Expanded phenotype of primary ciliary dyskinesia related to DRC1 pathogenic variant with dysmorphisms and vascular anomalies.

We present a case of a female diagnosed with primary ciliary dyskinesia (PCD) type 21 with non-previously reported extrapulmonary symptoms, including facial features and congenital vascular anomalies. Whole genome sequencing in our patient revealed a homozygous pathogenic variant in the DRC1 gene and no other notable structural nor punctual variants. This case demonstrates a unique clinical manifestation of PCD, which is possibly associated with the presence of a homozygous pathogenic DRC1 variant. Therefore, we suggest that analysis of DRC1 be considered with PCD type 21 when such features are present.

Role of Lipotoxicity and Contribution of the Renin-Angiotensin System in the Development of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes' size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS.

Evolution of metabolic alterations 5 Years after early puberty in a cohort of girls predisposed to polycystic ovary syndrome.

BACKGROUND: We and others have observed that young girls predisposed to polycystic ovary syndrome (PCOS) display defective insulin sensitivity, beta-cell function and non-esterified fatty acids (NEFA) suppressibility during early pubertal years, compared to controls. Our objective is to assess whether these differences in glucose and NEFA metabolisms persist after 5 years in late/post-puberty. METHODS: We conducted a prospective cohort study between 2007 and 2015 with 4-6 years of follow-up in an academic institution research center. We compared 8 daughters and sisters of PCOS women (PCOSr) to 8 age-matched girls unrelated to PCOS (±1.5 years). Girls were assessed initially at 8-14 years old and re-assessed after a median follow-up of 5.4 years, at 13-21 years old. Our main measures were a frequently sampled intravenous glucose tolerance test (FSivGTT)-derived insulin sensitivity (IS) and beta-cell function (disposition index, DIFSivGTT); and indices of NEFA suppression during FSivGTT (logn-linear slope of NEFA and T50 of NEFA suppression). RESULTS: At follow-up, both PCOSr and controls had similar results: IS = 3.2 vs 3.4 (p = 0.88), DIFSivGTT = 1926 vs 1380 (p = 0.44), logn-linear slope = -0.032 vs -0.032 (p = 0.88) and T50NEFA = 18.1 vs 20.8 min (p = 0.57). IS, DIFSivGTT and NEFA suppressibility were stable in PCOSr after 5 years, but decreased significantly in controls (all p < 0.05). CONCLUSIONS: Impaired metabolism observed during early puberty in girls predisposed to PCOS remains stable after 5 years whereas control girls deteriorated their metabolic parameters. Therefore, both groups become comparable in late/post-puberty. Early puberty may thus represent a window during which metabolic alterations are transiently apparent in girls at risk of PCOS.

Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 µU/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g·min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km (P = .009), which were strongly correlated together in all PCOS/cp rats (ρ = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.

A positive correlation between hydrogen peroxide and soluble TNF-alpha receptor 2 early in maternal blood and at term in placenta of pregnant women with preeclampsia.

OBJECTIVES: We hypothesized that hydrogen peroxide (H(2)O(2)) and soluble TNF-α receptor 2 (sTNF-R2) co-play a role in the pathogenesis of preeclampsia. METHODS: Correlation of H(2)O(2) and sTNF-R2 was assessed in vivo in maternal blood and placenta, and in vitro in cytotrophoblasts culture. RESULTS: We showed a positive correlation between increased levels of H(2)O(2) and sTNF-R2 early at 10-15 gestational weeks and at term in maternal serum, and in placenta of women with preeclampsia. Our in vitro experiments showed that H(2)O(2) induced the placental synthesis of sTNF-R2. CONCLUSION: We propose to consider H(2)O(2) and sTNF-R2 as potential biomarkers in predicting preeclampsia.

Maternal and fetal exposure to pesticides associated to genetically modified foods in Eastern Townships of Quebec, Canada.

Pesticides associated to genetically modified foods (PAGMF), are engineered to tolerate herbicides such as glyphosate (GLYP) and gluphosinate (GLUF) or insecticides such as the bacterial toxin bacillus thuringiensis (Bt). The aim of this study was to evaluate the correlation between maternal and fetal exposure, and to determine exposure levels of GLYP and its metabolite aminomethyl phosphoric acid (AMPA), GLUF and its metabolite 3-methylphosphinicopropionic acid (3-MPPA) and Cry1Ab protein (a Bt toxin) in Eastern Townships of Quebec, Canada. Blood of thirty pregnant women (PW) and thirty-nine nonpregnant women (NPW) were studied. Serum GLYP and GLUF were detected in NPW and not detected in PW. Serum 3-MPPA and CryAb1 toxin were detected in PW, their fetuses and NPW. This is the first study to reveal the presence of circulating PAGMF in women with and without pregnancy, paving the way for a new field in reproductive toxicology including nutrition and utero-placental toxicities.

Detrimental effects of high levels of antioxidant vitamins C and E on placental function: considerations for the vitamins in preeclampsia (VIP) trial.

AIM: Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications. In a recent study, it has been shown that this supplementation to above physiological doses does not reduce the risk of preeclampsia, but increases the rate of low birthweight babies, suggesting a detrimental effect on placental function, given the lower birthweight. The aim of the present study was to investigate the effects of high levels of antioxidants vitamins C and E on placental cells in vitro. METHODS: Isolated fresh human cytotrophoblasts were exposed to high concentrations of vitamins C and E for 48 h. Then the secretion of human chorionic gonadotropin (hCG) and the production of tumor necrosis factor-alpha (TNF-alpha) were assessed. RESULTS: High levels of vitamins C and E, separately or combined, decrease the secretion of hCG by cytotrophoblasts and increase their production of TNF-alpha. CONCLUSION: Exposure of cytotrophoblasts to high levels of antioxidant vitamins C and E may affect placental function, as reflected by decreased secretion of hCG; and placental immunity, as reflected by increased production of TNF-alpha. Such alterations are known to lead to endothelial dysfunction and adverse pregnancy outcomes, such as fetal growth restriction (FGR).

Dual action of H2O2 on placental hCG secretion: implications for oxidative stress in preeclampsia.

OBJECTIVE: Our previously published findings showed that circulating levels of H(2)O(2) were increased and correlated with high levels of hCG in women with preeclampsia, suggesting that oxidative stress modulates placental hormone synthesis. The aim of this study was to investigate in vitro the effects of H(2)O(2) on placental secretion of hCG. DESIGN AND METHODS: In vitro trophoblasts were stimulated with increasing concentrations of H(2)O(2) and the de novo hCG secretion was assayed. RESULTS: Stimulation with low concentrations of H(2)O(2) (1-50 microM) enhances cytotrophoblastic hCG secretion, whereas concentrations of H(2)O(2) >50 microM reduce hCG secretion in a dose-dependent manner. CONCLUSIONS: Our findings emphasize that: (1) H(2)O(2) may have dual action on placental activity and acts not only as a cytotoxic mediator, but also as a signaling molecule able to induce hCG secretion; (2) hCG may be a protective antioxidant released by the placenta to counter low oxidative stress challenge.