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Is female reproductive aging programmed in the womb?

Author:
Walker   Deena  


Journal:
Endocrine Disruptors


Issue Date:
2013


Abstract(summary):

Polychlorinated Biphenyls (PCBs) are industrial contaminants and a class of endocrine disrupting chemicals (EDCs) that are known to interact with the reproductive system (estrogenic and androgenic) as well as other endocrine systems. Our lab and others have shown that perinatal exposure to estrogenic PCBs alters numerous aspects of the reproductive physiology and behavior in adulthood. In our current study published in Endocrinology, we extended this work further into the lifecycle to understand how gestational exposure to EDCs might affect the process of reproductive aging. In females, we found that exposure to a PCB mixture, Aroclor 1221 (A1221), altered the progression of reproductive aging and gene expression profiles in two brain regions important for regulating reproductive physiology and function: the arcuate nucleus (ARC) and median eminence (ME). Fewer effects were found in males and were largely limited to the ARC. Here I expand upon the ideas presented in the original article to discuss how exposure to EDCs and early life history can inform treatment for the symptoms of menopause, explore new hypotheses regarding circadian alterations involved in the process of reproductive aging, and examine how different models of reproductive senescence may inform our understanding of the underlying cellular and molecular mechanisms involved in these physiological processes. Polychlorinated Biphenyls (PCBs) are industrial contaminants and a class of endocrine disrupting chemicals (EDCs) that are known to interact with the reproductive system (estrogenic and androgenic) as well as other endocrine systems. Our lab and others have shown that perinatal exposure to estrogenic PCBs alters numerous aspects of the reproductive physiology and behavior in adulthood. In our current study published in Endocrinology, we extended this work further into the lifecycle to understand how gestational exposure to EDCs might affect the process of reproductive aging. In females, we found that exposure to a PCB mixture, Aroclor 1221 (A1221), altered the progression of reproductive aging and gene expression profiles in two brain regions important for regulating reproductive physiology and function: the arcuate nucleus (ARC) and median eminence (ME). Fewer effects were found in males and were largely limited to the ARC. Here I expand upon the ideas presented in the original article to discuss how exposure to EDCs and early life history can inform treatment for the symptoms of menopause, explore new hypotheses regarding circadian alterations involved in the process of reproductive aging, and examine how different models of reproductive senescence may inform our understanding of the underlying cellular and molecular mechanisms involved in these physiological processes. Endocrine disrupting chemicals (EDCs) are compounds in the environment that interfere with any aspect of hormone action in the body. They are found throughout the environment in the form of plastics and plasticizers (bisphenol A and phthalates), pesticides (DDT and methoxychlor), and industrial contaminants (e.g., polychlorinated biphenyls [PCBs]). 1 1. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS. Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology 2012; 153:4097 - 110; http://dx.doi.org/10.1210/en.2012-1422; PMID: 22733974
[CrossRef], [PubMed], [Web of Science ®]
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Traditionally, EDCs have been studied by toxicologists and epidemiologists with the intention of determining an exposure level that poses the minimum risk to the human population. However, because these compounds interfere with the body’s endogenous endocrine system, we would not expect any dose to be “safe,” as any concentration of hormone, or hormonally active substance, elicits a response from cells expressing hormone receptors throughout the body. Therefore, in recent decades, studies began to use EDCs not only as toxicological agents but as a tool to investigate the cellular and molecular mechanisms of the endocrine system. In the case of our research in reproductive neuroendocrinology, this allows us to answer important questions regarding basic mechanisms as well as provide critical information regarding how EDCs might be altering reproductive physiology in exposed populations. This was the goal of our study published in Endocrinology, 2 2. Walker DM, Kermath BA, Woller MJ, Gore AC. Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors. Endocrinology 2013; 154:2129 - 43; http://dx.doi.org/10.1210/en.2012-2123; PMID: 23592748
[CrossRef], [PubMed], [Web of Science ®]
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in which we used a weakly estrogenic mixture of lightly chlorinated PCBs, Aroclor 1221 (A1221; 1 mg/kg), to investigate the mechanisms of reproductive aging in male and female rats. This enabled us to answer several questions: (1) how does early life experience affect the transition to reproductive senescence; (2) does gestational exposure to EDCs have sex-specific effects on the timing and process of reproductive aging; (3) can we identify novel molecular targets and/or somatic markers of reproductive senescence in males and females? By focusing on populations of cells in the hypothalamus, the region of the brain controlling reproduction, we were able to identify groups of genes and their relationships with physiological aging processes (e.g., erosion of reproductive cycles in aging females, and hormonal changes in both sexes) that may be important for both normal and disrupted aging processes. Here I discuss how our findings may impact strategies for the treatment of menopause in women, expand on our current hypothesis on the cellular and molecular mechanisms of reproductive aging in females, and briefly examine how the models of reproductive senscence in rodents inform our knowledge of these molecular mechanisms. As indicated above, many of the effects of perinatal A1221 exposure were observed in females with limited effects found in males. Therefore, this commentary will mainly focus on these concepts as they pertain to reproductive senescence in females. In 2002, the Women’s Health Initiative (WHI), a large clinical trial designed to investigate the effects of hormone replacement therapy in post-menopausal women, was terminated early due to the finding that estrogen plus progestin replacement resulted in small but significant overall cardiovascular health risks that outweighed any benefits of treatment. 3 3. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al, Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321 - 33; http://dx.doi.org/10.1001/jama.288.3.321; PMID: 12117397
[CrossRef], [PubMed], [Web of Science ®]
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Since then, studies investigating the menopausal transition have expanded upon this work. For example, further review of the population of women used in the WHI revealed that most participants were well beyond the perimenopausal transition, an age when it is unlikely that hormone treatments will be initiated for menopausal symptoms. In fact, when the population was broken up into subgroups by age relative to the menopause, those women who were younger and closer to the transition had significant health benefits from estrogen treatments. 4 4. Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women’s Health Initiative trials of menopausal hormone therapy. Obstet Gynecol 2013; 121:172 - 6; PMID: 23262943
[CrossRef], [PubMed], [Web of Science ®]
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This result, together with animal models consistently showing benefits of estrogen treatments following hormone deprivation, underscored the need for solid basic science research into mechanisms for reproductive transitions in women. Furthermore, comparable research into reproductive aging in men is lacking. Over the past decade, a clearer view of reproductive aging in both female animal models and humans is coming into focus. It is now evident that reproductive senescence is a complex process that involves much more than simply the loss of circulating hormones. For review, see reference 5 5. Kermath BA, Gore AC. Neuroendocrine control of the transition to reproductive senescence: lessons learned from the female rodent model. Neuroendocrinology 2012; 96:1 - 12; http://dx.doi.org/10.1159/000335994; PMID: 22354218
[CrossRef], [PubMed], [Web of Science ®]
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. Rather, there are many other factors (e.g., individual life differences; age, and time relative to menopause—known as the “timing hypothesis”) that contribute to reproductive senescence and a woman’s response to post-menopausal hormone therapy. For review, see reference 6 6. Davies E, Mangongi NP, Carter CL. Is timing everything? A meeting report of the Society for Women’s Health Research roundtable on menopausal hormone therapy. J Womens Health (Larchmt) 2013; 22:303 - 11; http://dx.doi.org/10.1089/jwh.2013.4386; PMID: 23586798
[CrossRef], [PubMed], [Web of Science ®]
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. Additionally, there are both genetic 7 7. Kok HS, van Asselt KM, van der Schouw YT, Peeters PH, Wijmenga C. Genetic studies to identify genes underlying menopausal age. Hum Reprod Update 2005; 11:483 - 93; http://dx.doi.org/10.1093/humupd/dmi024; PMID: 16024548
[CrossRef], [PubMed], [Web of Science ®]
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and environmental factors that influence the timing and progression of reproductive senescence in human and rodent models. 8 8. Dickerson SM, Gore AC. Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle. Rev Endocr Metab Disord 2007; 8:143 - 59; http://dx.doi.org/10.1007/s11154-007-9048-y; PMID: 17674209
[CrossRef], [PubMed], [Web of Science ®]
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Lessons from the WHI study and others suggest that an individual’s life history is an important factor to consider when discussing treatment for the symptoms of menopause in women. Based on our study in rats, early EDC exposure is likely one of those contributing factors to take into account. While exposure to PCBs has not been associated with an advancement of menopause in women, 9 9. Blanck HM, Marcus M, Tolbert PE, Schuch C, Rubin C, Henderson AK, Zhang RH, Hertzberg VS. Time to menopause in relation to PBBs, PCBs, and smoking. Maturitas 2004; 49:97 - 106; http://dx.doi.org/10.1016/j.maturitas.2003.10.011; PMID: 15474753
[CrossRef], [PubMed], [Web of Science ®]
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- 11 11. Yu ML, Guo YL, Hsu CC, Rogan WJ. Menstruation and reproduction in women with polychlorinated biphenyl (PCB) poisoning: long-term follow-up interviews of the women from the Taiwan Yucheng cohort. Int J Epidemiol 2000; 29:672 - 7; http://dx.doi.org/10.1093/ije/29.4.672; PMID: 10922344
[CrossRef], [PubMed], [Web of Science ®]
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there is epidemiological evidence that suggests that exposure to PCBs is associated with reduced fecundity, 12 12. Buck Louis GM, Sundaram R, Schisterman EF, Sweeney AM, Lynch CD, Gore-Langton RE, Maisog J, Kim S, Chen Z, Barr DB. Persistent environmental pollutants and couple fecundity: the LIFE study. Environ Health Perspect 2013; 121:231 - 6; PMID: 23151773
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, 13 13. Chevrier C, Warembourg C, Gaudreau E, Monfort C, Le Blanc A, Guldner L, Cordier S. Organochlorine pesticides, polychlorinated biphenyls, seafood consumption, and time-to-pregnancy. Epidemiology 2013; 24:251 - 60; http://dx.doi.org/10.1097/EDE.0b013e31827f53ec; PMID: 23348067
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increased risk of breast cancer, 14 14. Cohn BA, Terry MB, Plumb M, Cirillo PM. Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50. Breast Cancer Res Treat 2012; 136:267 - 75; http://dx.doi.org/10.1007/s10549-012-2257-4; PMID: 23053646
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- 16 16. Recio-Vega R, Velazco-Rodriguez V, Ocampo-Gómez G, Hernandez-Gonzalez S, Ruiz-Flores P, Lopez-Marquez F. Serum levels of polychlorinated biphenyls in Mexican women and breast cancer risk. J Appl Toxicol 2011; 31:270 - 8; http://dx.doi.org/10.1002/jat.1672; PMID: 21480306
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and increased length 17 17. Buck Louis GM, Rios LI, McLain A, Cooney MA, Kostyniak PJ, Sundaram R. Persistent organochlorine pollutants and menstrual cycle characteristics. Chemosphere 2011; 85:1742 - 8; http://dx.doi.org/10.1016/j.chemosphere.2011.09.027; PMID: 22018858
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or abnormal menstrual cycles. 11 11. Yu ML, Guo YL, Hsu CC, Rogan WJ. Menstruation and reproduction in women with polychlorinated biphenyl (PCB) poisoning: long-term follow-up interviews of the women from the Taiwan Yucheng cohort. Int J Epidemiol 2000; 29:672 - 7; http://dx.doi.org/10.1093/ije/29.4.672; PMID: 10922344
[CrossRef], [PubMed], [Web of Science ®]
View all references
We have been able to model some of these effects in rodents. For example, reproductive senescence was not advanced in the A1221-exposed females but the length of their estrous cycles was increased throughout the lifecycle. Additionally, our laboratory has previously reported that female rats exposed to A1221 perinatally take longer to mate than their control counterparts, 18 18. Steinberg RM, Juenger TE, Gore AC. The effects of prenatal PCBs on adult female paced mating reproductive behaviors in rats. Horm Behav 2007; 51:364 - 72; http://dx.doi.org/10.1016/j.yhbeh.2006.12.004; PMID: 17274994
[CrossRef], [PubMed], [Web of Science ®]
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suggesting a reduction of fecundidty in those animals. By investigating molecular endpoints in rodents who display similar reproductive phenotypes in the human population, we hope to identify biomarkers and therapeutic targets for the treatment of menopausal symptoms in women exposed to estrogenic EDCs. In addition, our study provides novel insight into the progression of reproductive senescence and suggests that the physiological characteristics of reproductive aging in rodents may be influenced by early life experience/exposure, something that could be of consequence when considering treatments for perimenopausal women. For example, the females exposed to A1221 perinatally showed few peripheral signs of reproductive aging; however, neither acyclic nor cyclic females displayed regular estrous cycles or a luteinizing hormone (LH) surge—two hallmarks of reproductive senescence. Furthermore, gene expression profiles in two key hypothalamic regions involved in reproduction, the arcuate nucleus (ARC) and median eminence (ME), of acyclic females exposed to A1221 in utero were similar to the profiles observed in the cyclic control females, as were their uterine and gonadal weights and serum estradiol concentrations. This suggests that A1221 exposure during gestation results in an atypical progression of reproductive aging in female rats. Taken together, these data suggest that the phenotype of acyclicity is a complex trait with multiple molecular and physiological underpinnings that can be programmed in utero. Thus, it follows that life history, including exposure to EDCs, should be considered when discussing medical intervention in women experiencing menopausal symptoms. In the females, exposure to A1221 in utero resulted in altered expression profiles of a number of genes in the ARC and ME that were dependent on cycling status—an effect that was not observed in another region of the hypothalamus, the anteroventral periventricular nucleus (AVPV). This was surprising as the AVPV is necessary for the preovulatory LH surge in rats, 19 19. Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology 1982; 34:395 - 404; http://dx.doi.org/10.1159/000123335; PMID: 6808412
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which was diminished in the cycling females exposed to A1221. However, using network analysis, we identified relationships between gene expression in the hypothalamus and somatic markers and hormones in the periphery during reproductive aging. This provided us with a hypothesis-generating tool, which can be used to identify potential gene targets that may be important for the transition to acyclicity in females. In the AVPV, we observed thought-provoking relationships that deserve follow-up investigation. For example, in the AVPV of cycling females, expression of kisspeptin ( Kiss1) mRNA was positively correlated with expression of arginine vasopressin ( Avp) mRNA, and Avp served as a “hub” of positive correlations. This suggests that vasopressin may be an important regulator of cyclicity in the AVPV. Interestingly, Avp is one of the two main signaling molecules in the suprachiasmatic nucleus (SCN), the brain’s principal circadian clock, the other being vasoactive intestinal protein ( Vip). 20 20. Krajnak K, Kashon ML, Rosewell KL, Wise PM. Sex differences in the daily rhythm of vasoactive intestinal polypeptide but not arginine vasopressin messenger ribonucleic acid in the suprachiasmatic nuclei. Endocrinology 1998; 139:4189 - 96; http://dx.doi.org/10.1210/en.139.10.4189; PMID: 9751499
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Avp in this region is thought to regulate circadian gonadotropin-releasing hormone (GnRH) release, which is the hypothalamus’ final neurohormonal output to the pituitary gland in the regulation of gonadotropins, and subsequently, gonadal steroid hormones. 21 21. Mahoney MM, Smale L. Arginine vasopressin and vasoactive intestinal polypeptide fibers make appositions with gonadotropin-releasing hormone and estrogen receptor cells in the diurnal rodent Arvicanthis niloticus. Brain Res 2005; 1049:156 - 64; http://dx.doi.org/10.1016/j.brainres.2005.04.071; PMID: 15936731
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Additionally, there is evidence that Avp neurons in the SCN project to the Kiss1 neurons in the AVPV 22 22. Vida B, Deli L, Hrabovszky E, Kalamatianos T, Caraty A, Coen CW, Liposits Z, Kalló I. Evidence for suprachiasmatic vasopressin neurones innervating kisspeptin neurones in the rostral periventricular area of the mouse brain: regulation by oestrogen. J Neuroendocrinol 2010; 22:1032 - 9; http://dx.doi.org/10.1111/j.1365-2826.2010.02045.x; PMID: 20584108
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and that Kiss1 in the AVPV displays a circadian expression pattern, 23 23. Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS. Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. Endocrinology 2009; 150:3664 - 71; http://dx.doi.org/10.1210/en.2009-0247; PMID: 19443569
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suggesting a role for the AVPV in circadian regulation of GnRH secretion. With regard to aging, circadian responsiveness was reported to decline with aging in male rodents (females were not investigated), 24 24. Biello SM. Circadian clock resetting in the mouse changes with age. Age (Dordr) 2009; 31:293 - 303; http://dx.doi.org/10.1007/s11357-009-9102-7; PMID: 19557547
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and circadian expression of Vip but not Avp is diminished with age in the female SCN. 25 25. Krajnak K, Kashon ML, Rosewell KL, Wise PM. Aging alters the rhythmic expression of vasoactive intestinal polypeptide mRNA but not arginine vasopressin mRNA in the suprachiasmatic nuclei of female rats. J Neurosci 1998; 18:4767 - 74; PMID: 9614250
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In addition, reproductive senescence is associated with a marked reduction in morning estradiol and progesterone surges in women, 26 26. Ahn RS, Choi JH, Choi BC, Kim JH, Lee SH, Sung SS. Cortisol, estradiol-17β, and progesterone secretion within the first hour after awakening in women with regular menstrual cycles. J Endocrinol 2011; 211:285 - 95; http://dx.doi.org/10.1530/JOE-11-0247; PMID: 21965547
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and the LH surge is delayed and attenuated in the aging female rodent. 27 27. Scarbrough K, Wise PM. Age-related changes in pulsatile luteinizing hormone release precede the transition to estrous acyclicity and depend upon estrous cycle history. Endocrinology 1990; 126:884 - 90; http://dx.doi.org/10.1210/endo-126-2-884; PMID: 2404750
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Taken together, the network analysis provides support for a role of Avp and Kiss1 in the circadian regulation of the female reproductive system. While further investigation is necessary, these data provide intriguing evidence for a circadian component in the transition to reproductive senescene, and specifically, a role for the AVPV in the regulation of circadian GnRH release. Thus, we hypothesize that gestational exposure to estrogenic EDCs results in a circadian clock that is less sensitive to regulation by central and peripheral cues. This could potentially lead to a phase shift in the LH surge and a decoupling of the precise timing of the preovulatory GnRH/LH surge and reproductive behavior in females. Furthermore, circadian disruption is a plausible explanation for the suppressed serum LH concentrations in the cycling females exposed to A1221 in utero. This is supported by data obtained in a companion study investigating the younger siblings of the animals discussed herein. 28 28. Walker DM, Gillette R, Gore AC. Fetal exposures to environmental endocrine disruptors cause long-term molecular reprogramming of the hypothalamus. The Endocrine Society Annual Meeting. Houston, TX, 2012.

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In that study, we found that exposure to A1221 in utero resulted in irregular estrous cycles and altered expression of two genes involved in regulation of circadian rhythms in the female adult (P90) AVPV—aryl hydrocarbon receptor nuclear translocator-like ( Arntl) and period 2 ( Per2). Thus, future studies into the circadian component of reproductive senescence should be conducted in the SCN, as well as the AVPV and ARC, to add more comprehensive information about other regions of the central nervous system involved in circadian regulation/dysregulation during reproductive aging. The vast majority of neuroendocrine studies investigating relationships among expression of hypothalamic genes and serum hormones used gonadectomized animals given steroid hormone replacement. For reviews, see references 5 5. Kermath BA, Gore AC. Neuroendocrine control of the transition to reproductive senescence: lessons learned from the female rodent model. Neuroendocrinology 2012; 96:1 - 12; http://dx.doi.org/10.1159/000335994; PMID: 22354218
[CrossRef], [PubMed], [Web of Science ®]
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and 29 29. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev 2009; 30:713 - 43; http://dx.doi.org/10.1210/er.2009-0005; PMID: 19770291
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. However, the current study, as well as others from the Gore laboratory, 30 30. Walker DM, Juenger TE, Gore AC. Developmental profiles of neuroendocrine gene expression in the preoptic area of male rats. Endocrinology 2009; 150:2308 - 16; http://dx.doi.org/10.1210/en.2008-1396; PMID: 19147677
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, 31 31. Walker DM, Kirson D, Perez LF, Gore AC. Molecular profiling of postnatal development of the hypothalamus in female and male rats. Biol Reprod 2012; 87:129; http://dx.doi.org/10.1095/biolreprod.112.102798; PMID: 23034157
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indicate that the “classical” relationships found in the aforementioned studies rarely hold up in an intact model or across developmental timepoints. A likely explanation for many of these differences is that intact animals experience a variety of biological rhythms (e.g., estrous cycles in females, and circadian hormonal rhythms) that are not mimicked by hormone treatments that typically involve constant exposure to a steroid, e.g., via implantation of a Silastic capsule containing estradiol or testosterone. The network analysis performed in Walker et al. 2 2. Walker DM, Kermath BA, Woller MJ, Gore AC. Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors. Endocrinology 2013; 154:2129 - 43; http://dx.doi.org/10.1210/en.2012-2123; PMID: 23592748
[CrossRef], [PubMed], [Web of Science ®]
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revealed surprisingly few “classical” relationships between genes and circulating hormones in intact rats. For example, we observed a negative correlation between serum estradiol and the progesterone receptor, a relationship that has traditionally been reported to be positive in several brain regions. 32 32. Lauber AH, Romano GJ, Pfaff DW. Sex difference in estradiol regulation of progestin receptor mRNA in rat mediobasal hypothalamus as demonstrated by in situ hybridization. Neuroendocrinology 1991; 53:608 - 13; http://dx.doi.org/10.1159/000125781; PMID: 1876238
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- 35 35. Quadros PS, Wagner CK. Regulation of progesterone receptor expression by estradiol is dependent on age, sex and region in the rat brain. Endocrinology 2008; 149:3054 - 61; http://dx.doi.org/10.1210/en.2007-1133; PMID: 18308846
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Additionally, Kiss1 expression has been reported to be positively regulated by serum estradiol in the AVPV and negatively regulated by serum estradiol in the ARC. For review, see reference 29 29. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev 2009; 30:713 - 43; http://dx.doi.org/10.1210/er.2009-0005; PMID: 19770291
[CrossRef], [PubMed], [Web of Science ®]
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. However, in our analyses, these predicted correlations were not observed, with one notable exception: in the ARC of acyclic females, Kiss1 and neurokinin B ( Tac2) were negatively correlated with serum estradiol. While network analysis was not conducted for the males in this study, similar disparities have been identified in males. For example, androgen receptor (Ar) is reported to be regulated by serum testosterone. 36 36. Handa RJ, Kerr JE, DonCarlos LL, McGivern RF, Hejna G. Hormonal regulation of androgen receptor messenger RNA in the medial preoptic area of the male rat. Brain Res Mol Brain Res 1996; 39:57 - 67; http://dx.doi.org/10.1016/0169-328X(95)00353-T; PMID: 8804714
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, 37 37. McAbee MD, DonCarlos LL. Regulation of androgen receptor messenger ribonucleic acid expression in the developing rat forebrain. Endocrinology 1999; 140:1807 - 14; http://dx.doi.org/10.1210/en.140.4.1807; PMID: 10098519
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However, in intact juvenile males, Ar mRNA expression is increasing at a time when serum testosterone is almost undetectable. 30 30. Walker DM, Juenger TE, Gore AC. Developmental profiles of neuroendocrine gene expression in the preoptic area of male rats. Endocrinology 2009; 150:2308 - 16; http://dx.doi.org/10.1210/en.2008-1396; PMID: 19147677
[CrossRef], [PubMed], [Web of Science ®]
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These and other results suggests that there may be crucial differences between intact and gonadectomized models, which should be taken into account when investigating the molecular and cellular mechanisms of reproductive transitions. In addition, the novel and complex relationships observed between serum hormone concentrations and gene expression are specific to age, sex, cycle status, and brain region. As a whole, these data highlight the necessity for experimentation to include intact and cycling animals to allow for a more complete understanding of reproductive neuroendocrinology. Our recent publication 2 2. Walker DM, Kermath BA, Woller MJ, Gore AC. Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors. Endocrinology 2013; 154:2129 - 43; http://dx.doi.org/10.1210/en.2012-2123; PMID: 23592748
[CrossRef], [PubMed], [Web of Science ®]
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provides novel insights into the molecular mechanisms of reproductive aging in males and females, as well as the disruption of these processes by early life exposure to EDCs. Studying effects of EDCs on reproductive neuroendocrine systems is important from the perspective of understanding whether early life exposures to ecologically relevant PCBs perturb reproduction across the lifecycle and the mechanisms underlying these perturbations. In addition, the use of EDCs can provide a powerful tool to illuminate novel functional roles for well-characterized nuclei in the hypothalamus as well as identify and characterize specific targets that are crucial for reproductive function that may be “reprogrammed” by exposure. These data suggest that while the phenotype of acyclicity may be common among individuals, the molecular and physiological underpinnings may be quite different. Further investigation is necessary to understand the common mechanisms underlying the transition to reproductive senescence. Finally, network analysis is a valuable hypothesis-generating tool that allowed us to identify unexpected relationships between hypothalamic genes and serum hormones in cyclic and acylic rats, suggesting that future studies should include gonadally intact animals. Because exposure to EDCs is ubiquitous, we hope that these findings can help identify potential biomarkers for exposure and developmental timepoints when intervention may be most beneficial. Author note: Please include affiliation information for author on the title page. No potential conflicts of interest were disclosed. I would like to thank Dr Andrea Gore, Bailey Kermath, and Hannah Cates for their thoughtful review and comments. Grant support came from 1F31 AG034813.
  • 1. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS. Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology 2012; 153:4097 - 110; http://dx.doi.org/ 10.1210/en.2012-1422 ; PMID: 22733974 [CrossRef], [PubMed], [Web of Science ®]
  • 2. Walker DM, Kermath BA, Woller MJ, Gore AC. Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors. Endocrinology 2013; 154:2129 - 43; http://dx.doi.org/ 10.1210/en.2012-2123 ; PMID: 23592748 [CrossRef], [PubMed], [Web of Science ®]
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