Fetal Estrogens are not Involved in Sex Determination But Critical for Early Ovarian Differentiation in Rabbits

Jolivet, Geneviève; Daniel-Carlier, Nathalie; Harscoët, Erwana; Airaud, Eloïse; Dewaele, Aurélie; Pierson, Cloé; Giton, Frank; Boulanger, Laurent; Daniel, Nathalie; Mandon‐Pepin, Béatrice; Pannetier, Maëlle; Pailhoux, Eric

doi:10.1210/endocr/bqab210

Cited by 18 publications

(33 citation statements)

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“…The roles for a local production of estrogens at this developmental stage, as well as the consequences of its alterations, remain to be determined in humans. The alteration of the oogonia pool with decreased local estrogens could be consistent with the phenotype reported in CYP19A1-deficient rabbits ( 56 ). However, to the best of our knowledge, this is the first report of an ex vivo specific endocrine disruption of the steroidogenesis in the hFO.…”

Section: Discussionsupporting

confidence: 88%

Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Lecante

Leverrier-Penna

Gicquel

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Acetaminophen (APAP, paracetamol) is widely used by pregnant women. Although long considered safe, growing evidence indicates that APAP is an endocrine disruptor since in utero exposure may be associated with a higher risk of male genital tract abnormalities. In rodents, fetal exposure has long-term effects on the reproductive function of female offspring. Human studies have also suggested harmful APAP exposure effects. Objective Given that disruption of fetal ovarian development may impact women’s reproductive health, we investigated the effects of APAP on fetal human ovaries in culture. Design and setting Human ovarian fragments from 284 fetuses aged 7 to 12 developmental weeks (DW) were cultivated ex vivo for 7 days in the presence of human-relevant concentrations of APAP (10 -8 to 10 -3 M) or vehicle control. Main outcome measures Outcomes included examination of postculture tissue morphology, cell viability, apoptosis, and quantification of hormones, APAP and APAP metabolites in conditioned culture media. Results APAP reduced the total cell number specifically in 10-12 DW ovaries induced cell death and decreased KI67-positive cell density independently of fetal age. APAP targeted sub-populations of germ cells and disrupted human fetal ovarian steroidogenesis, without affecting prostaglandin or inhibin B production. Human fetal ovaries were able to metabolize APAP. Conclusions Our data indicate that APAP can impact first trimester human fetal ovarian development, especially during a 10-12 DW window of heightened sensitivity. Overall, APAP behaves as an endocrine disruptor in the fetal human ovary.

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Section: Discussionsupporting

confidence: 88%

Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Lecante

Leverrier-Penna

Gicquel

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…At this stage, CYP19A1 , ESR1 and FOXL2 are located in distinct cell populations. CYP19A1 and ESR1 are expressed in the coelomic epithelium and contribute to cortex development whereas FOXL2 is expressed in the supporting cells located in the medulla ( Jolivet et al, 2022 ). Concomitantly, intracytoplasmic lipid droplets, which provide the main source of cholesterol for steroid synthesis, accumulate in granulosa cells at 19 dpc ( Gondos et al, 1983 ).…”

Section: Role Of Estrogens In Ovarian Differentiationmentioning

confidence: 99%

“…Based on these observations, it has been hypothesized that this estrogen surge plays a role during rabbit ovary differentiation. However, loss of CYP19A1 in the XX rabbit embryo has no impact on fetal ovary formation ( Figure 2D ), although ovaries are smaller and eventually contain a reduced follicular reserve ( Jolivet et al, 2022 ). In the CYP19A1 KO adult ovary, DMRT1 expression is upregulated in some granulosa cells while SOX9 expression is absent, and no structural masculinization of the ovary is observed.…”

Section: Role Of Estrogens In Ovarian Differentiationmentioning

confidence: 99%

“…To date, no knockout models are available to study the role of the WNT4, RSPO1 and FOXL2 in the rabbit ovary. In the XX CYP19A1 KO fetal ovary, the expression of both FOXL2 and RSPO1 is decreased at 22 dpc while Frontiers in Cell and Developmental Biology frontiersin.org WNT4 expression is increased, suggesting that WNT/βcatenin signaling is stimulated in KO ovaries and may contribute to absence of sex reversal (Figure 5B) (Jolivet et al, 2022).…”

Section: Rabbitmentioning

confidence: 99%

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Becoming female: Ovarian differentiation from an evolutionary perspective

Nicol

Estermann

Yao

et al. 2022

Front. Cell Dev. Biol.

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Differentiation of the bipotential gonadal primordium into ovaries and testes is a common process among vertebrate species. While vertebrate ovaries eventually share the same functions of producing oocytes and estrogens, ovarian differentiation relies on different morphogenetic, cellular, and molecular cues depending on species. The aim of this review is to highlight the conserved and divergent features of ovarian differentiation through an evolutionary perspective. From teleosts to mammals, each clade or species has a different story to tell. For this purpose, this review focuses on three specific aspects of ovarian differentiation: ovarian morphogenesis, the evolution of the role of estrogens on ovarian differentiation and the molecular pathways involved in granulosa cell determination and maintenance.

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“…The physiological ER agonist, 17-βestradiol (E2), constitutes an important link of the hypothalamic-pituitary-ovarian axis contributing to the regulation of gonadotrophin secretion that governs ovarian cyclicity. Within the adult ovary, estrogens have a less well characterized role, but it is beyond a doubt that estrogens contribute to the development of the functional unit of the ovary, the follicle ( Emmen et al, 2005 ; Dewailly et al, 2016 ; Jolivet et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Bovine In Vitro Oocyte Maturation and Embryo Production Used as a Model for Testing Endocrine Disrupting Chemicals Eliciting Female Reproductive Toxicity With Diethylstilbestrol as a Showcase Compound

et al. 2022

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Endocrine disrupting chemicals (EDCs) can interfere with normal hormonal action and regulation. Exposure of women to EDCs has been associated with adverse reproductive health outcomes. The assays currently used to identify EDCs that elicit female reproductive toxicity lack screening tests that address effects on the maturation of oocytes, a process that enables them to be fertilized and develop into embryos. Here, a screening method employing the bovine model of in vitro oocyte maturation and embryo production is described. Endpoints explored address important events in oocyte maturation and developmental competence acquisition. To test the method, the effects of the known human EDC diethylstilbestrol (DES; an estrogen receptor agonist) were evaluated in a range of concentrations (10–9 M, 10–7 M, 10–5 M). Bovine oocytes were exposed to DES during in vitro maturation (IVM) or embryos were exposed during in vitro embryo culture (IVC). The endpoints evaluated included nuclear maturation, mitochondrial redistribution, cumulus cell expansion, apoptosis, and steroidogenesis. DES-exposed oocytes were fertilized to record embryo cleavage and blastocyst rates to uncover effects on developmental competence. Similarly, the development of embryos exposed to DES during IVC was monitored to assess the impact on early embryo development. Exposure to 10–9 M or 10–7 M DES did not affect the endpoints addressing oocyte maturation or embryo development. However, there were considerable detrimental effects observed in oocytes exposed to 10–5 M DES. Specifically, compared to vehicle-treated oocytes, there was a statistically significant reduction in nuclear maturation (3% vs 84%), cumulus expansion (2.8-fold vs 3.6-fold) and blastocyst rate (3% vs 32%). Additionally, progesterone and pregnenolone concentrations measured in IVM culture media were increased. The screening method described here shows that bovine oocytes were sensitive to the action of this particular chemical (i.e., DES), albeit at high concentrations. In principle, this method provides a valuable tool to assess the oocyte maturation process and early embryo development that can be used for reproductive toxicity screening and possibly EDC identification. Further studies should include EDCs with different mechanisms of action and additional endpoints to further demonstrate the applicability of the bovine oocyte model for chemical risk assessment purposes and EDC identification.

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Fetal Estrogens are not Involved in Sex Determination But Critical for Early Ovarian Differentiation in Rabbits

Cited by 18 publications

References 66 publications

Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Acetaminophen (APAP, Paracetamol) Interferes With the First Trimester Human Fetal Ovary Development in an Ex Vivo Model

Becoming female: Ovarian differentiation from an evolutionary perspective

Bovine In Vitro Oocyte Maturation and Embryo Production Used as a Model for Testing Endocrine Disrupting Chemicals Eliciting Female Reproductive Toxicity With Diethylstilbestrol as a Showcase Compound

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