Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

Risal, Sanjiv; Li, Congru; Luo, Qing; Fornes, Romina; Lu, Haojiang; Eriksson, Gustaw; Manti, Maria; Ohlsson, Claes; Lindgren, Eva; Crisosto, Nicolás; Maliqueo, Manuel; Echiburú, Bárbara; Recabarren, Sergio E; Petermann, Teresa Sir; Benrick, Anna; Brusselaers, Nele; Qiao, Jie; Deng, Qiaolin; Stener‐Victorin, Elisabet

doi:10.1016/j.xcrm.2023.101035

Cited by 16 publications

(8 citation statements)

References 97 publications

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“…These findings are in agreement with those reported by Lazic and colleagues, 57 who have already suggested that androgen developmental programing effects of some metabolic traits would be sex-specific. In a recent study, contrary to our results, Risal et al 58 have reported that exposure to the androgen DHT in utero leads to obesity and an altered metabolic profile including and altered glucose tolerance. Thus, these results suggest that, as also reported for females, DHT fetal programing effects lead to a worse metabolic profile than those caused by prenatal testosterone exposure.…”

Section: Discussioncontrasting

confidence: 99%

“…7,69,70 In accordance with this evidence, we also found that embryos that resulted from a mating between F1-PHm and control females presented a longer crown-rump length than that of the embryos of control animals mating, thus suggesting a paternal-mediated inheritance. In addition, a recent study, 58 showed that males prenatally exposed to androgens and their descendants up to the 2 following generations present a different pattern of sperm small-non coding RNAs as compared to control males. Despite the possible direct male-derived epigenetic effects on the offspring, it has also been described that there is a paternal effect, probably mediated by epigenetic factors, on placental functions.…”

Section: Discussionmentioning

confidence: 99%

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Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Abruzzese,

Ferreira,

Ferrer

et al. 2023

Clin Med Insights Endocrinol Diabetes

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Background: It is still unelucidated how hormonal alterations affect developing organisms and their descendants. Particularly, the effects of androgen levels are of clinical relevance as they are usually high in women with Polycystic Ovary Syndrome (PCOS). Moreover, it is still unknown how androgens may affect males’ health and their descendants. Objectives: We aimed to evaluate the multigenerational effect of prenatal androgen excess until a second generation at early developmental stages considering both maternal and paternal effects. Design And Methods: This is an animal model study. Female rats (F0) were exposed to androgens during pregnancy by injections of 1 mg of testosterone to obtain prenatally hyperandrogenized (PH) animals (F1), leading to a well—known animal model that resembles PCOS features. A control (C) group was obtained by vehicle injections. The PH-F1 animals were crossed with C males (m) or females (f) and C animals were also mated, thus obtaining 3 different mating groups: Cf × Cm, PHf × Cm, Cf × PHm and their offspring (F2). Results: F1-PHf presented altered glucose metabolism and lipid profile compared to F1-C females. In addition, F1-PHf showed an increased time to mating with control males compared to the C group. At gestational day 14, we found alterations in glucose and total cholesterol serum levels and in the placental size of the pregnant F1-PHf and Cf mated to F1-PHm. The F2 offspring resulting from F1-PH mothers or fathers showed alterations in their growth, size, and glucose metabolism up to early post-natal development in a sex-dependent manner, being the females born to F1-PHf the most affected ones. Conclusion: androgen exposure during intrauterine life leads to programing effects in females and males that affect offspring health in a sex-dependent manner, at least up-to a second generation. In addition, this study suggests paternally mediated effects on the F2 offspring development.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Abruzzese,

Ferreira,

Ferrer

et al. 2023

Clin Med Insights Endocrinol Diabetes

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“…The significance of the intrauterine environment cannot be overstated, as it serves as a mediator of the environment during vital developmental periods. Numerous studies have shown that an inadequate maternal diet ( 120 ), stress ( 121 ), and hormonal imbalances during pregnancy ( 122 , 123 ) can affect the developmental programming of future generations. Women who undergo ART may face various challenges, including endocrine issues, advanced maternal age, chronic pelvic inflammation, and insulin resistance ( 124 ), all of which could contribute to cardiovascular dysfunction in the offspring.…”

Section: Cardiovascular Alterations Induced By Assisted Reproductive ...mentioning

confidence: 99%

Cardiovascular health of offspring conceived by assisted reproduction technology: a comprehensive review

Li,

Liu,

Huang

et al. 2024

Front. Cardiovasc. Med.

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Recently, the use of assisted reproductive technology (ART) has rapidly increased. As a result, an increasing number of people are concerned about the safety of offspring produced through ART. Moreover, emerging evidence suggests an increased risk of cardiovascular disease (CVD) in offspring conceived using ART. In this review, we discuss the epigenetic mechanisms involved in altered DNA methylation, histone modification, and microRNA expression, as well as imprinting disorders. We also summarize studies on cardiovascular changes and other risk factors for cardiovascular disease, such as adverse intrauterine environments, perinatal complications, and altered metabolism following assisted reproductive technology (ART). Finally, we emphasize the epigenetic mechanisms underlying the increased risk of CVD in offspring conceived through ART, which could contribute to the early diagnosis and prevention of CVD in the ART population.

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“…[4] These obstetric challenges confer a predisposition upon offspring to develop reproductive and cardiometabolic disorders in adulthood. [1,5,6] The placenta, a transient organ, facilitates the supply of oxygen and nutrients to the developing fetus throughout the entire gestation. Despite variances in physiological and morphological features, both human and mouse placentas exhibit a hemochorial structure, wherein the fetal trophoblast establishes direct contact with maternal blood circulation.…”

Section: Introductionmentioning

confidence: 99%

“…[6,23] Conversely, sons born to women with PCOS face an elevated risk of developing obesity, hyperlipidemia, anxiety, and depression. [5,24,25] Previous studies show that androgen receptor activation results in altered implantation and uterine mitochondrial dysfunction in androgenized pregnant rats, as well as diminish decidualization and angiogenesis potentially mediating the transmitted effects to the offspring. [17] However, whether and how maternal androgen exposure affect the placenta, early embryo and primordial germ cell development, and whether co-treatment targeting androgen pathways has the potential to prevent placenta dysfunction, results in normal fetal and germ cell development as well as healthy offspring remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Impact of Maternal Androgen Exposure on Offspring Health through Targeting the Androgen Receptor in Developmental Programming

Lu,

Jiang,

et al. 2023

Preprint

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Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse neonatal outcomes. Yet, further investigation is required to understand the precise mechanisms and the impact on cell-type specific placental dysfunction. To explore these dynamics, a PCOS-like mice model was induced with continuous androgen exposure throughout pregnancy, mimicking the human-PCOS. This resulted in impaired placental and embryonic development, leading to mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevented this lethality. Comprehensive analysis using whole-genome bisulfite and RNA sequencing revealed the diminished proportion of trophoblast precursors by downregulation ofCdx2. The absence ofGcm1,Synb,andPrl3b1further resulted in decreased numbers of syncytiotrophoblasts and sinusoidal trophoblast giant cells, leading to observed compromised placenta labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibited analogous alterations, highlighting impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. Remarkably, all effects were mediated through the androgen receptor pathways, as demonstrated by comparable offspring phenotypes to controls when treated with flutamide. These findings provide novel insight into the PCOS-related pregnancy complications, and potential cellular targets for future treatment.

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Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

Cited by 16 publications

References 97 publications

Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Prenatal Androgen Excess Induces Multigenerational Effects on Female and Male Descendants

Cardiovascular health of offspring conceived by assisted reproduction technology: a comprehensive review

Dissecting the Impact of Maternal Androgen Exposure on Offspring Health through Targeting the Androgen Receptor in Developmental Programming

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