[One patient with severe phenol burn complicated with acute poisoning].

On April 26, 2018, a 55-year-old male patient with severe phenol burn complicated with acute poisoning was admitted to the Second Affiliated Hospital of Zhejiang University School of Medicine. The patient quickly developed the symptoms of central nervous system including blurred consciousness and restlessness, anuria, and respiratory failure. After self-rescue before admission and a series of measures in hospital including wound decontamination to reduce phenol absorption, rapid massive infusion and hemodialysis+ hemoperfusion, continuous renal replacement therapy for speeding up phenol excretion and organ function maintenance, the poisoning symptoms were effectively alleviated, and the patient was finally rescued successfully and discharged on post injury day 29. This case suggests that early hemodialysis combined with hemoperfusion and continuous renal replacement therapy are effective methods for treating severe phenol burn complicated with acute poisoning.

Role of Antioxidants in Alleviating Bisphenol A Toxicity.

Bisphenol A (BPA) is an oestrogenic endocrine disruptor widely used in the production of certain plastics, e.g., polycarbonate, hard and clear plastics, and epoxy resins that act as protective coating for food and beverage cans. Human exposure to this chemical is thought to be ubiquitous. BPA alters endocrine function, thereby causing many diseases in human and animals. In the last few decades, studies exploring the mechanism of BPA activity revealed a direct link between BPA-induced oxidative stress and disease pathogenesis. Antioxidants, reducing agents that prevent cellular oxidation reactions, can protect BPA toxicity. Although the important role of antioxidants in minimizing BPA stress has been demonstrated in many studies, a clear consensus on the associated mechanisms is needed, as well as the directives on their efficacy and safety. Herein, considering the distinct biochemical properties of BPA and antioxidants, we provide a framework for understanding how antioxidants alleviate BPA-associated stress. We summarize the current knowledge on the biological function of enzymatic and non-enzymatic antioxidants, and discuss their practical potential as BPA-detoxifying agents.

Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine.

Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine-5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns.

Bisphenol A: an emerging threat to female fertility.

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

The Use and Misuse of Historical Controls in Regulatory Toxicology: Lessons from the CLARITY-BPA Study.

For many endocrine-disrupting chemicals (EDCs) including Bisphenol A (BPA), animal studies show that environmentally relevant exposures cause harm; human studies are consistent with these findings. Yet, regulatory agencies charged with protecting public health continue to conclude that human exposures to these EDCs pose no risk. One reason for the disconnect between the scientific consensus on EDCs in the endocrinology community and the failure to act in the regulatory community is the dependence of the latter on so-called "guideline studies" to evaluate hazards, and the inability to incorporate independent scientific studies in risk assessment. The Consortium Linking Academic and Regulatory Insights on Toxicity (CLARITY) study was intended to bridge this gap, combining a "guideline" study with independent hypothesis-driven studies designed to be more appropriate to evaluate EDCs. Here we examined an aspect of "guideline" studies, the use of so-called "historical controls," which are essentially control data borrowed from prior studies to aid in the interpretation of current findings. The US Food and Drug Administration authors used historical controls to question the plausibility of statistically significant BPA-related effects in the CLARITY study. We examined the use of historical controls on 5 outcomes in the CLARITY "guideline" study: mammary neoplasms, pituitary neoplasms, kidney nephropathy, prostate inflammation and adenomas, and body weight. Using US Food and Drug Administration-proposed historical control data, our evaluation revealed that endpoints used in "guideline" studies are not as reproducible as previously held. Combined with other data comparing the effects of ethinyl estradiol in 2 "guideline" studies including CLARITY-BPA, we conclude that near-exclusive reliance on "guideline" studies can result in scientifically invalid conclusions.

"Bisphenol a: an emerging threat to male fertility".

BACKGROUND: Among the factors causing male infertility, one of the most debated is the exposure to environmental contaminants. Recently, the chemical compound Bisphenol A (BPA) has drawn attention from the reproductive science community, due to its ubiquitous presence in day-to-day life. Its toxic action appears to mainly affect the male reproductive system, directly impacting male fertility. MAIN: The purpose of this review is to investigate current research data on BPA, providing an overview of the findings obtained from studies in animal and human models, as well as on its supposed mechanisms of action. CONCLUSION: A clear understanding of BPA action mechanisms, as well as the presumed risks deriving from its exposure, is becoming crucial to preserve male fertility. The development and validation of methodologies to detect BPA toxic effects on reproductive organs can provide greater awareness of the potential threat that this chemical represents.

Recovery From a Myocardial Infarction Is Impaired in Male C57bl/6 N Mice Acutely Exposed to the Bisphenols and Phthalates That Escape From Medical Devices Used in Cardiac Surgery.

Bisphenols and phthalates leach from medical devices, and this exposure is likely to increase in postcardiac surgery patients. Previous studies suggest that such chemical exposure may impact recovery and wound healing, yet the direct effects of bisphenols and phthalates are unknown in this context. To study the direct effect of clinically based chemical exposures, we measured the metabolites representative of 6 bisphenols and 10 phthalates in men before and after cardiac surgery and then replicated this exposure in a mouse model of cardiac surgery and assessed survival, cardiac function and inflammation. Bisphenol A (BPA), di-ethyl hexyl phthalate (DEHP), butylbenzyl phthalate, di-isodecyl phthalate, and di-n-butyl phthalate metabolites were increased after surgery. DEHP exposure predominated, was positively correlated with duration on the cardiopulmonary bypass machine and exceeded its tolerable daily intake limit by 37-fold. In vivo, C57bl/6 N male mice treated with BPA+phthalates during recovery from surgery-induced myocardial infarction had reduced survival, greater cardiac dilation, reduced cardiac function and increased infiltration of neutrophils, monocytes and macrophages suggesting impaired recovery. Of interest, genetic ablation or estrogen receptor beta (ERß) antagonism did not improve recovery and replacement of DEHP with tri-octyl trimellitate or removal of BPA from the mixture did not ameliorate these effects. To examine the direct effects on inflammation, treatment of human THP-1 macrophages with BPA and phthalates induced a dysfunctional proinflammatory macrophage phenotype with increased expression of M1-type macrophage polarization markers and MMP9 secretion, yet reduced phagocytic activity. These results suggest that chemicals escape from medical devices and may impair patient recovery.

Steroidal and phenolic endocrine disrupting chemicals (EDCs) in surface water of Bahe River, China: Distribution, bioaccumulation, risk assessment and estrogenic effect on Hemiculter leucisculus.

This study investigated selected steroidal and phenolic endocrine disrupting compounds (EDCs) in the surface water of the Bahe River (China) using gas chromatography mass spectrometry (GC-MS). Their effect on the wild sharpbelly Hemiculter leucisculus was investigated. The concentrations of 4-t-octylphenol, nonylphenol, bisphenol-A, estrone, 17 ß-estradiol, 17 α-Ethinylestradiol, and estriol were up to 126.0, 634.8, 1573.1, 55.9, 23.9, 31.5, and 5.2 ng L-1 in the surface water, and up to 26.4, 103.5, 146.9, 14.2, 9.3, 13.8, and 1.3 ng g-1 in the fish muscle tissue, respectively. High estrogen equivalent levels and hazard quotients were found in the middle and lower reaches of the river, and the pollution in these regions caused enhanced growth conditions, inhibition of gonad growth, and suppression of spermatogenesis in H. leucisculus. The up-regulation of Vitellogenin mRNA expression in male fish, collected from relatively heavily EDCs contaminated areas, indicates a potential estrogenic effect. The differential expression profiles of genes related to steroidogenesis at all sampling sites suggests that these endpoints may play an important role for the pollution monitoring of estrogenic EDCs in the Bahe River.

Human cholestatic hepatitis owing to polyoxyethylene nonylphenol ingestion: A case report.

RATIONALE: The purpose of this study was to identify the chemical responsible for cholestatic hepatitis in a 55-year-old woman who ingested 1,1'-iminodi (octamethylene) diguanidinium triacetate (iminoctadine triacetate), a fungicide. The fungicide formulation was also composed of polyoxyethylene nonylphenol (NP-40) and methanol. PATIENT CONCERNS: Severe cholestatic hepatitis developed, which led to the patient's death on day 88 of hospitalization. Post-mortem necropsy of the liver showed focal hepatocyte necrosis involving mostly the mid-zone, along with intracytoplasmic and intracanalicular cholestasis. DIAGNOSES: To identify the chemical responsible for hepatic injury, the cellular toxicity of all chemicals in the fungicide formulation was assessed in HepG2 cells using the 3-(4,5-dimethylthiaxol-2yl)-2, 5-diphenyl tetrazolium bromide test. OUTCOMES: Viability of cells treated with the surfactant NP-40 was significantly lower (P < .001), but that of cells treated with other components of the fungicide, including the active ingredient, iminoctadine triacetate, was unaffected. Fluorescence-activated cell sorting analysis confirmed that necrosis was induced in HepG2 cells treated with 25-80 µM of NP-40, while significant numbers of apoptotic cells were not detected. LESSONS: NP-40 appears to be the chemical responsible for the patient's irreversible hepatic injury, accompanied by intracytoplasmic and intracanalicular cholestasis.

A tapentadol related fatality: Case report with postmortem concentrations.

Tapentadol (TAP) is an analgesic agent indicated for the management of different types of pain. It has a novel mechanism of action in that it induces analgesia via both µ-opioid receptor agonism and norepinephrine reuptake inhibition. Although deaths associated with TAP use have been reported, there is a paucity of published literature regarding TAP concentrations in biological samples obtained from TAP-associated fatalities. We report a case of TAP toxicity resulting in death with postmortem peripheral and central blood concentrations, liver, vitreous, urine, and gastric contents. A 41-year-old female was found slumped over a sink at home following a welfare check by police. She was transported to a local hospital where she was pronounced dead despite all resuscitative measures. The autopsy was remarkable only for pulmonary edema and signs of aspiration pneumonia. Postmortem concentrations of TAP were confirmed in peripheral blood at 1.1mg/L, central blood 1.3mg/L, liver 9.9mg/kg, vitreous humor 0.94mg/L, urine 88mg/L, and the gastric contained 2mg. Also of note, oxycodone was found in the decedent's blood at a concentration of 0.58mg/L. We report a death related to an intentional ingestion of TAP and oxycodone-the cause and manner of death were determined to be mixed drug intoxication; suicide. We hope that the variety of TAP concentrations identified in this case provide valuable points of reference for future cases of TAP intoxication.

Bisphenol A and congenital developmental defects in humans.

Over 50% of the causes of fetal malformations in humans are still unknown. Recent evidence suggests the relationship between environmental exposure to endocrine disruptors and fetal malformations. Our study aims to establish the role of Bisphenol A (BPA), if any, in altering human reproduction. We enrolled 151 pregnant women who were divided into two groups: case group (CS, n=101), women with established diagnosis of developmental defect, and control group (CL, n=50), pregnant women with normally developed fetus. Total, free and conjugated BPA were measured in their blood using GC-MS with isotopic dilution. The results show a correlation between environmental exposure to BPA and the genesis of fetal malformations. Conjugated BPA, which was higher in the CL, casts light on the hypothesis that a reduced ability to metabolize the chemical in the mother can concur to the occurrence of malformation. In a more detailed manner, in case of chromosomal malformations, the average value of free BPA appears to be nearly three times greater than that of the controls. Similarly, in case of central and peripheral nervous system non-chromosomal malformations, the value of free BPA is nearly two times greater than that of the controls.

Tapentadol toxicity in children.

BACKGROUND: Tapentadol (Nucynta) is indicated for the treatment of moderate to severe pain in adults. Tapentadol's mechanism of action consists of acting as an agonist on the µ-opioid receptor and by inhibiting the reuptake of norepinephrine. There are no published reports on the toxicity of tapentadol in pediatric patients. The goals of this study are to describe the incidence, medical outcomes, clinical effects, and treatment secondary to tapentadol exposure. METHODS: This retrospective observational study used data from the National Poison Data System. Inclusion criteria were exposure to tapentadol from November 1, 2008 to December 31, 2013; age 0 to 17 years; single ingestion; and followed to a known outcome. RESULTS: There were 104 patients who met the inclusion criteria. Eighty patients were aged ≤ 6, 2-year-olds the most common age group (60.6%). There were 52 male and 52 female patients. Of the 104 patients, 93 had unintentional exposures. No deaths were reported. Sixty-two of the patients had no effect, 34 had minor effects, 6 had moderate and 2 had major effects. Thirty patients reported drowsiness and lethargy. Other effects reported included nausea, vomiting, miosis, tachycardia, respiratory depression, dizziness/vertigo, coma, dyspnea, pallor, vomiting, edema, hives/welts, slurred speech, pruritus, and hallucinations/delusions. Fifty-three patients were reported to have no medical intervention. CONCLUSIONS: This is the first study examining the toxic effects of tapentadol in a pediatric population. Although a majority of the patients in this review developed no effect from their exposure, two had life-threatening events. The most common effects reported were opioidlike.

Phenol Toxicity Following Cutaneous Exposure to Creolin®: A Case Report.

INTRODUCTION: Phenol is a caustic that may cause cutaneous or gastrointestinal burns depending on the route of exposure. Significant absorption may result in systemic toxicity. We present a case of topical phenol exposure resulting in cutaneous burns and systemic phenol toxicity. CASE REPORT: A 9-year-old girl was exposed to Creolin(®), a general-purpose disinfectant containing phenol, when her mother applied this product to her head and upper torso. The patient required endotracheal intubation due to depressed mental status; she had cutaneous erythema in the distribution of contact with the cleanser. An initial EKG revealed sinus tachycardia with brief runs of monomorphic ventricular tachycardia. On hospital day (HD) 1, the area of erythema extended to both upper extremities and hyperpigmentation developed over the affected areas, which continued to darken during the hospital course. The patient was extubated late on HD 1. On HD 2, the patient's urine was noted to be a dark green color that resolved later that day. On HD 3, areas of desquamation and decreased sensation developed in skin areas of maximal contact with the cleanser. The patient developed a mild transaminitis with peak AST and ALT levels of 84 units/l and 99 units/l, respectively. The patient was discharged to home on HD 4. DISCUSSION: Our patient presented with signs of cutaneous and systemic phenol toxicity characterized by dermal burns, depressed mental status, cardiac dysrhythmias, and elevated hepatic transaminases. Phenol exposure may cause systemic toxicity following limited dermal exposure.

Case report of a fatal intoxication by Nucynta.

Tapentadol (Nucynta) is a centrally acting opioid analgesic prescribed for the treatment of moderate to severe acute pain. Its efficacy is believed to be due to µ-opioid receptor agonist activity and inhibition of norepinephrine reuptake resulting in increased norepinephrine concentrations. There is only one other case in the literature relating to the toxicity of this agent or report of a fatality. This case report documents a case in which tapentadol was identified as the cause of death. The tapentadol concentration found in the heart blood submitted in this case was more than 20 times the upper limit of the therapeutic range. Possible mechanisms of death include respiratory depression, central nervous system depression, and serotonin syndrome. Based on the scene investigation and autopsy findings in this case, the medical examiner determined that the cause of death was narcotic (Nucynta) intoxication and the manner of death was undetermined.

Machine learning-based detection of chemical risk.

Chemical risk appears with chemical substances that are dangerous for human or animal health, or for environment, such as with Bisphenol A and phtalates. Chemical risk causes several severe health disorders and is particularly dangerous for human health. Specific agencies are involved in the verification of the suitability of products and goods to be marketed. For this, a large amount of scientific and institutional literature is manually analyzed to study the current knowledge on the associated chemical risk. We propose to use machine learning and dedicated classification for the automatic detection of chemical risk statements. We test several algorithms and features and obtain between 0.60 and 0.95 F-measure.

The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes.

Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.

Bisphenol A (BPA) and its potential role in the pathogenesis of the polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is the most common and the most heterogeneous endocrine disorder in premenopausal women. Apart from signs of hyperandrogenism such as acne, hirsutism and hair loss, women with PCOS usually present with menstrual irregularities and fertility problems.Additionally, they are often characterized by impaired glucose tolerance, which usually leads to the development of type 2 diabetes mellitus (T2DM). This review article describes current and novel approach to the pathomechanisms of PCOS and the potential role of an endocrine disrupting chemical ("endocrine disruptor" - ED) - bisphenol A (BPA), which is commonly used as a plasticizer and due to its molecular structure can interact with estrogen receptors (ERs). Recent observations point to the higher levels of BPA in biological fluids of women with PCOS and its role in the pathogenesis of hyperandrogenism and hyperinsulinemia. It seems that mother's exposure to BPA during pregnancy may also lead to the development of PCOS in the female offspring.

Neurotoxic effects of nonylphenol: a review.

Nonylphenol (NP), identified as an environmental endocrine disruptor, used as important raw materials for detergents, emulsifiers, and wetting agents in industry and is also found in paints, pesticides, and household toiletries. NP has been reported to have deleterious effects on central nervous system (CNS) other than reproductive and immune systems including disrupting neuroendocrine homeostasis, altering cognitive function, and neurotoxicity of tissues, etc., particularly when NP's disruption occurs during critical developmental window of brain. This review will discuss the evidence for environmental endocrine disruption of NP and the sequelae on endocrine, reproductive and nerve functions, as well as causal relationships between endocrine disruption and cognitive behavior effects.

Death due to apparent intravenous injection of tapentadol.

This case report describes a 34-year-old male who died as the result of tapentadol toxicity. This case apparently represents the first reported description of a death because of this drug. The toxicologic features of this case, namely concentrations of tapentadol in the femoral blood and heart blood, 1.05 and 3.20 mg/L, respectively, may assist other individuals in evaluating deaths where tapentadol concentration is a factor. Analysis of the blood based upon enzyme-linked immunosorbent assays, liquid chromatography-mass spectrometry, and gas chromatography-mass spectrometry revealed no other substance of significance, only nicotine and cotinine, and the autopsy findings were consistent with an opiate-type drug overdose, and indicated no competing cause of death.