Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: Is there a link to endocrine disrupting chemicals?

Johansson, Hanna Katarina Lilith; Svingen, Terje

doi:10.1016/j.crtox.2020.10.001

Cited by 9 publications

(7 citation statements)

References 75 publications

(92 reference statements)

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“…In conclusion, we have shown that perinatal exposure to a chemical that has the capacity to antagonize the HH pathway may disrupt rodent ovary development. Although we saw no adverse effect in vivo in our study, it is likely that HH perturbation could affect theca cell recruitment as shown in vitro and similarly to effects postulated to take place in Leydig cells of the testes ( Johansson and Svingen, 2020 ). This would ultimately affect folliculogenesis, with negative impacts on fertility later in life, but also other female reproductive disorders such as polycystic ovarian syndrome, premature ovarian insufficiency and ovarian cancers, as these diseases are linked to compromised steroid hormone signaling originating from the ovarian steroidogenic cells, not least the theca lineage.…”

Section: Discussionsupporting

confidence: 57%

“…As shown herein, gestational exposure to 50 mg/kg bw/day itraconazole induced no severe toxicity or teratogenicity, nor any effects on the ovaries; but a dose of 100 mg/kg bw/day induced teratogenicity in a previous study ( El-Shershaby et al , 2014 ), which is why we opted not to expose our rats to these high doses as it would render any potential effects on ovary development of secondary interest. Reproductive-specific effects at lower doses of HH inhibitors would therefore more likely only manifest in combination with inhibition of other hormone-sensitive signaling pathways, as recently discussed ( Johansson and Svingen, 2020 ).…”

Section: Discussionmentioning

confidence: 88%

“…By disrupting HH ligands in either ovaries or testes, differentiation of the steroidogenic cell lineages—theca and Leydig cells, respectively—is compromised. Thus, it can be speculated that, if a fetus is exposed to chemicals capable of disrupting HH signaling in the gonads, this could lead to disrupted ovary development and reproductive disorders similar to those manifesting if the sex hormone pathways are blocked ( Johansson and Svingen, 2020 ).…”

mentioning

confidence: 99%

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Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

Johansson

Taxvig

Olsen

et al. 2021

Toxicological Sciences

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Early ovary development is considered to be largely hormone independent; yet, there are associations between fetal exposure to endocrine disrupting chemicals and reproductive disorders in women. This can potentially be explained by perturbations to establishment of ovarian endocrine function rather than interference with an already established hormone system. In this study we explore if Hedgehog (HH) signaling, a central pathway for correct ovary development, can be disrupted by exposure to HH-disrupting chemicals, using the antifungal itraconazole as model compound. In the mouse Leydig cell line TM3, used as a proxy for ovarian theca cells, itraconazole exposure had a suppressing effect on genes downstream of HH signaling, such as Gli1. Exposing explanted rat ovaries (gestational day 22 or postnatal day 3) to 30 µM itraconazole for 72 h induced significant suppression of genes in the HH signaling pathway with altered Ihh, Gli1, Ptch1, and Smo expression similar to those previously observed in Ihh/Dhh knock-out mice. Exposing rat dams to 50 mg/kg bw/day in the perinatal period did not induce observable changes in the offspring’s ovaries. Overall, our results suggest that HH signal disruptors may affect ovary development with potential long-term consequences for female reproductive health. However, potent HH inhibitors would likely cause severe teratogenic effects at doses lower than those causing ovarian dysgenesis, so the concern with respect to reproductive disorder is for the presence of HH disruptors at low concentration in combination with other ovary or endocrine disrupting compounds.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

Johansson

Taxvig

Olsen

et al. 2021

Toxicological Sciences

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“…Hedgehog (HH) signaling is a highly conserved developmental pathway that relies on cholesterol interacting with specific sterol-binding proteins. Endocrine disruption is known to interfere with HH signaling ( Johansson and Svingen, 2020 ). Developmentally-regulated signaling pathways involving apoptosis, embryogenesis, cell proliferation, and development of diseases present in higher animals are also found in cnidarians including Exaiptasia ( Technau et al, 2005 ; Matus et al, 2008 ; Sinkovics, 2015 ; Bucher et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Sea Anemones Responding to Sex Hormones, Oxybenzone, and Benzyl Butyl Phthalate: Transcriptional Profiling and in Silico Modelling Provide Clues to Decipher Endocrine Disruption in Cnidarians

et al. 2022

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Endocrine disruption is suspected in cnidarians, but questions remain how occurs. Steroid sex hormones are detected in corals and sea anemones even though these animals do not have estrogen receptors and their repertoire of steroidogenic enzymes appears to be incomplete. Pathways associated with sex hormone biosynthesis and sterol signaling are an understudied area in cnidarian biology. The objective of this study was to identify a suite of genes that can be linked to exposure of endocrine disruptors. Exaiptasia diaphana were exposed to nominal 20ppb concentrations of estradiol (E2), testosterone (T), cholesterol, oxybenzone (BP-3), or benzyl butyl phthalate (BBP) for 4 h. Eleven genes of interest (GOIs) were chosen from a previously generated EST library. The GOIs are 17β-hydroxysteroid dehydrogenases type 14 (17β HSD14) and type 12 (17β HSD12), Niemann-Pick C type 2 (NPC2), Equistatin (EI), Complement component C3 (C3), Cathepsin L (CTSL), Patched domain-containing protein 3 (PTCH3), Smoothened (SMO), Desert Hedgehog (DHH), Zinc finger protein GLI2 (GLI2), and Vitellogenin (VTG). These GOIs were selected because of functional associations with steroid hormone biosynthesis; cholesterol binding/transport; immunity; phagocytosis; or Hedgehog signaling. Quantitative Real-Time PCR quantified expression of GOIs. In silico modelling utilized protein structures from Protein Data Bank as well as creating protein structures with SWISS-MODEL. Results show transcription of steroidogenic enzymes, and cholesterol binding/transport proteins have similar transcription profiles for E2, T, and cholesterol treatments, but different profiles when BP-3 or BBP is present. C3 expression can differentiate between exposures to BP-3 versus BBP as well as exposure to cholesterol versus sex hormones. In silico modelling revealed all ligands (E2, T, cholesterol, BBP, and BP-3) have favorable binding affinities with 17β HSD14, 17β HSD12, NPC2, SMO, and PTCH proteins. VTG expression was down-regulated in the sterol treatments but up-regulated in BP-3 and BBP treatments. In summary, these eleven GOIs collectively generate unique transcriptional profiles capable of discriminating between the five chemical exposures used in this investigation. This suite of GOIs are candidate biomarkers for detecting transcriptional changes in steroidogenesis, gametogenesis, sterol transport, and Hedgehog signaling. Detection of disruptions in these pathways offers new insight into endocrine disruption in cnidarians.

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“…However, the role of endocrine-disrupting chemicals (EDCs) in the aetiology of ED is unclear. The WHO defines an EDC as "an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations" [Johansson and Svingen, 2020]. The term EDC in this review refers specifically to chemicals which are known to alter hormonal pathways and cause adverse health effects in humans.…”

mentioning

confidence: 99%

Erectile Dysfunction in Men on the Rise: Is There a Link with Endocrine Disrupting Chemicals?

Cripps

Mattiske

Pask³

2021

Sex Dev

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Erectile dysfunction (ED) is one of the most prevalent chronic conditions affecting men. ED can arise from disruptions during development, affecting the patterning of erectile tissues in the penis and/or disruptions in adulthood that impact sexual stimuli, neural pathways, molecular changes, and endocrine signalling that are required to drive erection. Sexual stimulation activates the parasympathetic system which causes nerve terminals in the penis to release nitric oxide (NO). As a result, the penile blood vessels dilate, allowing the penis to engorge with blood. This expansion subsequently compresses the veins surrounding the erectile tissue, restricting venous outflow. As a result, the blood pressure localised in the penis increases dramatically to produce a rigid erection, a process known as tumescence. The sympathetic pathway releases noradrenaline (NA) which causes detumescence: the reversion of the penis to the flaccid state. Androgen signalling is critical for erectile function through its role in penis development and in regulating the physiological processes driving erection in the adult. Interestingly, estrogen signalling is also implicated in penis development and potentially in processes which regulate erectile function during adulthood. Given that endocrine signalling has a prominent role in erectile function, it is likely that exposure to endocrine disrupting chemicals (EDCs) is a risk factor for ED, although this is an under-researched field. Thus, our review provides a detailed description of the underlying biology of erectile function with a focus on the role of endocrine signalling, exploring the potential link between EDCs and ED based on animal and human studies.

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Hedgehog signal disruption, gonadal dysgenesis and reproductive disorders: Is there a link to endocrine disrupting chemicals?

Abstract: Graphical abstract

Cited by 9 publications

References 75 publications

Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

Effects of the Hedgehog Signaling Inhibitor Itraconazole on Developing Rat Ovaries

Sea Anemones Responding to Sex Hormones, Oxybenzone, and Benzyl Butyl Phthalate: Transcriptional Profiling and in Silico Modelling Provide Clues to Decipher Endocrine Disruption in Cnidarians

Erectile Dysfunction in Men on the Rise: Is There a Link with Endocrine Disrupting Chemicals?

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