Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance.

The Adverse Outcome Pathway (AOP) framework has gained widespread acceptance in toxicological disciplines as a tool for aiding chemical hazard assessment. Despite increased activity in AOP development, progress towards a high volume of fully endorsed AOPs has been slow, partly due to the challenging task of constructing complete AOPs according to the AOP Developer's Handbook. To facilitate greater uptake of new knowledge units onto the open-source AOP-wiki platform, a pragmatic approach was recently proposed. This approach involves considering Key Event Relationships (KERs) for individual development through systematic approaches, as they represent essential units of knowledge from which causality can be inferred; from low complexity test data to adverse outcomes in intact organisms. However, more broadly adopted harmonized methodologies for KER development would be desirable. Using the AOP Developer's Handbook as a guide, a KER linking 'decreased androgen receptor (AR) activity' with 'reduced anogenital distance (AGD)' was developed to demonstrate a methodology applicable for future developments of KERs requiring systematic literature retrieval approaches.

Endocrine effect of phthalate metabolites and a butterfly effect of prenatal exposure to androgens on qualitative aspects of female sexual response- an initial survey.

There is growing evidence that endocrine disruptive chemicals have deleterious effects on sexual and reproductive function. To examine subjective sexual functions in human females and their relationship to postnatal phthalate exposure and perinatal androgenization, a Sexuality Score (SS) was established from a first-stage survey questionnaire of subjective sexual function filled out by female university students (n = 68; average age 25.23 ± 5.17 years; rural 25.51 ± 6.74 vs. urban 25.85 ± 1.43 years). Seventeen phthalate metabolites in urine samples were analyzed by high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Females were also assessed for the 2D:4D digit ratio as an index of perinatal androgenization. The mean age of menarche was 12.82 ± 1.35 years (rural 12.59 ± 1.39 vs. urban 13.18 ± 1.27; p = 0.01). The mean age at first sexual intercourse was 14.88 ± 6.89 years (rural 14.62 ± 7.20 vs. urban 15.24 ± 6.55), and as the age of first sexual intercourse increases, the SS score tends to increase as well, albeit moderately (r = 0.25, p = 0.037). Mono-iso-butyl phthalate, mono(2-ethyl-5-carboxypentyl) phthalate, mono(hydroxy-n-butyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate (p ≤ 0.05) and mono(2-carboxymethylhexyl) phthalate (p ≤ 0.01) were negatively associated with SS. A compounding butterfly effect of prenatal exposure to androgens was observed with disruptive effects of mono(2-ethyl-5-oxohexyl) phthalate and mono(2-ethyl-5-carboxypentyl) phthalate on sexual function. Exposure to phthalates in adult females may lead to disruption of subjective sexual function, especially concerning sexual desire and sexual satisfaction, and perinatal androgenization could augment these effects.

Urinary Phthalate Biomarkers during Pregnancy, and Maternal Endocrine Parameters in Association with Anthropometric Parameters of Newborns.

Adverse birth outcomes present risk factors resulting in neonatal morbidity and mortality. Sufficient maternal hormonal concentrations are crucial for normal foetal development. Previous studies have shown a relationship between phthalate exposure and maternal hormonal levels during pregnancy. This study aims to investigate if neonatal anthropometric parameters are associated with maternal endocrine parameters during the ≤15th week of gestation and the third trimester of pregnancy concerning phthalate exposure in pregnant women from Nitra, Slovakia. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to quantify urinary concentrations of phthalates and serum concentrations of hormones and sex hormone-binding globulin (SHBG), respectively. We observed a mostly positive correlation between neonatal anthropometric parameters (gestational age, birth length, birth weight, head circumference) and maternal concentration of phthalate metabolites (p ≤ 0.05). The hierarchical multivariate regression results showed a statistically significant association between Apgar score at 5 min after delivery, gestational age, birth weight, head circumference, and maternal endocrine parameters during pregnancy (p ≤ 0.05), adjusted to phthalate metabolites. To the best of our knowledge, our study is the first to indicate that prenatal exposure to phthalates may also affect birth outcomes through interaction with the maternal endocrine system.

The Joint Effect of Perceived Psychosocial Stress and Phthalate Exposure on Hormonal Concentrations during the Early Stage of Pregnancy: A Cross-Sectional Study.

Phthalates alter the hormonal balance in humans during pregnancy, potentially affecting embryonic and fetal development. We studied the joint effect of exposure to phthalates, quantified by urinary phthalate metabolite concentration, and perceived psychological stress on the concentration of hormones in pregnant women (n = 90) from the Nitra region, Slovakia, up to the 15th week of pregnancy. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to determine urinary concentrations of phthalates and serum concentrations of hormones, respectively. We used Cohen perceived stress scale (PSS) to evaluate the human perception of stressful situations. Our results showed that mono(carboxy-methyl-heptyl) phthalate (cx-MiNP) and a molar sum of di-iso-nonyl phthalate metabolites (ΣDiNP) were negatively associated with luteinizing hormone (LH) (p ≤ 0.05). Mono(hydroxy-methyl-octyl) phthalate (OH-MiNP) and the molar sum of high-molecular-weight phthalate metabolites (ΣHMWP) were positively associated with estradiol (p ≤ 0.05). PSS score was not significantly associated with hormonal concentrations. When the interaction effects of PSS score and monoethyl phthalate (MEP), cx-MiNP, ΣDiNP, and ΣHMWP on LH were analyzed, the associations were positive (p ≤ 0.05). Our cross-sectional study highlights that joint psychosocial stress and xenobiotic-induced stress caused by phthalates are associated with modulated concentrations of reproductive hormones in pregnant women.

Risk of Abdominal Obesity Associated with Phthalate Exposure of Nurses.

Background: Occupational health hazards associated with phthalate exposure among nurses are still not well understood. Methods: We used high-performance liquid chromatography and tandem mass spectrometry to analyze phthalates. Anthropometric measurements and questionnaires were conducted. Results: We observed associations between mono-benzyl phthalate (MBzP) and body mass index (BMI), hip circumference (HC), waist circumference (WC), waist to height ratio (WHtR), and fat mass index (FMI), visceral fat content, BMI risk and hip index risk (HIrisk), adjusted to consumer behavior and consumer practices (r = 0.36−0.61; p ≤ 0.046). In the same model, we detected an association between mono-n-butyl phthalate (MnBP) and waist to hip ratio (WHR; r = 0.36; p = 0.046), mono-carboxy-isononyl phthalate (cx-MiNP) and BMI (r = 0.37; p = 0.043), HC (r = 0.4; p = 0.026) and WHtR (r = 0.38; p = 0.037), between mono-oxo-isononyl phthalate oxo (MiNP) and HC (r = 0.36; p = 0.045), mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (oxo-MEHP) and HIrisk (r = 0.38−0.41; p ≤ 0.036), between oxo-MEHP and Anthropometric Risk Index (ARI risk; r = 0.4; p = 0.028). We detected a relationship between BMI and MBzP (ß = 0.655; p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; ß = −0.365; p = 0.003), between hip circumference and MBzP (ß = 0.486; p < 0.001), MEHP (ß = −0.402; p = 0.001), and sum of secondary metabolites of diisononyl phthalate (∑DiNP; ß = 0.307; p = 0.016). We observed a relationship between fat content and MBzP (ß = 0.302; p = 0.033), OH-MnBP (ß = −0.736; p = 0.006) and MiBP (ß = 0.547; p = 0.046), visceral fat content and MBzP (ß = 0.307; p = 0.030), HI-risk and MBzP (ß = 0.444; p = 0.001), ARI-risk and sum of di-n-butyl phthalate metabolites (∑DnBP; ß = 0.337; p = 0.018). We observed an association between the use of protective equipment with cx-MiNP. Conclusions: Occupational exposure to phthalates may induce abdominal obesity and result in obesity-related metabolic disorders.

Effect of prenatal phthalate exposure on the association of maternal hormone levels during early pregnancy and reproductive markers in infants at the age of 3 months.

Phthalates belong to the endocrine-disrupting chemicals, altering the hormonal balance in humans during pregnancy with further effects on the reproductive system. This study aimed to investigate the associations between maternal hormone levels during early pregnancy (≤15th week of pregnancy) and reproductive markers in infant boys (n = 37; 61.67 %; average age 3.51 ±â€¯0.73 months) and girls (n = 23; 38.33 %; average age 3.30 ±â€¯0.33 months) concerning prenatal exposure to phthalates. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to quantify urinary concentrations of phthalates and serum concentrations of hormones, respectively. In Mother-Infant Study Cohort (PRENATAL), we observed positive and negative correlations between infants' reproductive markers and phthalate metabolites (p ≤ 0.05). Next, we noticed associations between the penile length and maternal testosterone (ß = 0.464) and estradiol levels (ß = -0.365) with increasing significance after adjustment to maternal mono-n-butyl phthalate (MnBP) and monobenzyl phthalate (MBzP) (p ≤ 0.05). We observed a positive association (ß = 0.337) between penile width and maternal testosterone with increasing significance after adjustment to maternal mono-iso-butyl phthalate (MiBP) (p ≤ 0.05). In a group of girls, we reported a negative association between ACD/AFD ratio and maternal follicle-stimulating hormone (FSH) and estradiol levels with increasing significance after adjustment to maternal monoethyl phthalate (MEP), MnBP, and mono(hydroxy-iso-butyl) phthalate (OH-MiBP). Our results highlight that prenatal phthalate exposure may modulate the effects of maternal hormone levels during early pregnancy on infants' reproductive markers.

Effects and mechanisms of phthalates' action on neurological processes and neural health: a literature review.

During the period of mass industrial production of plastic products, the quality of human health has decreased significantly, especially in children's neurodevelopmental disorders. Phthalates are endocrine-disrupting chemicals that can induce neurological disorders. This review aims to compile evidence concerning the associations between neurological disorders, such as attention-deficit/hyperactivity disorder, autism spectrum disorder, decreased masculine behavior, and phthalate exposure. Phthalates dysregulate the hypothalamic-pituitary-gonadal, adrenal, and thyroid axis, which is crucial for the neurodevelopmental process. Phthalates interfere with nuclear receptors in various neural structures involved in controlling brain functions and the onset of neurological disorders at the intracellular level. It is critical to increase the current knowledge concerning phthalates' toxicity mechanism to comprehend their harmful effect on human health.

Effects and Mechanisms of Phthalates' Action on Reproductive Processes and Reproductive Health: A Literature Review.

The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

Occupational Hazards and Risks Associated with Phthalates among Slovakian Firefighters.

Despite increasing attention to the occupational risk of firefighters, little is known about phthalate exposure. In our study, we detected mono-isobutyl phthalate (MiBP), mono-n-buthyl phthalate (MnBP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MECPP), and mono(2-ethyl-5-oxohexyl) phthalate (5oxo-MEHP) in each urine sample. We detected positive association between MnBP, MiBP, mono-2-ethylhexyl phthalate (MEHP), 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, mono-isononyl phthalate (MiNP), the sum of low (∑LMWP) and high molecular-weight phthalates (∑HMWP). and Tiffeneau-Pinelli index (the ratio of forced expiratory volume in 1/ forced vital capacity; FEV1/FVC; p = 0.001-0.04) and the percent predicted value (%PV) of FEV1/FVC (p = 0.005-0.05) and negative association between MiNP and peak expiratory flow (PEF; r = -0.31; p = 0.084). We observed a positive association between phthalate metabolites (MnBP, 5OH-MEHP, 5oxo-MEHP, 5cx-MECPP, 2cx-MMHP, ∑LMWP, and ∑HMWP) and waist-to-hip ratio (WHR; p = 0.003-0.09) and body shape index (ABSI; p = 0.039-0.09) and a negative association between MnBP, ∑LMWP, and hip circumference (p = 0.005-0.02). We detected association between concentrations of 5OH-MEHP, 5cx-MECPP, 5oxo-MEHP, and MnBP and consumption of food heating in plastic material in microwave (p = 0.02-0.04) and between probands who ate margarines and vegetable fat packed in plastic containers and concentration of MMP (p = 0.03). Results of multivariate regression indicated that exposure to phthalates could be linked with changing body structure, which subsequently affects values of pulmonary functions in firefighters.