New findings in oligogenic inheritance of congenital hypogonadotropic hypogonadism.

Introduction: Congenital hypogonadotropic hypogonadism results from a dysfunction of the hypothalamic-pituitary-gonadal axis, which is essential for the development and function of the reproductive system. It may be associated with anosmia, referred to as Kallmann syndrome, or a normal sense of smell. Numerous studies have proven that hypogonadotropic hypogonadism is not simply a monogenic Mendelian disease, but that more than one gene may be involved in its pathogenesis in a single patient. The oligogenic complex architecture underlying the disease is still largely unknown. Material and methods: Targeted next-generation sequencing (NGS) was used to screen for DNA variants in a cohort of 47 patients with congenital hypogonadotropic hypogonadism. The NGS panel consists of over 50 well-known and candidate genes, associated with hypogonadotropic state. Results: Here we report the identification of new oligogenic variants in SPRY4/SEMA3A, SRA1/SEMA7A, CHD7/SEMA7A, CCDC141/POLR3B/POLR3B, and PROKR2/SPRY4/NSMF. These genes are known to contribute to the phenotype of hypogonadotropic hypogonadism, yet our results point to potential new "partners" underlying digenic and trigenic patterns. Conclusions: The finding supports the importance of oligogenic inheritance and demonstrates the complexity of genetic architecture in hypogonadotropic hypogonadism. It also underlines the necessity for developing fine-tuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.

Novel Mutations Within Collagen Alpha1(I) and Alpha2(I) Ligand-Binding Sites, Broadening the Spectrum of Osteogenesis Imperfecta - Current Insights Into Collagen Type I Lethal Regions.

Osteogenesis imperfecta (OI) is a rare genetic disorder demonstrating considerable phenotypic and genetic heterogeneity. The extensively studied genotype-phenotype correlation is a crucial issue for a reliable counseling, as the disease is recognized at increasingly earlier stages of life, including prenatal period. Based on population studies, clusters in COL1A1 and COL1A2 genes associated with the presence of glycine substitutions leading to fatal outcome have been distinguished and named as "lethal regions." Their localization corresponds to the ligand-binding sites responsible for extracellular interactions of collagen molecules, which could explain high mortality associated with mutations mapping to these regions. Although a number of non-lethal cases have been identified from the variants located in lethal clusters, the mortality rate of mutations has not been updated. An next generation sequencing analysis, using a custom gene panel of known and candidate OI genes, was performed on a group of 166 OI patients and revealed seven individuals with a causative mutations located in the lethal regions. Patients' age, ranging between 3 and 25 years, excluded the expected fatal outcome. The identification of non-lethal cases caused by mutations located in lethal domains prompted us to determine the actual mortality caused by glycine substitutions mapping to lethal clusters and evaluate the distribution of all lethal glycine mutations across collagen type I genes, based on records deposited in the OI Variant Database. Finally, we identified six glycine substitutions located in lethal regions of COL1A1 and COL1A2 genes, of which four are novel. The review of all mutations in the dedicated OI database, revealed 33 distinct glycine substitutions in two lethal domains of COL1A1, 26 of which have been associated with a fatal outcome. Similarly, 109 glycine substitutions have been identified in eight lethal clusters of COL1A2, of which 51 have been associated with a fatal manifestation. An analysis of all glycine substitutions leading to fatal phenotype, showed that their distribution along collagen type I genes is not regular, with 17% (26 out of 154) of mutations reported in COL1A1 and 64% (51 out of 80) in COL1A2 corresponding to localization of the lethal regions.

Association between idiopathic recurrent pregnancy loss and genetic polymorphisms in cytokine and matrix metalloproteinase genes.

OBJECTIVES: Recurrent reproductive loss (RPL) is a global health issue affecting a significant number of women. Approximately half of miscarriages have an unexplained etiology. Familial aggregation and twins studies prove that some cases of the RPL could have a genetic background. Recent evidences suggest that cytokines (e.g. IL-6, TNF alpha or TGF beta) and matrix metalloproteinases (MMP) are important for maintenance of pregnancy. Single gene polymorphisms (SNP), affecting these proteins production or their function may predispose to the loss of the pregnancy. The aim of this study was to evaluate the association between the following polymorphisms of IL6 (rs1800795), TNF (rs1800629), TGFB1 (rs1800471), MMP1 (rs1799750), MMP2 (rs2285053 and rs243865), MMP3 (rs35068180), MMP9 (rs3918242) and the recurrent pregnancy loss in polish population. MATERIAL AND METHODS: Study subjects comprised of 67 patients with a history of recurrent pregnancy loss (≥ 2 miscarriages in history) and 75 controls. The distribution of genotypes for selected polymorphisms were determined by RFLP-PCR. RESULTS: Maternal genotypes GG TNF, or 5A/5A MMP3 may be associated with the recurrent pregnancy loss. No association between the IL6, TGFB1, MMP1, MMP2, or MMP9 studied polymorphisms and the predisposition to miscarriage was found. CONCLUSIONS: This study demonstrated a possible association between rs1800629 TNF, rs35068180 MMP3 polymorphisms and recurrent pregnancy loss.

Expanding the mutational spectrum of monogenic hypogonadotropic hypogonadism: novel mutations in ANOS1 and FGFR1 genes.

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease, triggered by defective GnRH secretion, that is usually diagnosed in late adolescence or early adulthood due to the lack of spontaneous pubertal development. To date more than 30 genes have been associated with CHH pathogenesis with X-linked recessive, autosomal dominant, autosomal recessive and oligogenic modes of inheritance. Defective sense of smell is present in about 50-60% of CHH patients and called Kallmann syndrome (KS), in contrast to patients with normal sense of smell referred to as normosmic CHH. ANOS1 and FGFR1 genes are all well established in the pathogenesis of CHH and have been extensively studied in many reported cohorts. Due to rarity and heterogenicity of the condition the mutational spectrum, even in classical CHH genes, have yet to be fully characterized. METHODS: To address this issue we screened for ANOS1 and FGFR1 variants in a cohort of 47 unrelated CHH subjects using targeted panel sequencing. All potentially pathogenic variants have been validated with Sanger sequencing. RESULTS: Sequencing revealed two ANOS1 and four FGFR1 mutations in six subjects, of which five are novel and one had been previously reported in CHH. Novel variants include a single base pair deletion c.313delT in exon 3 of ANOS1, three missense variants of FGFR1 predicted to result in the single amino acid substitutions c.331C > T (p.R111C), c.1964 T > C (p.L655P) and c.2167G > A (p.E723K) and a 15 bp deletion c.374_388delTGCCCGCAGACTCCG in exon 4 of FGFR1. Based on ACMG-AMP criteria reported variants were assigned to class 5, pathogenic or class 4, likely pathogenic. Protein structural predictions, the rarity of novel variants and amino acid conservation in case of missense substitutions all provide strong evidence that these mutations are highly likely to be deleterious. CONCLUSIONS: Despite the fact that ANOS1 and FGFR1 are classical CHH genes and were thoroughly explored in several CHH cohorts we identified new, yet undescribed variants within their sequence. Our results support the genetic complexity of the disorder. The knowledge of the full genetic spectrum of CHH is increasingly important in order to be able to deliver the best personalised medical care to our patients.

Novel synonymous and missense variants in FGFR1 causing Hartsfield syndrome.

Hartsfield syndrome is a rare clinical entity characterized by holoprosencephaly and ectrodactyly with the variable feature of cleft lip/palate. In addition to these symptoms patients with Hartsfield syndrome can show developmental delay of variable severity, isolated hypogonadotropic hypogonadism, central diabetes insipidus, vertebral anomalies, eye anomalies, and cardiac malformations. Pathogenic variants in FGFR1 have been described to cause phenotypically different FGFR1-related disorders such as Hartsfield syndrome, hypogonadotropic hypogonadism with or without anosmia, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, and trigonocephaly Type 1. Here, we report three patients with Hartsfield syndrome from two unrelated families. Exome sequencing revealed two siblings harboring a novel de novo heterozygous synonymous variant c.1029G>A, p.Ala343Ala causing a cryptic splice donor site in exon 8 of FGFR1 likely due to gonadal mosaicism in one parent. The third case was a sporadic patient with a novel de novo heterozygous missense variant c.1868A>G, p.(Asp623Gly).

The level of extracellular superoxide dismutase in the first week of life in very and extremely low birth weight infants and the risk of developing bronchopulmonary dysplasia.

Background Antioxidant enzymes may play a significant role in the development of bronchopulmonary dysplasia (BPD). The aim of the study was to assess the relationship between the level of extracellular superoxide dismutase (SOD3) in the serum at days 1 and 7 of life and the risk of developing BPD. Methods The study comprised 103 neonates born before 32 weeks' gestation with a birth weight of ≤1500 g. Results In the investigated group, the median serum SOD3 level at day 1 of life was 4.01 ng/mL [interquartile range (IQR) 2.59-5.09 ng/mL] and at day 7 of life 3.13 ng/mL (IQR 2.49-4.34 ng/mL). A statistically significant decrease in the serum SOD3 level was found in the first week of life, P < 0.0001. No correlation was found between the serum SOD3 level at day 1 of life and gestational age R = 0.07, P = 0.4543 and birth weight R = 0.10, P = 0.3083. No statistically significant correlation was found between the dynamics of change in the SOD3 level in serum at days 1 and 7 of life and the risk of BPD development for the definition of BPD at day 28 of life, P = 0.8764 nor at 36 weeks' postmenstrual age, P = 0.6598. Conclusion The study revealed a statistically significant decrease in the serum SOD3 level in the first week of life in very and extremely low birth weight infants born before 32 weeks of gestation. In the clinical setting, no relationship was observed between the level of SOD3 in serum and the risk of developing BPD.

Air Pollution and Human Sperm Sex Ratio.

The present study was designed to address the hypothesis that exposure to specific air pollutants may impact human sperm Y:X chromosome ratio. The study population consisted of 195 men who were attending an infertility clinic for diagnostic purposes and who had normal semen concentration of 15-300 mln/ml (WHO, 2010). Participants represented a subset of men in a multicenter parent study conducted in Poland to evaluate environmental factors and male fertility. Participants were interviewed and provided a semen sample. The Y:X ratio was assessed by fluorescent in situ hybridization (FISH). Air quality data were obtained from the AirBase database. In multivariate analysis the significant reduction was observed in the proportion of Y/X chromosome bearing sperm and exposure to particulate matter >10 µm in aerodynamic diameter PM10 ( p = .009) and particulate matter <10 µm in aerodynamic diameter PM2.5 ( p = .023). The observed effects of a lower Y:X sperm chromosome ratio among men exposed to air pollution support the evidence that the trend of declining sex ratio in several societies over past decades has been due to exposure to air pollution; however due to limited data on this issue, the obtained results should be confirmed in longitudinal studies.

Environmental exposure to parabens and sperm chromosome disomy.

Parabens are widely used as antimicrobial preservatives in cosmetics, pharmaceuticals, food and beverage processing due to their board spectrum of activity, inertness, and low cost. The study population consisted of 156 men under 45 years of age who attended the infertility clinic for diagnostic purposes with normal semen concentration of 15-300 mln/ml. Participants were interviewed and provided a semen sample. The parabens concentrations: ethyl paraben (EP), butyl paraben (BP), methyl paraben (MP), and iso-butyl paraben (iBuP) were analyzed in the urine using a validated gas chromatography ion-tap mass spectrometry method. The positive association was found between urinary level of BP and XY18 disomy (p = 0.045) and PP and disomy of chromosome 13 (p = 0.007). This is the first study to examine these relationships, and replication of our findings is needed before the association between parabens concentration in urine and aneuploidy can be fully defined. These findings may be of concern due to increased parabens use.

Cell-free fetal DNA testing in prenatal diagnosis: Recommendations of the Polish Gynecological Society and the Polish Human Genetics Society.

This paper contains a joint position of the Polish Gynecological Society and Polish Human Genetics Society on the cell-free fetal DNA testing in prenatal diagnosis. We present situations where the cell-free fetal DNA testing should be applied and cases in which performing of the test is not useful. We indicate what diagnostic steps should be performed before the test and how the test results should be interpreted and followed.

Folate status, regulatory T cells and MTHFR C677T polymorphism study in allergic children.

PURPOSE: This study aimed to investigate early-life folate serum concentrations in children with food, inhalant or mixed type allergy. The influence of folate levels on the FoxP3 expression in Treg (regulatory T) cells in the studied children, taking into account the MTHFR (5,10-methylenetetrahydrofolate reductase) genotypes was also analyzed. MATERIAL AND METHODS: The study was performed in 83 allergic children (study group) and 49 healthy children (control group), aged 2-72 months. Medical history of each child was obtained and laboratory tests (serum folic acid concentrations and MTHFR C677T polymorphism) were carried out. The percentage of Treg cells was evaluated in almost a half of the examined subjects (48.5%). RESULTS: Significantly higher serum folate levels in the group of children with food allergy than in those with inhalant allergy was confirmed (P=0.037). In the study group the TT homozygotes were characterized by significantly lower folate concentrations than CC homozygotes (P=0.045). A negative correlation was demonstrated between the FoxP3 expression in CD4+CD25highFoxP3+ peripheral blood lymphocytes and serum folic acid concentrations. The correlation was more pronounced in the group of allergic children and it was statistically significant (r=-0.339, P<0.05). CONCLUSIONS: The results of the study indicate a possibility of some effects of folate status on Treg cells, thus suggesting their potential role in the development and course of allergy in children.

Exposure to widespread environmental endocrine disrupting chemicals and human sperm sex ratio.

In recent years, a trend toward a declining proportion of male births has been noted in several, but not all, industrialized countries. The underlying reason for the drop in the sex ratio is unclear, but one theory states that widespread environmental endocrine disrupting chemicals affecting the male reproductive system in a negative manner could be part of the explanation. The present study was designed to investigate whether the urinary phthalate, pyrethroids and polycyclic aromatic hydrocarbons metabolites concentrations were associated with sperm Y:X ratio. The study population consisted of 194 men aged under 45 years of age who attended infertility clinic in Lodz, Poland for diagnostic purposes with normal semen concentration of 20-300 mln/ml or with slight oligozoospermia (semen concentration of 15-20 mln/ml) (WHO, 1999). The Y:X ratio was assessed by fluorescent in situ hybridization. Urinary concentrations of 1-hydroxypyrene were measured by high performance liquid chromatography, phthalate metabolites were analyzed using a procedure based on the LC-MS/MS methods and metabolites of synthetic pyrethroids were assessed by gas chromatography ion-tap mass spectrometry method. After adjustment for potential confounders (past diseases, age, abstinence, smoking, alcohol consumption, sperm concentration, motility, morphology) 5OH MEHP, CDCCA to TDCCA and 1-OHP was negatively related to Y:X sperm chromosome ratio (p = 0.033, p < 0.001, p = 0.047 respectively). As this is the first study to elucidate the association between the level of metabolites of widespread environmental endocrine disrupting chemicals (phthalates, synthetic pyrethroids, polycyclic aromatic hydrocarbons) on sex chromosome ratio in sperm therefore, these findings require further replication in other populations.

Dietary Patterns and the Frequency of Disomy in Human Sperm.

OBJECTIVES: To determine whether dietary patterns are associated with the frequency of sperm aneuploidy in a human sperm. It was shown that the role of nutrition, especially dietary pattern, remains unexamined as a risk factor in sperm aneuploidy. In contrast to the traditional analytical approach used in nutritional epidemiology, dietary pattern analysis considers overall diet rather than individual nutrients or foods. METHODS: The study population consisted of 212 men who were attending an infertility clinic for diagnostic purposes and who had semen concentration of ≥15 (10(6)/ml) (World Health Organization, 2010). Sperm aneuploidy was assessed using multicolor fluorescent in situ hybridization (DNA probes specific for chromosomes 13, 18, 21, X, Y). Diet was assessed via food frequency questionnaire and dietary patterns were identified by factor analysis. Men were classified into 3 groups according to scores of each dietary pattern: Western, Mixed, Prudent. RESULTS: In multivariate analysis, Prudent dietary pattern characterized by high intakes of fish, chicken, fruit, cruciferous vegetables, tomatoes, leafy green vegetables, legumes, and whole grains decreases disomy of chromosomes XX and 21 (P = .01 and P = .005) compared with Western dietary pattern characterized by high intakes of red and processed meat, butter, high fat dairy, refined grains, pizza, snacks, high-energy drinks, and sweets. CONCLUSION: Higher consumption of Prudent dietary pattern was associated with decreased frequencies of sperm disomy. As this is the first study to analyze the relation of diet and the frequency of sperm aneuploidy, our findings merit further studies, in other populations.

Familial partial lipodystrophy as differential diagnosis of polycystic ovary syndrome.

UNLABELLED: According to current diagnostic criteria, polycystic ovary syndrome (PCOS) is effective as a diagnosis of exclusion. Here, we present a case of a 31-year-old woman with a history of oligomenorrhoea and hirsutism, who, despite a "muscular" appearance and a normal body mass index (22.27 kg/m2), was found to have an extreme insulin resistance and diabetes accompanied by hyperandrogenism and polycystic ovaries. An autoimmune screen for possible latent autoimmune diabetes in adults was negative. She was subsequently found to have familial partial lipodystrophy (FPLD2, OMIM #151660) caused by an R482Q mutation in the LMNA gene encoding lamin A/C. This mutation results in arginine to glutamine substitution at the protein level, while phenotypically this condition presents with a loss of body fat, insulin resistance, dyslipidaemia, and other features mimicking PCOS. Interestingly her mother, with a history of myocardial infarction and diabetes at the age of 46 but no oligomenorrhoea, was also found to harbour the same mutation (LMNA R482Q). CONCLUSIONS: Our case highlights the importance of assessment of adipose tissue distribution, as well as a significance of assessment of glucose tolerance and insulin resistance in the differential diagnosis of PCOS. Furthermore, patients with atypical adipose tissue distribution should be referred for formal genetic testing.

The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients.

INTRODUCTION: In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. MATERIAL AND METHODS: A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. RESULTS: Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). CONCLUSIONS: Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

Human sperm aneuploidy after exposure to polycyclic aromatic hydrocarbons.

The purpose of this cross-sectional study was to investigate whether environmental exposure to polycyclic aromatic hydrocarbons (PAHs) was associated with sperm aneuploidy. A sample of 181 men who attended an infertility clinic for diagnostic purposes and who had a normal semen concentration of 20-300×106 spermatozoa mL-1 or slight oligozoospermia (semen concentration of 15-20×106 spermatozoa mL-1;

The association between environmental exposure to pyrethroids and sperm aneuploidy.

The aim of the present study is to determine whether the environmental exposure to pyrethroids was associated with males sperm chromosome disomy. The study population consisted of 195 men who attended the infertility clinic for diagnostic purposes and who had normal semen concentration of 20-300×10(6) mL(-1) or slight oligozoospermia (semen concentration of 15-20×10(6) mL(-1)) (WHO, 1999). Participants were interviewed and provided a semen sample. The pyrethroids metabolites: 3-phenoxybenzoic acid (3PBA), cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (TDCCA) and cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) were analysed in the urine using a validated gas chromatography ion-tap mass spectrometry method. Sperm aneuploidy was assessed using multicolor FISH (DNA probes specific for chromosomes X, Y, 18, 13, 21). Our results showed that CDCCA >50th percentile was associated with disomy of chromosome 18 (p=0.05) whereas the level of TDCCA in urine >50th percentile was related to XY disomy (p=0.04) and disomy of chromosome 21 (p=0.05). Urinary 3PBA level ⩽50 and >50 percentile was related to disomy of sex chromosomes: XY disomy (p=0.05 and p=0.02 respectively), Y disomy (p=0.04 and 0.02 respectively), disomy of chromosome 21 (p=0.04 and p=0.04 respectively) and total disomy (p=0.03 and p=0.04 respectively). Additionally disomy of chromosome 18 was positively associated with urinary level of 3PBA >50 percentile (p=0.03). The results reported here are found that pyrethroids may be a sperm aneugens. These findings may be of concern due to increased pyrethroid use and prevalent human exposure.

Occupational risk factors and frequency of sex chromosome disomy.

Possible reproductive toxicants such as occupational factors may affect the normal disjunction of chromosomes during meiosis, thereby altering the number of chromosomes in sperm nuclei. The purpose of the present analysis was to determine whether exposure to occupational factors existing in a contemporary work setting affected sperm aneuploidy. The study population consisted of 212 men who attended the infertility clinic for diagnostic purposes. The men either had a normal semen concentration of 20-300 million/ml or slight oligozoospermia (semen concentration of 15-20 million/ml) ( WHO 1999 ). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH. After adjustment for potential confounders, positive associations were found between disomy XY18, 18, and sex chromosome disomy and exposure to mechanical vibrations (p = 0.03, p = 0.04, p = 0.03, respectively). In addition, sitting for more than 6 h at work increased X and Y disomy (p = 0.03, p = 0.04, respectively). To the best of our knowledge, this is the first study to show a significant effect of occupational factors on sperm aneuploidy. As such, the results need to be confirmed in larger studies.

The relationship between exposure to air pollution and sperm disomy.

The causes of the chromosome abnormalities have been studied for decades. It has been suggested that exposure to various environmental agents can induce chromosomal abnormalities in germ cells. This study was designed to address the hypothesis that exposure to specific air pollutants increases sperm disomy. The study population consisted of 212 men who were attending an infertility clinic for diagnostic purposes. They represented a subset of men in a multicenter parent study conducted in Poland to evaluate environmental factors and male fertility. Sperm aneuploidy for chromosomes 13, 18, 21, X, and Y was assessed using multicolor fluorescence in situ hybridization. Air quality data were obtained from the AirBase database. After adjusting for age, smoking, alcohol consumption, temperature (90 days), season, past diseases, abstinence interval, distance from the monitoring station, concentration, motility and morphology, positive associations were observed between exposure to PM2.5 and disomy Y (P = 0.001), sex chromosome disomy (P = 0.05) and disomy 21 (P = 0.03). Exposure to PM10 was associated with disomy 21 (P = 0.02). Conversely, exposure to ozone, CO, SO2, and NOx did not affect sperm aneuploidy. A separate analysis conducted among men who were nonsmokers (n = 117) showed that the relationship between PM2.5 and disomy Y and disomy 21 remained significant (P = 0.01, P = 0.05, respectively). The present findings indicate that exposure to air pollution induces sperm aneuploidy.

Lifestyle factors and sperm aneuploidy.

Different environmental and lifestyle factors may interfere with the normal disjunction of sister chromatids/chromosomes during meiosis and may cause aneuploidy. The aim of the study was to examine the association between lifestyle factors and sperm aneuploidy. The study population consisted of 212 healthy men under 45 years of age attending an infertility clinic for diagnostic purposes and who had a normal semen concentration of 20-300×106mL or slight oligozoospermia (semen concentration of 15-20×106/mL). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH (DNA probes specific for chromosomes X, Y, 18, 13, 21). Results from the study suggest that lifestyle factors are related to sperm aneuploidy. A positive relationship was found between coffee drinking everyday and the lack of chromosome X or Y, as well as coffee drinking 1-6 times per week and additional chromosome 18. Wearing boxer shorts decrease the copy number changes in the whole chromosome 18, the number of additional chromosome 18 and the lack of chromosome 13. Additionally, obesity (BMI 30-40 kg/m²) was positively associated with additional chromosome 21 after being adjusted for potential confounders. These findings demonstrate that changing the men's lifestyle habits may contribute to reduction of the incidence of sperm aneuploidy. It is necessary that men continue to follow sensible health advice concerning excess weight, coffee drinking and wearing tight fitting underwear. As this is the first such study to examine different lifestyle factors and sperm aneuploidy, the results need to be confirmed on larger population.