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MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, classically presenting with disrupted ovulation, polycystic ovaries, and androgen excess, as well as many non-reproductive comorbidities. For instance, PCOS patients exhibit increased stress reactivity and higher r...

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Autores principales: Ho, Emily V, Shi, Chengxian, Mellon, Pamela L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207897/
http://dx.doi.org/10.1210/jendso/bvaa046.1317
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author Ho, Emily V
Shi, Chengxian
Mellon, Pamela L
author_facet Ho, Emily V
Shi, Chengxian
Mellon, Pamela L
author_sort Ho, Emily V
collection PubMed
description Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, classically presenting with disrupted ovulation, polycystic ovaries, and androgen excess, as well as many non-reproductive comorbidities. For instance, PCOS patients exhibit increased stress reactivity and higher rates of depression and anxiety compared to the general population. The prenatal anti-Mullerian hormone (pAMH)-induced model of PCOS was recently shown to recapitulate reproductive phenotypes in female mice, however little remains known about the consequences of pAMH exposure. We first aimed to expand upon this model by investigating pAMH-induced effects on offspring of both sexes. Pregnant dams on a C57Bl/6 background received daily i.p. injections of either AMH (0.12 mg/kg/d) or VEH late in gestation. Offspring were born into 4 groups (pAMH vs. VEH females, pAMH vs. VEH males) and assessed starting at weaning for changes in body weight, anogenital distance, pubertal onset, estrous cyclicity, fertility, and reproductive senescence. Statistical differences were determined by t-test or 2-way ANOVA when applicable, and significance set at p<0.05. As expected, pAMH increased anogenital distance in females but not males. Pubertal onset was delayed not only in females as previously reported, but also in males. Additionally, pAMH adult females showed significant disruptions in estrous cycling at P60 (increased time spent in diestrus, decreased number of cycles, increased cycle length), only mild disruptions by P90, then robust disruptions at 8 mo, 10 mo, and 12 mo of age that were distinct from reproductive senescence. When paired with wildtype untreated mates for a fertility assay starting at 3 mo of age, pAMH females had smaller and fewer number of litters, while pAMH males showed only delayed plugging behavior. Although pAMH males showed no difference in testis weight, pAMH females also had significantly reduced ovarian and uterine weights in diestrus. Interestingly, during the fertility assay, we found increased fetal death from both the pAMH females and males, even though pAMH males were paired with wildtype untreated females. We hypothesized that the increased fetal death could be the result of an pAMH-induced stress phenotype in both sexes. Using a simple stress response test measuring defecation and urination during exposure to a novel environment, we found that pAMH robustly increased stress response in both sexes at multiple timepoints. We also assessed glucocorticoid response to a restraint stress paradigm in adult females. While we observed no differences in baseline serum corticosterone levels, the pAMH group showed increased peak levels followed by a prolonged elevation levels after 2 hr. Together, these results enhance existing knowledge of the effects of pAMH exposure by demonstrating alterations in both male and female mice on both reproductive and non-reproductive measures.
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spelling pubmed-72078972020-05-13 MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring Ho, Emily V Shi, Chengxian Mellon, Pamela L J Endocr Soc Reproductive Endocrinology Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, classically presenting with disrupted ovulation, polycystic ovaries, and androgen excess, as well as many non-reproductive comorbidities. For instance, PCOS patients exhibit increased stress reactivity and higher rates of depression and anxiety compared to the general population. The prenatal anti-Mullerian hormone (pAMH)-induced model of PCOS was recently shown to recapitulate reproductive phenotypes in female mice, however little remains known about the consequences of pAMH exposure. We first aimed to expand upon this model by investigating pAMH-induced effects on offspring of both sexes. Pregnant dams on a C57Bl/6 background received daily i.p. injections of either AMH (0.12 mg/kg/d) or VEH late in gestation. Offspring were born into 4 groups (pAMH vs. VEH females, pAMH vs. VEH males) and assessed starting at weaning for changes in body weight, anogenital distance, pubertal onset, estrous cyclicity, fertility, and reproductive senescence. Statistical differences were determined by t-test or 2-way ANOVA when applicable, and significance set at p<0.05. As expected, pAMH increased anogenital distance in females but not males. Pubertal onset was delayed not only in females as previously reported, but also in males. Additionally, pAMH adult females showed significant disruptions in estrous cycling at P60 (increased time spent in diestrus, decreased number of cycles, increased cycle length), only mild disruptions by P90, then robust disruptions at 8 mo, 10 mo, and 12 mo of age that were distinct from reproductive senescence. When paired with wildtype untreated mates for a fertility assay starting at 3 mo of age, pAMH females had smaller and fewer number of litters, while pAMH males showed only delayed plugging behavior. Although pAMH males showed no difference in testis weight, pAMH females also had significantly reduced ovarian and uterine weights in diestrus. Interestingly, during the fertility assay, we found increased fetal death from both the pAMH females and males, even though pAMH males were paired with wildtype untreated females. We hypothesized that the increased fetal death could be the result of an pAMH-induced stress phenotype in both sexes. Using a simple stress response test measuring defecation and urination during exposure to a novel environment, we found that pAMH robustly increased stress response in both sexes at multiple timepoints. We also assessed glucocorticoid response to a restraint stress paradigm in adult females. While we observed no differences in baseline serum corticosterone levels, the pAMH group showed increased peak levels followed by a prolonged elevation levels after 2 hr. Together, these results enhance existing knowledge of the effects of pAMH exposure by demonstrating alterations in both male and female mice on both reproductive and non-reproductive measures. Oxford University Press 2020-05-08 /pmc/articles/PMC7207897/ http://dx.doi.org/10.1210/jendso/bvaa046.1317 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Reproductive Endocrinology
Ho, Emily V
Shi, Chengxian
Mellon, Pamela L
MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title_full MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title_fullStr MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title_full_unstemmed MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title_short MON-039 Prenatal Anti-Mullerian Hormone (pAMH) Exposure in Mice Induces Changes in Pubertal Onset, Fertility, and Stress Response in Both Male and Female Offspring
title_sort mon-039 prenatal anti-mullerian hormone (pamh) exposure in mice induces changes in pubertal onset, fertility, and stress response in both male and female offspring
topic Reproductive Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207897/
http://dx.doi.org/10.1210/jendso/bvaa046.1317
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