The Aryl Hydrocarbon Receptor Is Important for Proper Seminiferous Tubule Architecture and Sperm Development in Mice1

Hansen, Deborah A.; Esakky, Prabagaran; Drury, Andrea; Lamb, Laura E.; Moley, Kelle H.

doi:10.1095/biolreprod.113.108845

Cited by 48 publications

(37 citation statements)

References 41 publications

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“…The overall success rate for control mating pairs was 95% ( Table 1 ) and control males in our study exhibited normal sperm numbers ( Figure 2 ) with the percent of morphologically normal sperm within the range reported by others for adult C57bl/6 mice [39], [40] ( Figure 3 ). Regardless of exposure (or lack of exposure), tail defects were the most common morphological abnormality.…”

Section: Resultssupporting

confidence: 85%

“…We therefore subjected caudal sperm smears to immunolocalization of the AhR. In agreement with data described by Hansen et al [40], sperm from control animals exhibited minimal AhR expression, which was localized to the acrosome and mid-piece ( Figure 4A ). However, sperm obtained from mice with a direct (F1-F2) or indirect (F3) TCDD exposure history had significantly (p≤0.001) increased immunolocalization of AhR compared to control cells ( Figure 4B–D ).…”

Section: Resultssupporting

confidence: 76%

“…Relevant to the current study, increased spermatocyte AhR expression has been linked to infertility in humans [10] and toxicant exposure in adult rats [40]. We therefore subjected caudal sperm smears to immunolocalization of the AhR.…”

Section: Resultsmentioning

confidence: 90%

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Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

et al. 2014

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TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly known as dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Using a mouse model, we previously found that adult female mice exposed in utero to TCDD (F1 generation) as well as multiple subsequent generations (F2-F4) exhibited reduced fertility and an increased incidence of spontaneous preterm birth. Additional studies revealed that male F1 mice with a similar in utero/developmental TCDD exposure also exhibited diminished fertility and conferred an increased risk of preterm birth to their unexposed mating partners. Herein, we extend these previous observations, reporting that reduced fertility in male F1 mice is linked to testicular inflammation which coincides with apoptosis of developing spermatocytes, sub-fertility and an increased risk of preterm birth in their unexposed mating partners. Significantly, in the absence of additional toxicant exposure, testicular inflammation and reduced fertility persisted in F2 and F3 males and their control mating partners also frequently exhibited spontaneous preterm birth. Although a steady, global decline in male fertility has been noted over the last few decades, the reasons for these changes have not been firmly established. Likewise, the PTB rate in the U.S. and other countries has paralleled industrial development, suggesting a possible relationship between environmental toxicant exposure and adverse pregnancy outcomes. Most current clinical strategies to prevent preterm birth are focused solely on the mother and have yielded limited benefits. In contrast, our studies strongly suggest that the preconception testicular health of the father is a critical determinant of pregnancy outcomes in mice. Future clinical studies should examine the potential contribution of the male to gestation length in women and whether efforts to reduce the incidence of preterm birth should be initiated in both parents prior to pregnancy.

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Section: Resultssupporting

confidence: 85%

Section: Resultssupporting

confidence: 76%

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Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

et al. 2014

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“…Further experiments illustrated that depletion of AhR induced germ cell apoptosis. This result is similar to the finding from another report, which used a different strategy to knock out AhR in mice (22). Along with infertility in this study, we found ductal growth in the mammary fat pad of male AhR −/− mice.…”

Section: Discussionsupporting

confidence: 92%

Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Huang

Butler

Miao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The aryl hydrocarbon receptor (AhR) is now recognized as an important physiological regulator in the immune and reproductive systems, and in the development of the liver and vascular system. AhR regulates cell cycle, cell proliferation, and differentiation through interacting with other signaling pathways, like estrogen receptor α (ERα), androgen receptor (AR), and Notch signaling. In the present study, we investigated Notch and estrogen signaling in AhR−/− mice. We found low fertility with degenerative changes in the testes, germ cell apoptosis, and a reduced number of early spermatids. There was no change in aromatase, AR, ERα, or ERβ expression in the testis and no detectable change in serum estrogen levels. However, expression of Notch receptors (Notch1 and Notch3) and their target Hairy and Enhancer of Split homolog 1 (HES1) was reduced. In addition, the testosterone level was slightly reduced in the serum. In the mammary fat pad, AhR appeared to regulate estrogen signaling because, in AhR−/− males, there was significant growth of the mammary ducts with high expression of ERα in the ductal epithelium. The enhanced mammary ductal growth appears to be related to overexpression of ERα accompanied by a high proliferation index, whereas the reduced fertility appears to be related defects in Notch signaling that leads to reduced expression of HES1 and, consequently, early maturation of spermatocytes and a depletion of primary spermatids. Previous reports have indicated that AhR pathway is associated with infertility in men. Our results provide a mechanistic explanation for this defect.

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“…We were unable to evaluate a direct role for AHR in mammalian healthspan because Ahr −/− mice lack ILC3s (40), which themselves may mediate indole effects in aged mice. Notably, Ahr −/− mice also exhibit diminished reproductive capacity, which is at least in part due to deficiencies in sperm production, motility, and sensitivity to oxidative stress (41). Although, indole and ICA bind AHR and activate AHR-dependent transcriptional responses (23), AHR-independent mechanisms may also mediate effects of indole or its derivatives.…”

Section: Discussionmentioning

confidence: 99%

Indoles from commensal bacteria extend healthspan

Sonowal

Swimm

Sahoo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

153

157

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Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan. We show that indoles from commensal microbiota extend healthspan of diverse organisms, including Caenorhabditis elegans, Drosophila melanogaster, and mice, but have a negligible effect on maximal lifespan. Effects of indoles on healthspan in worms and flies depend upon the aryl hydrocarbon receptor (AHR), a conserved detector of xenobiotic small molecules. In C. elegans, indole induces a gene expression profile in aged animals reminiscent of that seen in the young, but which is distinct from that associated with normal aging. Moreover, in older animals, indole induces genes associated with oogenesis and, accordingly, extends fecundity and reproductive span. Together, these data suggest that small molecules related to indole and derived from commensal microbiota act in diverse phyla via conserved molecular pathways to promote healthy aging. These data raise the possibility of developing therapeutics based on microbiota-derived indole or its derivatives to extend healthspan and reduce frailty in humans.C. elegans | aging | frailty | aryl hydrocarbon receptor | microbiota R ecent advances in health care have contributed to a significant increase in life expectancy of individuals, especially in developed countries, which predict an expansion of geriatric populations by as much as 350-fold over the next 40 y (1). However, extension of lifespan is often accompanied by increased frailty, and attendant increases in global healthcare expenditures are expected to be both massive and unsustainable (2). Such data highlight the need to develop means to extend healthspan, which is broadly defined as the length of time that an individual remains healthy and free of age-related infirmities (3, 4).Healthspan has often been convolved with lifespan, and extended healthspan has been associated with slowed onset of normal age-related changes (e.g., sarcopenia). Thus, mutations that extend lifespan might be expected to likewise extend healthspan. Recent studies in Caenorhabditis elegans indicate that, relative to wild-type animals, mutations that extend lifespan do indeed extend the period of youthfulness, in which animals are motile and resistant to bacterial infection (healthspan), but also extend the period of decrepitude or frailty, where animals are relatively immobile (5, 6) Other studies in C. elegans that take into account multiple measures of health, each normalized to maximal lifespan, indicate that mutations or conditions that extend lifespan minimally impact or ev...

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The Aryl Hydrocarbon Receptor Is Important for Proper Seminiferous Tubule Architecture and Sperm Development in Mice1

Cited by 48 publications

References 41 publications

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

Dysregulation of Notch and ERα signaling in AhR^−/−male mice

Indoles from commensal bacteria extend healthspan

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The Aryl Hydrocarbon Receptor Is Important for Proper Seminiferous Tubule Architecture and Sperm Development in Mice1

Cited by 48 publications

References 41 publications

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

Dysregulation of Notch and ERα signaling in AhR−/−male mice

Indoles from commensal bacteria extend healthspan

Contact Info

Product

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Dysregulation of Notch and ERα signaling in AhR^−/−male mice