Environmental Contaminants and Environmental Contaminants and Infertility in Women Infertility in Women Ulrike Luderer, M.D., Ph.D. Ulrike Luderer, M.D., Ph.D. Division of Occupational and Division of Occupational and Environmental Medicine, Department of Environmental Medicine, Department of Medicine Medicine Department of Developmental and Cell Department of Developmental and Cell Biology Biology
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Environmental Contaminants and Infertility in Women Ulrike Luderer, M.D., Ph.D. Division of Occupational and Environmental Medicine, Department of Medicine.
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Environmental Contaminants and Environmental Contaminants and Infertility in Women Infertility in Women
Division of Occupational and Environmental Division of Occupational and Environmental Medicine, Department of MedicineMedicine, Department of Medicine
Department of Developmental and Cell BiologyDepartment of Developmental and Cell Biology
Infertility and premature ovarian Infertility and premature ovarian failurefailure
12-13% of all couples are infertile12-13% of all couples are infertile Premature ovarian failure is responsible for 20-Premature ovarian failure is responsible for 20-
30% of infertility in women30% of infertility in women Defined as menopause before age 40Defined as menopause before age 40 Affects 1-2% of women Affects 1-2% of women
Ovarian follicular developmentOvarian follicular development
primaryPrimordial
Secondary AntralMature/Preovulatory
Ovulation Ovulated OocyteCorpora Lutea
Hypothalamus
Anterior Pituitary
GnRH
LH, FSH
Ovary
Inhibin
E, P
E
Hormonal regulation of ovarian Hormonal regulation of ovarian functionfunction
The human The human menstrual cyclemenstrual cycle
FSHmIU/ml
Primordial
Primary
Secondary/Preantral
Antral
Large antral/Preovulatory
Not responsive togonadotropins
Responsive togonadotropins Gonadotropin-dependent
Photos of sheep follicles(Juengel and McNatty, 2005Human Reprod Update11:144-61)
Stages of Follicular DevelopmentStages of Follicular Development
Infertility and AgeInfertility and Age
Age of Wife 1965 1982 1995 2002
15 to 19 0.6 2.1
20 to 24 3.6 10.6 4.7
25 to 29 7.2 8.7 7.1
30 to 34 14.0 13.6 9.1 10.9
35 to 39 18.4 24.6 10.5
40 to 44 27.7 27.2 19.6 20.2
Total, 15 to44
13.3 13.9 12.0 11.3
a Percent of married couples excluding those surgically sterilized.
Age: 5 mos gest birth puberty menopause# oocytes: 7 million 2 million 400,000 0
Age-Related Decline in Human Oocytes
- Only 350 oocytes progress to ovulation between puberty and menopause
Causes of premature ovarian failureCauses of premature ovarian failure
Cytogenetic abnormalities of the X chromosomeCytogenetic abnormalities of the X chromosome Fragile X syndromeFragile X syndrome
Immune disturbancesImmune disturbances Viral infectionViral infection Chemical or physical agentsChemical or physical agents Cause is unknown in many casesCause is unknown in many cases
Environmental exposures that cause Environmental exposures that cause ovarian failureovarian failure
25-26 day old pre-pubertal rats were injected with 10 I.U. 25-26 day old pre-pubertal rats were injected with 10 I.U. eCGeCG
48 h later preovulatory follicles were dissected by hand48 h later preovulatory follicles were dissected by hand Immediately processed for assays (0h, negative control) Immediately processed for assays (0h, negative control)
OROR cultured for 2 to 48h with :cultured for 2 to 48h with :
MEM medium alone (positive control)MEM medium alone (positive control)
Gclc overexpression protects Gclc overexpression protects against ionizing radiation against ionizing radiation
Empty Vector (CMV9b)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 72 96
Treatment Time (Hours)
Fold Control Absorbance (A.U.)
O Gy
1 Gy
5 Gy
Parental Cell Line (COV434)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 72 96
Treatment Time (Hours)
Fold Control Absorbance (A.U.)
Gclc Overexpression (C6a)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 72 96
Treatment Time (Hours)
Fold Control Absorbance (A.U.)
Gclm Overexpression (M5a)
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 72 96
Treatment Time (Hours)
Fold Control Absorbance (A.U.)
ROS and apoptosis in granulosa ROS and apoptosis in granulosa cellscellsSpontSpont DMBADMBA 4HC4HC RadRad
Early increase in ROSEarly increase in ROS YesYes YesYes YesYes YesYes
Apoptosis prevented by Apoptosis prevented by GSH supplementationGSH supplementation
YesYes YesYes YesYes YesYes
Apoptosis potentiated Apoptosis potentiated by GSH depletionby GSH depletion
YesYes YesYes YesYes --
Variations in ovarian GSH synthesizing capacity in human Variations in ovarian GSH synthesizing capacity in human populations may be responsible for interindividual differences populations may be responsible for interindividual differences in susceptibility to ovarian toxicants and to premature ovarian in susceptibility to ovarian toxicants and to premature ovarian failure.failure.
AcknowledgmentsAcknowledgments
Luderer Lab Current MembersLuderer Lab Current Members Mabel Cortés-WanstreetMabel Cortés-Wanstreet Yvonne HoangYvonne Hoang Brooke NakamuraBrooke Nakamura Laura OrtizLaura Ortiz Victoria FloresVictoria Flores
Past Lab MembersPast Lab Members Miyun Tsai-TurtonMiyun Tsai-Turton Youming TanYouming Tan Brian LuongBrian Luong Pedro MorgadoPedro Morgado Sarah LopezSarah Lopez Matilde GonzalezMatilde Gonzalez Jennifer LavorinJennifer Lavorin
UC IrvineUC Irvine Charles LimoliCharles Limoli
University of WashingtonUniversity of Washington Terry KavanaghTerry Kavanagh
University of LeidenUniversity of Leiden Peter SchrierPeter Schrier
UCI Developmental Biology UCI Developmental Biology Center and Chao Family Center and Chao Family Comprehensive Cancer CenterComprehensive Cancer Center
FundingFunding NIEHS ES10963NIEHS ES10963 Center for Occupational and Center for Occupational and