Semin Reprod Med 2006; 24(3): 168-177
DOI: 10.1055/s-2006-944423
Published in 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Role of Exposure to Environmental Chemicals in the Developmental Basis of Reproductive Disease and Dysfunction

Jerrold J. Heindel1
  • 1Scientific Program Administrator, Division of Extramural Research and Training, Cellular, Organs, and Systems Pathobiology Branch, National Institute of Environmental Health Sciences, Department of Health and Human Service, Research Triangle Park, North Carolina
Further Information

Publication History

Publication Date:
28 June 2006 (online)

ABSTRACT

There is a paradigm shift in science at present that indicates that the onset of many diseases, including reproductive diseases and dysfunctions, are already programmed in utero or in the early postnatal period. This new field is called the developmental basis of health and disease. Although focus has been on the role of in utero nutrition and its effects on subsequent adult-onset diseases, it is clear that exposure to environmental stressors/toxicants in utero or during early development can also increase susceptibility to disease later in life. The mechanism for this in utero and early developmental effect is thought to be altered epigenetic control of gene expression, which alters developmental programming and results in a tissue that may appear normal but is functionally compromised. Although this concept is still a hypothesis, this review addresses the current state of data relating to proving its importance and role in reproductive diseases. If the developmental basis of disease is shown to be true, then examination of the etiology of disease and prevention and intervention strategies will need to be modified to fit the new paradigm.

REFERENCES

  • 1 Gluckman P D, Hanson M A. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective.  Pediatr Res. 2004;  56 311-317
  • 2 Bern H. The fragile fetus. In: Colborn T, Clement C Chemically-Induced Alternations in Sexual and Functional Development: The Wildlife/Human Connection. Princeton, NJ; Princeton Scientific 1992
  • 3 Miller K P, Gorgeest C, Greenfeld C, Tomic D, Flaws J A. In utero effects of chemicals on reproductive tissues in females.  Toxicol Appl Pharmacol. 2004;  198 111-131
  • 4 Vidaeff A C, Sever L E. In utero exposure to environmental estrogens and male reproductive health: a systematic review of biological and epidemiologic evidence.  Reprod Toxicol. 2005;  20 5-20
  • 5 Lau C, Rogers J M. Embryonic and fetal programming of physiological disorders in adulthood.  Birth Defects Res C Embryo Today. 2004;  72 300-302
  • 6 Drake A J, Walker B R. The intergenerational effects of fetal programming: non genomic mechanisms for the inheritance of low birth weight and cardiovascular risk.  J Endocrinol. 2005;  180 1-16
  • 7 Needham L L, Sexton K. Assessing children's exposure to hazardous environmental chemicals: an overview of selected research challenges and complexities.  J Expo Anal Environ Epidemiol. 2000;  10 611-629
  • 8 Mori C, Komiyama M, Adachi T et al.. Application of toxicogenomic analysis to risk assessment of delayed long-term effects of multiple chemicals, including endocrine disruptors in human fetuses.  Environ Health Perspect Toxicogenomics. 2003;  111 7-13
  • 9 Younglai E V, Foster W G, Hughes E G, Trim K, Farrell J F. Levels of environmental contaminants in human follicular fluid, serum and seminal plasma of couples undergoing in vitro fertilization.  Arch Environ Contam Toxicol. 2002;  43 121-126
  • 10 Environmental Working Group .Body burden: the pollution in newborns. Available at: http://www.ewg.org/reports/bodyburden2 Accessed September 15, 2005
  • 11 CDC .National Report on Human Exposures to Environmental Chemicals. http://www.cdc.gov/exposurereport Accessed Month, Day, 2005
  • 12 Herbst A L, Ulfeder H, Poskanzer D C, Longo L D. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women.  N Engl J Med. 1971;  284 878-881
  • 13 Palmer J R, Hatch E E, Rosenberg C L et al.. Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States).  Cancer Causes Control. 2002;  13 753-758
  • 14 McLachlan J A, Newbold R R, Bullock B C. Long term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol.  Cancer Res. 1980;  40 3988-3999
  • 15 Newbold R R, Bullock B C, McLachlan J A. Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis.  Cancer Res. 1990;  50 7677-7681
  • 16 Li S, Hansman R, Newbold R, Davis B, McLachlan J. Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation of its exon-4 in mouse uterus.  Mol Carcinog. 2003;  38 78-84
  • 17 Miyagawa S, Katsu Y, Watanabe H, Iguchi T. Estrogen-independent activation of erBs signaling and estrogen receptor a in the mouse vagina exposed neonatally to diethylstilbestrol.  Oncogene. 2004;  23 340-349
  • 18 Nagai A, Ikeda Y, Aso T, Eto K, Ikeda M A. Exposure of neonatal rats to diethylstilbestrol affects the expression of genes involved in ovarian differentiation.  J Med Dent Sci. 2003;  50 35-40
  • 19 Newbold R R, Banks P, Jefferson W N. Adverse effects of the model environmental estrogen diethylstilbestrol (DES) are transmitted to subsequent generations.  Endocrinology. 2006;  , In press
  • 20 Cook J, Davis B J, Cai S, Barrett J C, Conti C J, Walker C L. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance.  Proc Natl Acad Sci USA. 2005;  102 8644-8649
  • 21 Baird D D, Newbold R. Prenatal diethylstilbestrol exposure is associated with uterine leiomyoma development.  Reprod Toxicol. 2005;  20 81-84
  • 22 Birnbaum L S, Fenton S E. Cancer and developmental exposures to endocrine disruptors.  Environ Health Perspect. 2003;  111 389-394
  • 23 Hunt P A, Koehler K E, Susiarjo M et al.. Bisphenol A exposure causes meiotic aneuploidy in the female mouse.  Curr Biol. 2003;  13 546-553
  • 24 Markey C M, Luque E H, Munoz de Toro M, Sonnenschein C, Soto S M. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland.  Biol Reprod. 2001;  65 1215-1223
  • 25 Muñoz-de-Toro M, Markey C M, Wadia P et al.. Perinatal exposure to bisphenol-A alters peripubertal mammary gland development in mice.  Endocrinology. 2005;  146 4138-4147
  • 26 Brown P K, Manzolillo P A, Zhang J X, Wang J, Lamartiniere C A. Prenatal TCDD and predisposition to mammary cancer in the rat.  Carcinogenesis. 1998;  19 1623-1629
  • 27 Fenton S E, Hamm J T, Birnbaum L S, Youngblood G I. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD).  Toxicol Sci. 2002;  67 63-74
  • 28 Rayner J L, Enoch R R, Fenton S E. Adverse effects of prenatal exposure to atrazine during a critical period of mammary gland growth.  Toxicol Sci. 2005;  4 255-266
  • 29 Alworth L C, Howdeshell K L, Ruhlen R L, Day J K, Lubahn D B, Huang T HM. Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low verses high doses.  Toxicol Appl Pharmacol. 2002;  183 10-22
  • 30 Jefferson W N, Padilla-Banks E, Couse J F, Korach K S, Newbold R R. Neonatal genistein exposure induces estrogen receptor mediated alterations in gene expression in the developing mouse uterus: differential effects of low versus high doses.  Mol Endocrinol. 2005;  , In press
  • 31 Hughes C L, Liu G, Beall S, Foster W G, Davis V. Effects of genistein or soy milk during late gestation and lactation on adult uterine organization in the rat.  Exp Biol Med. 2004;  229 108-117
  • 32 Kouki T, Kishitake M, Okamoto M, Talebe M, Yamanouchiu I. Effects of neonatal treatment with phytoestrogens, genestein and daidzein on sex difference in female rat brain function: estrous cycle and lordosis.  Horm Behav. 2003;  44 140-145
  • 33 Hilakivi-Clarke L, Cho E, Onokafe I, Raygada M, Clark R. Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring.  Oncol Rep. 1999;  6 1089-1095
  • 34 Newbold R R, Banks E P, Bullock B, Jefferson W N. Uterine adenocarcinoma in mice treated neonatally with genistein.  Cancer Res. 2001;  61 4325-4328
  • 35 Jefferson W N, Couse J F, Padilla-Banks E, Korach K S, Newbold R. Neonatal exposure to genistein induces estrogen receptor (ERa) expression and multioocyte follicles in the maturing mouse ovary: evidence for ERb-mediated and nonestrogenic actions.  Biol Reprod. 2002;  67 1285-1296
  • 36 Nakao M. Epigenetics: interaction of DNA methylation and chromatin.  Gene. 2001;  278 25-31
  • 37 Newbold R R, Padilla-Banks E, Snyder R J, Jefferson W N. Developmental exposure to estrogenic compounds and obesity.  Birth Defects Res Part A Clin Mol Technology. 2005;  73 478-480
  • 38 Doerge D R, Twaddle N C, Banks E P, Jefferson W N, Newbold R R. Pharmacokinetic analysis in serum of genistein administered subcutaneously to neonatal mice.  Cancer Lett. 2002;  184 21-27
  • 39 Goldman L R, Newbold R, Swan S H. Exposure to soy-based formula in infancy.  JAMA. 2001;  286 2402-2403
  • 40 Todaka E, Sakura K, Fukata H et al.. Fetal exposures to phytoestrogens-the difference in phytoestrogen status between mother and fetus.  Environ Res. 2004;  11 1-9
  • 41 Abbott D A, Dumesic D A, Eisner J R, Kemnitz R J, Goy R W. The Prenatally androgenized female rhesus monkey as a model for polycystic ovarian syndrome. In: Assiz R, Nestler JE, Dewailly D Androgen Excess Disorders in Women. Philadelphia; Lippincott-Raven 1997: 369-382
  • 42 Eisner F R, Barnett M A, Dumesic D A, Abbott D A. Ovarian hyperandrogenism in adult female rhesus monkeys exposed to prenatal androgen excess.  Fertil Steril. 2002;  77 167-172
  • 43 Padmanabhan V, Evans E, Taylor J A, Robinson J E. Prenatal exposure to androgens leads to the development of cystic ovaries in the sheep.  Biol Reprod. 1998;  56(suppl) 194-199
  • 44 Abbott D H, Dumesic D A, Franks S. Developmental origins of polycystic ovary syndrome: a hypothesis.  J Endocrinol. 2002;  174 1-5
  • 45 Takeuchi T, Tsutsynu O, Ikezuki Y, Takai Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction.  Endocr J. 2004;  51 165-169
  • 46 Lin T M, Rasmussen N T, Moore R W, Albrecht R M, Peterson R E. Region-specific inhibition of prostatic epithelial bud formation in the urogenital sinus of C57B6 mice exposed in utero to 2,3,7,8-tetrachlorodibenzo-P-dioxin.  Toxicol Sci. 2003;  76 171-181
  • 47 Timms B G, Peterson R E, Vom Saal F S. 2,3,7,8-Tetrachlorodibenzo-P-dioxin interacts with endogenous estradiol to disrupt prostate gland morphogenesis in male rat fetuses.  Toxicol Sci. 2002;  67 264-274
  • 48 Prins G S, Birch L, Habermann H et al.. Influence of neonatal estrogens on rat prostate developmental.  Reprod Fertil Dev. 2001;  13 241-252
  • 49 Pu Y, Huang L, Prins G S. Sonic hedgehog-patched gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching.  Dev Biol. 2004;  273 257-275
  • 50 Welshons W V, Nagel S C, Thayer A, Judy B M, Vom Saal F S. Low dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoychlor and other xenoestrogens increases adult prostate size in mice.  Toxicol Ind Health. 1999;  15 12-25
  • 51 Ramos J G, Varayoud J, Sonnenschein C, Soto A M, Munoz de Toro M M, Luque E H. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate.  Biol Reprod. 2001;  65 1271-1277
  • 52 Timms B G, Howdeshell K L, Barton L, Bradley S, Vom Saal F S. Estrogenic chemicals in plastic and oral contraceptives disrupt the fetal mouse prostate and urethra.  Proc Natl Acad Sci USA. 2005;  102 7014-7019
  • 53 Vom Saal F S, Timms B G, Montano M M et al.. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses.  Proc Natl Acad Sci USA. 1997;  94 2056-2061
  • 54 Woodham C, Birch L, Prins G S. Neonatal estrogen down-regulates prostatic androgen receptor through a proteosome-mediated protein degradation pathway.  Endocrinology. 2003;  144 4841-4850
  • 55 Lund T D, Munson D J, Adlercreutz H, Handa R J, Lephart E D. Androgen receptor expression in the rat prostate is down regulated by dietary phytoestrogens.  Reprod Biol Endocrinol. 2004;  16 5-11
  • 56 Karri S, Johnson H, Hendry III W J, Williams S C, Kahn S A. Neonatal exposures to diethylstilbestrol leads to impaired action of androgens in adult male hamsters.  Reprod Toxicol. 2005;  , In press
  • 57 Kelce W R, Gray L E, Wilson E M. Antiandrogens as environmental endocrine disruptors.  Reprod Fertil Dev. 1998;  10 105-111
  • 58 Gray L E, Ostby J, Monosson E, Kelce W R. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sex differentiation of the male rat.  Toxicol Ind Health. 1999;  15 48-64
  • 59 Anway M D, Cupp A S, Uzumcu M, Skinner M. Epigenetic transgenerational actions of endocrine disruptors on male fertility.  Science. 2005;  308 1466-1469
  • 60 Novik K L, Nimmrich I, Genc B et al.. Epigenomics: genome-wide study of methylation phenomena.  Curr Issues Mol Biol. 2002;  4 111-128
  • 61 Jones P A, Baylin S B. The fundamental role of epigenetic events in cancer.  Nat Rev Genet. 2002;  3 415-428
  • 62 Van Driel R, Fransz P F, Verschure P J. The eukaryotic genome: a system regulated at different hierarchical levels.  J Cell Sci. 2003;  116 4067-4075
  • 63 Reik W, Santos F, Dean W. Mammalian epigenomics: reprogramming the genome for development and therapy.  Theriogenology. 2003;  59 21-32
  • 64 Murphy S K, Jirtle R L. Imprinting evolution and the price of silence.  Bioessays. 2003;  25 577-588
  • 65 Kaneko-Ishino T, Kohda T, Ishino F. The regulation and biological significance of genomic imprinting.  J Biochem (Tokyo). 2003;  133 699-711

Jerrold J HeindelPh.D. 

Scientific Program Administrator, Division of Extramural Research and Training, Cellular, Organs, and Systems Pathobiology Branch, National Institute of Environmental Health Sciences, Department of Health and Human Service

79 T.W. Alexander Drive, Building 4401 3rd Floor, Mail Drop: EC-23, Room 3413, Research Triangle Park, NC 27709

Email: heindelj@niehs.nih.gov