Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 3 June 2005:
Vol. 308. no. 5727, pp. 1466 - 1469
DOI: 10.1126/science.1108190
Prev | Table of Contents | Next

Reports

Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility

Matthew D. Anway, Andrea S. Cupp,* Mehmet Uzumcu,{dagger} Michael K. Skinner{ddagger}

Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease etiology.

Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164–4231, USA.

* Present address: Department of Animal Science, University of Nebraska, Lincoln, NE 68583–0908, USA.

{dagger} Present address: Department of Animal Science, Rutgers University, 84 Lipman Drive, New Brunswick, NJ 08901–8525, USA.

{ddagger} To whom correspondence should be addressed. E-mail: skinner{at}mail.wsu.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Epigenetic responses to environmental change and their evolutionary implications.
B. M. Turner (2009)
Phil Trans R Soc B 364, 3403-3418
   Abstract »    Full Text »    PDF »
Defining specificity of transcription factor regulatory activities.
J. Eeckhoute, R. Metivier, and G. Salbert (2009)
J. Cell Sci. 122, 4027-4034
   Abstract »    Full Text »    PDF »
Transgenerational genetic effects on phenotypic variation and disease risk.
J. H. Nadeau (2009)
Hum. Mol. Genet. 18, R202-R210
   Abstract »    Full Text »    PDF »
Fetal and Neonatal Exposure to the Endocrine Disruptor Methoxychlor Causes Epigenetic Alterations in Adult Ovarian Genes.
A. M. Zama and M. Uzumcu (2009)
Endocrinology 150, 4681-4691
   Abstract »    Full Text »    PDF »
Epigenetics of endometriosis.
S.-W. Guo (2009)
Mol. Hum. Reprod. 15, 587-607
   Abstract »    Full Text »    PDF »
Fetal Alcohol Spectrum Disorders: The Epigenetic Perspective.
P. C. Haycock (2009)
Biol Reprod 81, 607-617
   Abstract »    Full Text »    PDF »
In vitro post-meiotic germ cell development from human embryonic stem cells.
B. Aflatoonian, L. Ruban, M. Jones, R. Aflatoonian, A. Fazeli, and H.D. Moore (2009)
Hum. Reprod.
   Abstract »    Full Text »    PDF »
Public Health Implications of Epigenetics.
A. E. Handel and S. V. Ramagopalan (2009)
Genetics 182, 1397-1398
   Full Text »    PDF »
Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement.
E. Diamanti-Kandarakis, J.-P. Bourguignon, L. C. Giudice, R. Hauser, G. S. Prins, A. M. Soto, R. T. Zoeller, and A. C. Gore (2009)
Endocr. Rev. 30, 293-342
   Abstract »    Full Text »    PDF »
Prospects for Epigenetic Epidemiology.
D. L. Foley, J. M. Craig, R. Morley, C. J. Olsson, T. Dwyer, K. Smith, and R. Saffery (2009)
Am. J. Epidemiol. 169, 389-400
   Abstract »    Full Text »    PDF »
Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice.
J. C. Jimenez-Chillaron, E. Isganaitis, M. Charalambous, S. Gesta, T. Pentinat-Pelegrin, R. R. Faucette, J. P. Otis, A. Chow, R. Diaz, A. Ferguson-Smith, et al. (2009)
Diabetes 58, 460-468
   Abstract »    Full Text »    PDF »
Aneuploid sperm formation in rainbow trout exposed to the environmental estrogen 17{alpha}-ethynylestradiol.
K. H. Brown, I. R. Schultz, J. G. Cloud, and J. J. Nagler (2008)
PNAS 105, 19786-19791
   Abstract »    Full Text »    PDF »
The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk.
J. L. Fleming, T. H-M. Huang, and A. E. Toland (2008)
Cancer Res. 68, 9116-9121
   Abstract »    Full Text »    PDF »
Fifteen Years after "Wingspread"--Environmental Endocrine Disrupters and Human and Wildlife Health: Where We are Today and Where We Need to Go.
A. K. Hotchkiss, C. V. Rider, C. R. Blystone, V. S. Wilson, P. C. Hartig, G. T. Ankley, P. M. Foster, C. L. Gray, and L. E. Gray (2008)
Toxicol. Sci. 105, 235-259
   Abstract »    Full Text »    PDF »
Endocrine disruptors and prostate cancer risk.
G. S Prins (2008)
Endocr. Relat. Cancer 15, 649-656
   Abstract »    Full Text »    PDF »
Environmental Estrogens and Endocrine Disruption: Importance of Comparative Endocrinology.
W. G. Foster (2008)
Endocrinology 149, 4267-4268
   Full Text »    PDF »
Epigenetic regulation in male germ cells.
N. M Zamudio, S. Chong, and M. K O'Bryan (2008)
Reproduction 136, 131-146
   Abstract »    Full Text »    PDF »
Oxidative stress and antioxidants: exposure and impact on female fertility.
E. H. Ruder, T. J. Hartman, J. Blumberg, and M. B. Goldman (2008)
Hum. Reprod. Update
   Abstract »    Full Text »    PDF »
Effects of Perinatal Polychlorinated Biphenyls on Adult Female Rat Reproduction: Development, Reproductive Physiology, and Second Generational Effects.
R. M. Steinberg, D. M. Walker, T. E. Juenger, M. J. Woller, and A. C. Gore (2008)
Biol Reprod 78, 1091-1101
   Abstract »    Full Text »    PDF »
Effects of environmental and occupational pesticide exposure on human sperm: a systematic review.
M. J. Perry (2008)
Hum. Reprod. Update 14, 233-242
   Abstract »    Full Text »    PDF »
Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease.
E. E Nilsson, M. D Anway, J. Stanfield, and M. K Skinner (2008)
Reproduction 135, 713-721
   Abstract »    Full Text »    PDF »
Increased Posthatching Mortality and Loss of Sexually Dimorphic Gene Expression in Alligators (Alligator mississippiensis) from a Contaminated Environment.
M. R. Milnes, T. A. Bryan, Y. Katsu, S. Kohno, B. C. Moore, T. Iguchi, and L. J. Guillette Jr. (2008)
Biol Reprod 78, 932-938
   Abstract »    Full Text »    PDF »
Combined Inhaled Diesel Exhaust Particles and Allergen Exposure Alter Methylation of T Helper Genes and IgE Production In Vivo.
J. Liu, M. Ballaney, U. Al-alem, C. Quan, X. Jin, F. Perera, L.-C. Chen, and R. L. Miller (2008)
Toxicol. Sci. 102, 76-81
   Abstract »    Full Text »    PDF »
Epigenetic analysis of human spermatozoa after their injection into ovulated mouse oocytes.
H. Fulka, I. Barnetova, T. Mosko, and J. Fulka (2008)
Hum. Reprod. 23, 627-634
   Abstract »    Full Text »    PDF »
Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location.
C. Yauk, A. Polyzos, A. Rowan-Carroll, C. M. Somers, R. W. Godschalk, F. J. Van Schooten, M. L. Berndt, I. P. Pogribny, I. Koturbash, A. Williams, et al. (2008)
PNAS 105, 605-610
   Abstract »    Full Text »    PDF »
Alterations of Sertoli cell activity in the long-term testicular germ cell death process induced by fetal androgen disruption.
L. Benbrahim-Tallaa, B. Siddeek, A. Bozec, V. Tronchon, A. Florin, C. Friry, E. Tabone, C. Mauduit, and M. Benahmed (2008)
J. Endocrinol. 196, 21-31
   Abstract »    Full Text »    PDF »
Claude Bernard, the first systems biologist, and the future of physiology.
D. Noble (2008)
Exp Physiol 93, 16-26
   Abstract »    Full Text »    PDF »
Genetics and occupational safety and health.
K. T Kelsey (2007)
Occup. Environ. Med. 64, 720-721
   Full Text »    PDF »
Reduced embryonic survival in rainbow trout resulting from paternal exposure to the environmental estrogen 17{alpha}-ethynylestradiol during late sexual maturation.
K. H Brown, I. R Schultz, and J. J Nagler (2007)
Reproduction 134, 659-666
   Abstract »    Full Text »    PDF »
The Dynamic Epigenome and its Implications in Toxicology.
M. Szyf (2007)
Toxicol. Sci. 100, 7-23
   Abstract »    Full Text »    PDF »
Dynamic Regulation of Histone H3 Methylation at Lysine 4 in Mammalian Spermatogenesis.
M. Godmann, V. Auger, V. Ferraroni-Aguiar, A. D. Sauro, C. Sette, R. Behr, and S. Kimmins (2007)
Biol Reprod 77, 754-764
   Abstract »    Full Text »    PDF »
Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female.
R. A. Waterland, M. Travisano, and K. G. Tahiliani (2007)
FASEB J 21, 3380-3385
   Abstract »    Full Text »    PDF »
Increased frequency of reproductive health problems among fathers of boys with hypospadias.
C. Asklund, N. Jorgensen, N.E. Skakkebaek, and T.K. Jensen (2007)
Hum. Reprod. 22, 2639-2646
   Abstract »    Full Text »    PDF »
Trans-generational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors.
M.-Y. J. Lam, J. D. Heaney, K. K. Youngren, J. H. Kawasoe, and J. H. Nadeau (2007)
Hum. Mol. Genet. 16, 2233-2240
   Abstract »    Full Text »    PDF »
Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development.
D. C. Dolinoy, D. Huang, and R. L. Jirtle (2007)
PNAS 104, 13056-13061
   Abstract »    Full Text »    PDF »
Altered reproductive success in rat pairs after environmental-like exposure to xenoestrogen.
L. Fusani, D. Della Seta, F. Dessi-Fulgheri, and F. Farabollini (2007)
Proc R Soc B 274, 1631-1636
   Abstract »    Full Text »    PDF »
Transgenerational epigenetic imprints on mate preference.
D. Crews, A. C. Gore, T. S. Hsu, N. L. Dangleben, M. Spinetta, T. Schallert, M. D. Anway, and M. K. Skinner (2007)
PNAS 104, 5942-5946
   Abstract »    Full Text »    PDF »
Perspectives: The Possible Influence of Assisted Reproductive Technologies on Transgenerational Reproductive Effects of Environmental Endocrine Disruptors.
T. M. Price, S. K. Murphy, and E. V. Younglai (2007)
Toxicol. Sci. 96, 218-226
   Abstract »    Full Text »    PDF »
A review of mechanisms of acrylamide carcinogenicity.
A. Besaratinia and G. P. Pfeifer (2007)
Carcinogenesis 28, 519-528
   Abstract »    Full Text »    PDF »
Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation.
J. Merlet, C. Racine, E. Moreau, S. G. Moreno, and R. Habert (2007)
PNAS 104, 3615-3620
   Abstract »    Full Text »    PDF »
Embryo stability and vulnerability in an always changing world.
A. Hamdoun and D. Epel (2007)
PNAS 104, 1745-1750
   Abstract »    Full Text »    PDF »
Fundamental questions about genes, inactivity, and chronic diseases.
F. W. Booth and S. J. Lees (2007)
Physiol Genomics 28, 146-157
   Abstract »    Full Text »    PDF »
Adult-only exposure of male rats to a diet of high phytoestrogen content increases apoptosis of meiotic and post-meiotic germ cells.
S. Assinder, R. Davis, M. Fenwick, and A. Glover (2007)
Reproduction 133, 11-19
   Abstract »    Full Text »    PDF »
Perturbation of spermatogenesis by androgen antagonists directly injected into seminiferous tubules of live mice.
K. Nagaosa, A. Kishimoto, R. Kizu, A. Nakagawa, A. Shiratsuchi, and Y. Nakanishi (2007)
Reproduction 133, 21-27
   Abstract »    Full Text »    PDF »
Pesticides and Polychlorinated Biphenyls as Potential Risk Factors for Erectile Dysfunction.
J. Y. Polsky, K. J. Aronson, J. P. W. Heaton, and M. A. Adams (2007)
J Androl 28, 28-37
   Abstract »    Full Text »    PDF »
Endocrine Disruptors: Do Family Lines Carry an Epigenetic Record of Previous Generations' Exposures?.
R. T. Zoeller (2006)
Endocrinology 147, 5513-5514
   Full Text »    PDF »
Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Reverse engineering gene networks to identify key drivers of complex disease phenotypes.
E. E. Schadt and P. Y. Lum (2006)
J. Lipid Res. 47, 2601-2613
   Abstract »    Full Text »    PDF »
Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease.
M. D. Anway, C. Leathers, and M. K. Skinner (2006)
Endocrinology 147, 5515-5523
   Abstract »    Full Text »    PDF »
Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination.
H.-S. Chang, M. D. Anway, S. S. Rekow, and M. K. Skinner (2006)
Endocrinology 147, 5524-5541
   Abstract »    Full Text »    PDF »
From The Cover: Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation.
J. E. Cropley, C. M. Suter, K. B. Beckman, and D. I. K. Martin (2006)
PNAS 103, 17308-17312
   Abstract »    Full Text »    PDF »
Germ cells from mouse and human embryonic stem cells..
B. Aflatoonian and H. Moore (2006)
Reproduction 132, 699-707
   Abstract »    Full Text »    PDF »
Transgenerational Effect of the Endocrine Disruptor Vinclozolin on Male Spermatogenesis.
M. D. Anway, M. A. Memon, M. Uzumcu, and M. K. Skinner (2006)
J Androl 27, 868-879
   Abstract »    Full Text »    PDF »
Estrogen effects on fetal and neonatal testicular development..
G. Delbes, C. Levacher, and R. Habert (2006)
Reproduction 132, 527-538
   Abstract »    Full Text »    PDF »
Commentary: Induction and selection of variations during cancer development.
E. Jablonka (2006)
Int. J. Epidemiol. 35, 1163-1165
   Full Text »    PDF »
Health issues and the environment--an emerging paradigm for providers of obstetrical and gynaecological health care.
S. J. Genuis (2006)
Hum. Reprod. 21, 2201-2208
   Abstract »    Full Text »    PDF »
Commentary: Prenatal exposure to diethylstilbestrol (DES): a continuing story.
J. A McLachlan (2006)
Int. J. Epidemiol. 35, 868-870
   Full Text »    PDF »
Epigenetics, Evolution, Endocrine Disruption, Health, and Disease.
D. Crews and J. A. McLachlan (2006)
Endocrinology 147, s4-s10
   Abstract »    Full Text »    PDF »
Endocrine Disruption for Endocrinologists (and Others).
A. C. Gore, J. J. Heindel, and R. T. Zoeller (2006)
Endocrinology 147, s1-s3
   Full Text »    PDF »
Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4.
S.-M. Ho, W.-Y. Tang, J. Belmonte de Frausto, and G. S. Prins (2006)
Cancer Res. 66, 5624-5632
   Abstract »    Full Text »    PDF »
Epigenetic Transgenerational Actions of Endocrine Disruptors.
M. D. Anway and M. K. Skinner (2006)
Endocrinology 147, s43-s49
   Abstract »    Full Text »    PDF »
Adverse Effects of the Model Environmental Estrogen Diethylstilbestrol Are Transmitted to Subsequent Generations.
R. R. Newbold, E. Padilla-Banks, and W. N. Jefferson (2006)
Endocrinology 147, s11-s17
   Abstract »    Full Text »    PDF »
Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide..
D N R Veeramachaneni, J S Palmer, R P Amann, C M Kane, T T Higuchi, and K-Y F Pau (2006)
Reproduction 131, 805-816
   Abstract »    Full Text »    PDF »
New Modes of Action for Endocrine-Disrupting Chemicals.
M. M. Tabb and B. Blumberg (2006)
Mol. Endocrinol. 20, 475-482
   Abstract »    Full Text »    PDF »
Alteration of Transforming Growth Factor-{beta} Signaling System Expression in Adult Rat Germ Cells with a Chronic Apoptotic Cell Death Process after Fetal Androgen Disruption.
M. Maire, A. Florin, K. Kaszas, D. Regnier, P. Contard, E. Tabone, C. Mauduit, R. Bars, and M. Benahmed (2005)
Endocrinology 146, 5135-5143
   Abstract »    Full Text »    PDF »
Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl.
N. El Chami, F. Ikhlef, K. Kaszas, S. Yakoub, E. Tabone, B. Siddeek, S. Cunha, C. Beaudoin, L. Morel, M. Benahmed, et al. (2005)
J. Cell Biol. 171, 651-661
   Abstract »    Full Text »    PDF »
Epigenetic Mechanisms and Gene Networks in the Nervous System.
C. M. Colvis, J. D. Pollock, R. H. Goodman, S. Impey, J. Dunn, G. Mandel, F. A. Champagne, M. Mayford, E. Korzus, A. Kumar, et al. (2005)
J. Neurosci. 25, 10379-10389
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)