruptors exposure
Carefully read the labels of foods, Carefully read the labels of foods, personal care products, household personal care products, household cleaners, cosmetics etc.cleaners, cosmetics etc.
Install a water filter (pesticides, other Install a water filter (pesticides, other chemicals and other debris combine in chemicals and other debris combine in drinking water and heavy metals from drinking water and heavy metals from household pipes and plumbing)household pipes and plumbing)
15/04/23Vichit Supornsilchai, MD 50
How to reduce the endocrine How to reduce the endocrine disruptors exposuredisruptors exposure
Don't let children chew on soft plastic Don't let children chew on soft plastic toys. Phthalates are added to soften PVC toys. Phthalates are added to soften PVC plastic toys. These plastic toys also retain plastic toys. These plastic toys also retain any pesticides sprayed in the house for any pesticides sprayed in the house for up to two weeks. up to two weeks.
Problems in the study of EDs Problems in the study of EDs
difficult to compare the results from each studydifficult to compare the results from each study are the environmental levels sufficient to are the environmental levels sufficient to
induce reproductive tract abnormalities?induce reproductive tract abnormalities? the mixture effects in the environments the mixture effects in the environments
(additive or synergistic manner) (additive or synergistic manner) organ specific effectsorgan specific effects
15/04/23Vichit Supornsilchai, MD 53
Thank Thank youyoufor for
your your attentionattention