Biphasic effects of perfluorooctanoic acid on steroidogenesis in mouse Leydig tumour cells

Perfluorooctanoic acid (PFOA) is a persistent organic pollutant, which may possess endocrine disrupting properties. Herein, we investigated the possible mechanism(s) of toxicity and steroidogenesis in mouse Leydig cells. MLTC-1 (mouse Leydig tumour cells) cells were exposed to 0, 50, 100 or 200 μM PFOA for 48 h to ascertain their effects on the nuclear (membrane) receptor responses, steroidogenesis pathway and related regulated gene expression and steroid hormone secretion profiles. Our results reveal that nuclear receptors PXR, SR-B1 and LHR are sensitive to PFOA exposure. PFOA can accumulate in mitochondria and alter cholesterol precursor (fatty acid) mitochondrial transport process-related gene expression and thus inhibit steroid hormone precursor (cholesterol) production. In particular, PFOA exhibits biphasic effects on testosterone and progesterone production at differing levels of exposure. These findings indicate the potential endocrine-related effects of PFOA on steroid hormone secretion in Leydig cells and point to a novel disruption model. [Abstract copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Phthalates Induce Androgenic Effects at Exposure Levels That Can Be Environmentally Relevant in Humans

Although anti-androgenic activity of various lipophilic chain phthalate acid esters (PAEs) has been reported in high-dose animal studies, their male reproductive risk remains a matter of debate because of conflicting epidemiological observations. Recently, we showed that PAEs acted as a preventative factor in male infertility, which implies these chemicals are androgenic in human steroidogenesis. To verify the androgenic observation, a reproductive age healthy male cohort (n = 84) was recruited by following a cross-sectional study design, in which infertility or clinical selection-introduced bias was avoided. Urine was used for both PAE exposure monitoring and androgen measurements, and sampling uncertainty was greatly reduced. Eight selected metabolites (i.e., MMP, MEP, MBP, MEHP, MBzP, MEHHP, MECPP, and MEOHP) and two androgens, i.e., androstenedione (ASD) and testosterone, were measured by using HPLC–MS/MS. Except for MBzP, the selected phthalates can be detected in all samples at concentrations (median [5th–95th percentile]) of 36.4 [2.0–261.0], 36.7 [5.6–318.5], 75.3 [13.1–301.0], 3.2 [1.1–10.2], 3.8 [0.6–11.9], 13.6 [1.6–51.1], and 7.4 [0.9–31.8] ng/mL for MMP, MEP, MBP, MEHP, MEOHP, MECPP, and MEHHP, respectively. Urinary PAE metabolites generally correlated with ASD and testosterone in positive ways; the trends are most significant for MMP, MEP, MBP, and ∑DEHP versus ASD and for ∑DEHP versus testosterone. This study reveals that the phenotypic effect of our participants’ exposure to PAEs at the typical environmental relevant exposure level is androgenic, which counters the notion of the well-accepted anti-androgenic effect

Gene-environment interactions between GSTs polymorphisms and targeted epigenetic alterations in hepatocellular carcinoma following organochlorine pesticides (OCPs) exposure

Exposure to environmental pollutant organochlorine pesticides (OCPs) and the role of tumour suppressor GSTs gene polymorphisms as well as epigenetic alterations have all been well reported in hepatocarcinogenesis. However, the interplay between environmental risk factors and polymorphic tumour suppressor genes or epigenetic factors in hepatocellular carcinoma (HCC) development remains ambiguous. Herein, we investigated the relationship of three GSTs polymorphisms (GSTT1 deletion, GSTM1 deletion, GSTP1 rs1695) as well as GSTP1 promoter region DNA methylation and HCC risk with a particular focus on the interaction with OCPs exposure among 90 HCC cases and 99 controls in a Chinese population. Serum samples were analysed for OCPs exposure employing gas chromatography coupled with mass selective detector (GC-MS). GSTs polymorphisms and epigenetic alterations were determined using high-resolution melting PCR (HRM PCR) and DNA sequencing. After adjusting for confounders (HBV infection, smoking, alcohol consumption, BMI, age, gender), OCPs exposure and GSTP1 methylation is significantly associated with elevated risk of HCC, while no significance is observed for GSTs polymorphisms. Moreover, the effects of OCPs exposure on HCC risk are more pronounced amongst GSTP1 (Ile/Val + Val/Val) and GSTP1 promoter methylation subjects than those who were GSTP1 (Ile/Ile) and unmethylated subjects. The interactions between OCPs exposure and GSTP1 genotype as well as GSTP1 epigenetic status are statistically significant. The current study demonstrates the importance of gene-environment interactions in the multifactorial development of HCC. [Abstract copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phthalate side side-chain structures and hydrolysis metabolism associated with steroidogenic effects in MLTC-1 Leydig cells

Although it is well acknowledged that the anti-androgenic phthalate diesters can be readily hydrolysed into their monoester counterparts, their metabolites’ toxicology remains obscure. Herein, we tested the hypothesis that hydrolysis of one of the two ester bonds can mediate phthalate diesters’ potential endocrine effects in MLTC-1 Leydig cells, in line with their ability to disrupt androgen secretion in humans. Five diesters (DMP, DEP, DBP, DBzP and DEHP) and five monoesters (MMP, MEP, MBP, MBzP and MEHP) phthalates as mixtures or individually were applied to cell lines to investigate differences in phthalates’ hydrolysis associated with varying side-chain structures and steroidogenic effects. Short-chain diesters DMP, DEP and DBP are more readily hydrolysed compared to the long-chain DEHP, while aromatic alkyl chain DBzP cannot be metabolized completely in vitro. When the hydrolysis processes are interrupted, the diester phthalates’ steroidogenic effects can be influenced via regulating related steroidogenic pathway genes. With 10 to 100 μM treatment exposures, androgenic effects were observed only with DMP or DEP but not for MMP or MEP; while the phthalate diesters DBP, DBzP or DEHP generally exhibited more complex steroidogenic effects than their corresponding monoester counterparts (i.e., biphasic androgen and anti-androgen effects for diesters but monotonic androgen effects for monoesters were observed). DBP elicited hydrolysis-related steroidogenic modulation, in which the anti-androgenic effects of diester DBP reversed into the androgenic effects of monoester MBP at 100 μM. Phthalate metabolites appear to exert different effects at an endocrine level compared to parent compounds, and deeper insights into how the hydrolytic process is related to this alternating toxicity would improve our understanding of a risk assessment for these widespread contaminants in male reproduction

Characteristics and pollution risks of Cu, Ni, Cd, Pb, Hg and As in farmland soil near coal mines

Heavy metal (loid) pollution poses a serious threat to the health and habitability of ecosystems worldwide. This study aims to investigate the concentration, pollution degree, pollution sources, and health risks of heavy metal (loid)s (HMs) in soil of Shanxi Province, China. The concentrations of Cu, Ni, Cd, Pb, Hg and As were measured by ICP-MS in 146 soil samples collected from agricultural land. The pollution degree and ecological risks of HMs were analyzed by variety of indexes, and the human health risks were assessed using the USEPA model. Results showed the average concentrations of Cu, Cd, Pb, Hg and As were 1.08, 1.15, 1.44, 1.50 and 1.25 times higher than the background values in the soil of investigated areas, respectively. The contamination factors revealed moderate pollution of Hg, Pb, As, Cd and Cu in the investigated areas, and the pollution load index indicated considerable contamination. The Nemerow index revealed low to severe contamination with HMs. The potential ecological risk of HMs indicates that Hg and Cd pose a moderate risk threat to the soil ecology. Coal mining was the primary sources of soil HMs identified by ACPS-MLR. Soil As (75.1%) and Ni (62.3%) were mainly derived from coal mining, Pb (73.1%) was from traffic emissions, and Hg (38.6%) originated from coal combustion. The health risks associated with these HMs due to soil exposure were within the acceptable levels for adults. The As concentration imposes the strongest effect based on the non-carcinogenic risk analysis in different exposed populations. In conclusion, the higher concentration of soil HMs moderately threatens soil ecology, but there was no significant human health risk found in the study. Furthermore, this study reveals the potential risk and sources of HMs in Shanxi Province, which is helpful for managing contaminated soil in the region

Association of environmental benzoapyrene exposure and DNA methylation alterations in hepatocellular carcinoma: a Chinese case-control study

Epidemiological studies implicate environmental risk factors and epigenetic alterations in the multistage process of hepatocellular carcinoma (HCC) development. However, associations between environmental factors and DNA methylation of tumour suppressor genes (TSGs) in HCC development remain ambiguous. Understanding how possible interactions influence risk may provide insights into the complexity of hepato-carcinogenesis. For this study, blood samples were collected from HCC patients (n = 90) and healthy volunteers (n = 99) from Xiamen (China) and data for selected environmental risk factors e.g., benzoa]pyrene (BaP), hepatitis B or C virus (HBV or HCV) infection, smoking and alcohol consumption were recorded; factors identified as significantly higher (P {\ensuremath{<}} 0.05) amongst case subjects compared to controls were identified. In order to assess associations for epigenetic alterations and HCC risk factors, serum DNA methylation of TSGs was quantified using high-resolution melting (HRM) analysis. Our results clearly indicate elevated methylation patterns for detoxification gene glutathione-S-transferase Pi (GSTP) promoter regions in cases compared to control subjects. Additionally, GSTP promoter hypermethylation and BaP diol epoxide-albumin (BPDE-Alb) were positively correlated with HCC incidence. Our epidemiological and in vitro cell model studies indicated that GSTP promoter DNA methylation regulates this gene's expression. Moreover, GSTP also plays an important role in BaP detoxification and potential protective role against BaP-induced liver cell toxicity and hepato-carcinogenesis

Additions and corrections to Association of DNA Methylation and Mitochondrial DNA Copy Number with Human Semen Quality

Whether there is a relationship between quality, DNA methylation, and mitochondrial DNA (mtDNA) copy number in human-derived sperm specimens is unknown. A cohort (n = 118) of male partners of couples who were undergoing fertility assessment because of an idiopathic inability to conceive were recruited. Sperm motility parameters were determined by computer-aided sperm analysis (CASA), while sperm quality was assessed using World Health Organization criteria, mtDNA copy number was measured by real-time PCR, and DNA methylation patterns were analyzed employing high-melting resolution PCR and bisulfite sequencing PCR. The mtDNA copy number negatively correlated with semen parameters, including sperm motility, concentration, morphology, progression, and motion characteristics (r for ?0.19 to ?0.54; P < 0.05 for all). As a surrogate marker for global DNA methylation, LINE-1 negatively correlated with sperm motility (r = ?0.25; P = 0.009). Meanwhile, after adjustment for age, length of abstinence, smoking, and alcohol intake, there was a suggested association for increased LINE-1 methylation and mtDNA copy number tertiles versus sperm motility (odd ratios were 1.0, 2.6, and 4.7, and 1.0, 2.5, and 4.9, respectively). Altered mtDNA copy number and DNA methylation may serve as genetic and epigenetic markers to assess human sperm quality together with CASA parameters

Associations between exposure to perfluoroalkyl substances and estimated glomerular filtration rate in population without kidney disease

BackgroundPerfluoroalkyl substances (PFASs) are classified as persistent organic pollutants and have been widely detected in human. Studies investigating the associations between PFASs exposure and estimated glomerular filtration rate (eGFR) yielded inconsistent results, and little is known about the effects of PFASs on eGFR in population without kidney disease. ObjectiveTo explore the associations of exposure to PFASs with eGFR and renal dysfunction in population without kidney disease. MethodsA total of 609 participants with an eGFR > 60 mL·min−1·1.73 m−2 and without renal impairment matched for sex and age (1∶1) were recruited from endocrinology department and medical examination center of two hospitals in Tianjin, China, from April 2021 to March 2022. Each subject was interviewed using a structured questionnaire to collect information about sex, age, height, weight, disease history, smoking, alcohol intake, etc. Clinical parameters were obtained from medical record, such as fasting blood glucose (FBG), creatinine (Cre), total cholesterol (TC), and triglyceride (TG). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by professionals using standard methods. The serum concentrations of PFASs were determined by liquid chromatography/mass spectrometry. Multivariable linear and logistic regression models were performed to evaluate the associations of PFASs exposure with eGFR and renal dysfunction, respectively. Subgroup analyses stratified by age and sex were also performed to assess the modified effects of covariates on the associations of PFASs exposure with eGFR. ResultsThere were 283 males, accounting for 46.5% of the total population. The mean age of the participants was (56.86±12.47) years, and the average body mass index (BMI) was (25.59±3.84) kg·m−2. Perfluoro-n-octanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluoro-n-nonanoic acid (PFNA), perfluoro-n-decanoic acid (PFDA), perfluoro-n-undecanoic acid (PFUnDA), sodium 1H, 1H, 2H, 2H-perfluoro-1-octanesulfonate (6:2 FTS), and perfluoropentane sulfonic acid (PFPeS) were positive in more than 75% of serum samples, and the corresponding median concentrations were 9.50, 1.67, 17.22, 1.86, 1.41, 0.78, 0.42, and 0.43 μg·L−1, respectively. After full adjustments of sex, age, BMI, hypertension, diabetes, TC, TG, smoking, and drinking, the linear regression models showed that log2-transformed PFHxS concentration was negatively associated with eGFR (b=−1.160, 95%CI: −2.280, −0.410). Compared with the lowest exposure tertile, the estimated change of eGFR in the highest tertile for PFHxS was significantly decreased (b=−2.471, 95%CI: −4.574, −0.368). Furthermore, compared with males, the negative association of PFHxS with eGFR was strengthened among females (female: b=−1.281, 95%CI: −2.388, −0.174; male: b=−0.781, 95%CI: −2.823, 1.261, Pinteraction=0.043). ConclusionA significant negative association between serum PFHxS and eGFR is observed in the sampled population without kidney disease, and females are more susceptible to PFASs exposure than the males

Recent advances in graphene and black phosphorus nonlinear plasmonics

Over the past decade, the plasmonics of graphene and black phosphorus (BP) were widely recognized as promising media for establishing linear and nonlinear light-matter interactions. Compared to the conventional metals, they support significant light-matter interaction of high efficiency and show undispersed optical properties. Furthermore, in contrast to the conventional metals, the plasmonic properties of graphene and BP structure can be tuned by electrical and chemical doping. In this review, a deep attention was paid toward the second- and third-order nonlinear plasmonic modes of graphene and BP. We present a theoretical framework for calculating the lifetime for surface plasmons modes of graphene and BP assisted by the coupled mode theory. The effect of the Fermi energy on the second-order and third-order nonlinear response is studied in detail. We survey the recent advances in nonlinear optics and the applications of graphene and BP-based tunable plasmonic devices such as light modulation devices, switches, biosensors, and other nonlinear photonic devices. Finally, we highlight a few representative current applications of graphene and BP to photonic and optoelectronic devices

Association of DNA Methylation and Mitochondrial DNA Copy Number with Human Semen Quality

Whether there is a relationship between quality, DNA methylation, and mitochondrial DNA (mtDNA) copy number in human-derived sperm specimens is unknown. A cohort (n = 118) of male partners of couples who were undergoing fertility assessment because of an idiopathic inability to conceive were recruited. Sperm motility parameters were determined by computer-aided sperm analysis (CASA), while sperm quality was assessed using World Health Organization criteria, mtDNA copy number was measured by real-time PCR, and DNA methylation patterns were analyzed employing high-melting resolution PCR and bisulfite sequencing PCR. The mtDNA copy number negatively correlated with semen parameters, including sperm motility, concentration, morphology, progression, and motion characteristics (r for ?0.19 to ?0.54; P < 0.05 for all). As a surrogate marker for global DNA methylation, LINE-1 negatively correlated with sperm motility (r = ?0.25; P = 0.009). Meanwhile, after adjustment for age, length of abstinence, smoking, and alcohol intake, there was a suggested association for increased LINE-1 methylation and mtDNA copy number tertiles versus sperm motility (odd ratios were 1.0, 2.6, and 4.7, and 1.0, 2.5, and 4.9, respectively). Altered mtDNA copy number and DNA methylation may serve as genetic and epigenetic markers to assess human sperm quality together with CASA parameters