Disruptors on Male Reproduction - Emerging Risk Factors, Volume II

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Lately, nickel oxide nanoparticles (NiO NPs) have been employed in different industrial and biomedical fields. Several studies have reported that NiO NPs may affect the development of reproductive organs inducing oxidative stress and, resulting in male infertility. We investigated the in vitro effects of NiO NPs on porcine pre-pubertal Sertoli cells (SCs) which undergone acute (24 h) and chronic (from 1 up to 3 weeks) exposure at two subtoxic doses of NiO NPs of 1 μg/ml and 5 μg/ml. After NiO NPs exposure we performed the following analysis: (a) SCs morphological analysis (Light Microscopy); (b) ROS production and oxidative DNA damage, gene expression of antioxidant enzymes (c) SCs functionality (AMH, inhibin B Real-time PCR analysis and ELISA test); (d) apoptosis (WB analysis); (e) pro-inflammatory cytokines (Real-time PCR analysis), and (f) MAPK kinase signaling pathway (WB analysis). We found that the SCs exposed to both subtoxic doses of NiO NPs didn’t sustain substantial morphological changes. NiO NPs exposure, at each concentration, reported a marked increase of intracellular ROS at the third week of treatment and DNA damage at all exposure times. We demonstrated, un up-regulation of SOD and HO-1 gene expression, at both concentrations tested. The both subtoxic doses of NiO NPs detected a down-regulation of AMH and inhibin B gene expression and secreted proteins. Only the 5 μg/ml dose induced the activation of caspase-3 at the third week. At the two subtoxic doses of NiO NPs a clear pro-inflammatory response was resulted in an up-regulation of TNF-α and IL-6 in terms of mRNA. Finally, an increased phosphorylation ratio of p-ERK1/2, p-38 and p-AKT was observed up to the third week, at both concentrations. Our results show the negative impact of subtoxic doses NiO NPs chronic exposure on porcine SCs functionality and viability.

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Hypothesis and Theory
19 October 2022
Hypothesis: Metformin is a potential reproductive toxicant
Maja Tavlo
5 more and 
Rune Lindahl-Jacobsen
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Metformin is the first-line oral treatment for type 2 diabetes mellitus and is prescribed to more than 150 million people worldwide. Metformin’s effect as a glucose-lowering drug is well documented but the precise mechanism of action is unknown. A recent finding of an association between paternal metformin treatment and increased numbers of genital birth defects in sons and a tendency towards a skewed secondary sex ratio with less male offspring prompted us to focus on other evidence of reproductive side effects of this drug. Metformin in humans is documented to reduce the circulating level of testosterone in both men and women. In experimental animal models, metformin exposure in utero induced sex-specific reproductive changes in adult rat male offspring with reduced fertility manifested as a 30% decrease in litter size and metformin exposure to fish, induced intersex documented in testicular tissue. Metformin is excreted unchanged into urine and feces and is present in wastewater and even in the effluent of wastewater treatment plants from where it spreads to rivers, lakes, and drinking water. It is documented to be present in numerous freshwater samples throughout the world – and even in drinking water. We here present the hypothesis that metformin needs to be considered a potential reproductive toxicant for humans, and probably also for wildlife. There is an urgent need for studies exploring the association between metformin exposure and reproductive outcomes in humans, experimental animals, and aquatic wildlife.

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Review
06 October 2022

A circadian rhythm is an internalized timing system that synchronizes the cellular, behavioral, and physiological processes of organisms to the Earth’s rotation. Because all physiological activities occur at a specific time, circadian rhythm disturbances can lead to various pathological disorders and diseases. Growing evidence has shown that the circadian clock is tightly connected to male fertility, and circadian perturbations contribute to infertility. The night shiftwork, insufficient sleep, and poor sleep quality are common causes of circadian disturbances, and many studies have reported that they impair sperm quality and increase the risk of male infertility. However, research on the impacts of light, body temperature, and circadian/circannual rhythms is relatively lacking, although some correlations have been demonstrated. Moreover, as the index of sperm quality was diverse and study designs were non-uniform, the conclusions were temporarily inconsistent and underlying mechanisms remain unclear. A better understanding of whether and how circadian disturbances regulate male fertility will be meaningful, as more scientific work schedules and rational lifestyles might help improve infertility.

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In recent years, the incidence of infertility has been increasing gradually, while the natural rate of population growth is declining or even at zero growth. China is observed to enter a depth of aging society, leading to more severe infertility. Infertility patients face many predicaments, and many unreasonable behaviors existed in seeking medical diagnosis and treatment, of which the main influencing factor is economic condition. In China, Beijing has taken the lead in providing medical insurance for 16 assisted reproductive technology items. Assuming that all infertile couples with the option of assisted reproduction are treated, there would be a huge market gap. The reimbursement rate can be adjusted based on some factors within the affordable range of the medical insurance fund. Progress on infertility coverage in other countries was also reviewed. This paper cited the data of medical insurance funds in China in the recent 4 years as a reference. Based on the data, it is not currently able to cover all the costs of infertility diagnosis and treatment during the research period, but it is feasible to access selective reimbursement and subsidies for those in particular need as well as to develop some commercial insurances. There is a big gap in the application of assisted reproductive technology between China and developed countries. More comprehensive and constructive policies should be formulated countrywide to standardize the market. Assisted reproduction-related technologies and acceleration of the domestic medical apparatus and instrument replacement should be improved to reduce the cost.

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Original Research
25 May 2022

Background: The association between snoring and erectile dysfunction (ED) is inconsistent in multiple observational studies. To clarify the causal association of snoring on ED, we performed this two-sample Mendelian randomization study.

Materials and Methods: The single nucleotide polymorphisms (SNPs) associated with snoring were retrieved from the UK biobank cohort with 314,449 participants (117,812 cases and 196,637 controls). The summary statistics of ED were obtained from the European ancestry with 223,805 subjects (6,175 cases and 217,630 controls). Single-variable Mendelian randomization (MR) and multivariable MR were used to assess the causal relationship between snoring and ED.

Results: Snoring increases the risk of ED (Odds ratio [OR] = 3.45, 95% confidence interval [CI] = 1.68 - 7.09, P < 0.001) in the inverse variance weighting estimator. In sensitivity analyses, the ORs for the weighted median, MR robust adjusted profile score, and MR Pleiotropy Residual Sum and Outlier approach, MR-Egger, and maximum likelihood method are 5.70 (95% CI = 1.19 - 27.21, P < 0.05), 3.14 (95% CI = 1.01 - 9.72, P < 0.05), 3.11 (95% CI = 1.63 - 5.91, P < 0.01), 1.23 (95% CI = 0.01 – 679.73, P > 0.05), and 3.59 (95% CI = 1.07 – 12.00, P < 0.05), respectively. No heterogeneity and pleiotropy are observed (P for MR-Egger intercept = 0.748; P for global test = 0.997; P for Cochran’s Q statistics > 0.05). After adjusting for total cholesterol, triglyceride, low-density lipoprotein, and cigarette consumption, the ORs for ED are 5.75 (95% CI = 1.80 - 18.34, P < 0.01), 4.16 (95% CI = 1.10 - 15.81, P < 0.05), 5.50 (95% CI = 1.62 - 18.69, P < 0.01), and 2.74 (95% CI = 1.06 - 7.10, P < 0.05), respectively.

Conclusion: This study provides genetic evidence supporting the causal role of snoring in ED.

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14 citations
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