Disruption of androgen receptor signaling by chlorpyrifos (CPF) and its environmental degradation products: a structural insight.

Androgen-disruptors are chemicals that interfere with the biosynthesis, metabolism or function of endogenous androgens affecting normal male reproductive development and health. Several epidemiological studies have indicated a link between exposure to androgen disrupting chemicals with reduced sperm counts and increased infertility. The actions of androgens within target cells are transduced by the androgen receptors (ARs). Chlorpyrifos (CPF), a chlorinated organophosphorus pesticide, is known to cause impairment in both male and female reproductive systems. Recent publications have shown molecular interactions of CPF and its environmental degradation products with human progesterone receptor and human estrogen receptor. Exposure to CPF causes a marked reduction in sperm counts with lowering in serum testosterone level, which suggests possible molecular interaction of CPF with AR. The investigation to reveal the possibility and the extent of binding of CPF and some of its degradation products (chlorpyrifos-oxon [CPYO], desethyl chlorpyrifos [DEC], trichloromethoxypyridine [TMP] and trichloropyridinol [TCP]) with AR using molecular docking simulation are reported. The findings of the present docking, binding energy and molecular dynamics studies reveal that CPF and its degradation products may bind to ARs and act as a potent androgen disruptor.Communicated by Ramaswamy H. Sarma.

A computational insight into the molecular interactions of chlorpyrifos and its degradation products with the human progesterone receptor leading to endocrine disruption.

Chlorpyrifos (CPF) is a widely used pesticide effective against a large number of target pests, which is used by farmers to protect food crops. Based on earlier epidemiologic reports, which indicate that CPF might interfere with the progesterone signaling pathway and can affect conception, the present study was undertaken to evaluate the binding interaction of CPF with the human progesterone receptor (hPR). Progesterone is one of the important hormones of the reproductive system and through its receptor, PR, the progesterone signaling pathway regulates important reproductive functions including reproductive cyclicity and initiation and continuation of pregnancy. The binding interactions of four major degradation products of CPF, viz. chlorpyrifos-oxon (CPYO), des-ethyl chlorpyrifos (DEC), 3,5,6-trichloro-2-methoxypyridine (TMP), 3,5,6-trichloro-2-pyridinol (TCP), were also studied to evaluate the possibility of endocrine disruption caused by these metabolites. Docking studies revealed that CPF, CPYO, and DEC were able to involve important interacting amino acid residues of the hPR during molecular interactions and are capable of competing with progesterone. Thus, CPF and its degradation products can act as potential xenoligands for the hPR and can disrupt normal progesterone signaling pathway.

Molecular interactions of chlorpyrifos and its environmental degradation products with human sex hormone-binding globulin: an in silico study.

In recent years, there has been a widespread interest and awareness about health issues posed by endocrine-disrupting chemicals present in the environment. These chemicals, often present in food and many consumer products, can interfere with hormone biosynthesis and metabolism and may result in deviation from normal homeostatic control. Chlorpyrifos (CPF), a major endocrine-disrupting chemical is used worldwide as an agricultural insecticide against a broad spectrum of insect pests in rice cultivation and to control termites. The insecticide mostly undergoes environmental degradation to chlorpyrifos-oxon (CPYO), des-ethyl chlorpyrifos (DEC), 3,5,6-trichloro-2-methoxypyridine (TMP) and 3,5,6-trichloro-2-pyridinol (TCP). Results from several epidemiological studies suggest that exposure to CPF can result in reproductive disorders, including infertility in male and female. Sex hormone-binding globulin (SHBG) is a circulatory protein that binds sex steroids and is a potential target for endocrine disruptors in the human body. The objective of the present study involved computational approaches to apprehend the mechanism of molecular interaction of CPF and its four degradation products (CPYO, DEC, TMP, TCP) with human SHBG using molecular docking simulation. All five compounds (CPF, CPYO, DEC, TMP, TCP) showed high binding affinity with SHBG; however, the binding affinity values were higher (more negative) for CPF, CPYO, DEC and TMP than for TCP indicating that CPF, CPYO, DEC and TMP formed a tight interaction with SHBG. From the results obtained with the docking analysis, it can be opined that CPF, CPYO, DEC and TMP could possibly act as potential endocrine disruptors for androgen signaling.

Analysis of Elevated Levels of Nandrolone Decanoate Induced Cytochrome- P450 Alterations in Mice.

BACKGROUND: Frequent recreational use of Anabolic Androgenic Steroids (AAS) is an instance of substance abuse which mimics the status of a natural hormone and upon prolonged exposure may lead to adverse drug reactions. These adverse drug reactions proceed in a manner so as to alter the normal metabolism of an enzyme mediated pathway such as the Cytochrome P450 (CYP) family of enzymes. OBJECTIVE: The present study was conducted to investigate the impact of overuse of Nandrolone Decanoate (ND), an AAS, upon CYP enzyme activity and a CYP gene, belonging to CYP1 family. METHODS: The study was carried out using normal and ND treated male albino mice. Genetic analysis was conducted using normalized and treated cDNA and reverse transcriptase polymerase chain reaction based assays. For enzyme assay, 0.1ml of 25 mg ND was administered to the animals twice a week for a period of 90 days. Genetic analysis was carried out with the same dose but administered for a period of 360 days. RESULTS: CYP enzyme activity increased significantly (p<0.01) in the ND treated group of animals compared to that in the normal group. However, no noticeable alteration was observed at the molecular level. CONCLUSION: From the present study it could be inferred that, at elevated doses, ND has the potential to alter hepatic CYP enzyme activity without any modification in the CYP gene. This could be due to a possible adaptive response of the living system to such drugs.

Effect of Administration of Nandrolone Decanoate upon Aldosterone Concentration and Serum Na+/K+ Levels in Albino Mice.

BACKGROUND: This article is a study of adverse effects associated with the abuse of recreational drugs such as anabolic androgenic steroids. Nandrolone decanoate is one such drug often abused by athletes and bodybuilders seeking enhanced physical strength or appearance. The use of such steroids has increased dramatically over the years. OBJECTIVE: The present study was conducted to investigate the impact of nandrolone decanoate when consumed at an abused dose, upon serum aldosterone concentration in albino mice. Sodium and potassium ion concentrations were also monitored with the same experimental dosage. METHOD: 0.1ml of 25 mg Nandrolone decanoate was administered to the animals twice a week for a period of 90 days. Blood samples for obtaining the serum from both normal and treated group of animals were collected at an interval of 15 days upto the 90th day. RESULT: The present investigation revealed a significant increase (p<0.01) in the serum aldosterone and sodium ion concentrations in the treated group of animals compared to that in the normal group. Potassium ion concentration in the treated group did not exhibit a significant alteration when compared with the untreated animals. CONCLUSION: From the above observation, nandrolone decanoate abuse could be suggested as one of the causes of aldosterone and electrolyte imbalance in the body that could possibly be a serious risk factor for cardiovascular related disorders.

Controlled release of tamoxifen citrate encapsulated in cross-linked guar gum nanoparticles.

Natural polysaccharides, due to their outstanding merits, have received more and more attention in the field of drug delivery. In the present study tamoxifen citrate, TMX (a non-steroidal antiestrogenic drug) loaded guar gum nanoparticles, GG NPs, crosslinked with glutaraldehyde were prepared for treatment of breast cancer. An oil in water (o/w) emulsion polymer cross-linking method was employed for preparation of blank and drug loaded sustained release nature biodegradable nanoparticles. Prepared nanoparticles were characterized by morphology in scanning electron microscope (SEM), size distribution in transmission electron microscope (TEM), TMX loading by high performance liquid chromatography (HPLC) and in vitro drug release characteristics. An overall sustained release of the drug from the biodegradable nanoparticles was observed in in vitro release studies. The release of TMX from GG NPs was found to be effected by guar gum and glutaraldehyde concentration. Regression coefficient (R(2)) analysis suggested that the predominant mechanism behind the drug release from the nanoparticles was time dependent release and diffusion. In vivo studies on female albino mice demonstrated maximum uptake of the drug by mammary tissue after 24h of administration with drug loaded guar gum nanoparticles in comparison with that with the tablet form of the drug. These findings demonstrate that controlled release of TMX from GG NPs could be a potential alternative pharmaceutical formulation in passive targeting of TMX in breast cancer treatments.

Nandrolone decanoate enhances the activities of cholanthrene induced glutathione-s-transferase in liver tissue of albino mice.

A concrete study is still fragmentary to correlate the effect of Nandrolone decanoate, a anabolic steroid, on the cholanthrene induced Glutathione-s-transferases (GST) activities in liver tissues. Administration of Nandrolone and 3-Methylcholanthrene in alone and combination is found to increase the activity of hepatic GST activity significantly (p< 0.01) suggesting Nandrolone as a potent inducer of GST activity.

Effect of Mimosa pudica root extract on vaginal estrous and serum hormones for screening of antifertility activity in albino mice.

BACKGROUND: Several plants are traditionally used as birth control agents by the rural people in India. Mimosa pudica is one of the folk medicinal plants commonly used as antifertility agent in some places in India. The present work was carried out to evaluate the claimed antifertility effect of the plant by carrying out pharmacological studies with the root extract of the plant. STUDY DESIGN: Air-dried roots of M. pudica were extracted using methanol. Dried methanol extract of the root was administered orally to Swiss albino mice for 21 consecutive days. Estrous cycle, reproductive hormones (LH, FSH, prolactin, estradiol and progesterone) and number of litters produced were studied in both control and extract-administered groups by using standard methods. Phytochemical studies of the methanolic root extract were carried out using qualitative and thin-layer chromatography methods. RESULTS: M. pudica root extract, when administered orally at a dose of 300 mg/kg body weight/day, prolonged the length of the estrous cycle with significant increase in the duration of the diestrous phase and reduced the number of litters in albino mice. The number of litters was increased in the posttreatment period. The analysis of the principal hormones (LH, FSH, prolactin, estradiol and progesterone) involved in the regulation of the estrous cycle showed that the root extract altered gonadotropin release and estradiol secretion. CONCLUSIONS: The root extract of M. pudica has antifertility effect as it prolongs the estrous cycle and disturbs the secretion of gonadotropin hormones in albino mice. The decrease in FSH level in the proestrus and estrus stages in the extract-administered group compared with those of control animals indicates the disturbance of estrous cycle and ovulation through suppression of FSH.

Antifertility activity of the methanolic leaf extract of Cissampelos pareira in female albino mice.

meenakshi Cissampelos pareira Linn. is one of the folk medicinal plants commonly used as antifertility agent in some places of India. The aim of the present study was to evaluate the validity of the antifertility effect of the leaf extract. Cissampelos pareira leaf extract, when administered orally, altered the estrous cycle pattern in female mice, prolonged the length of estrous cycle with significant increase in the duration of diestrus stage and reduced significantly the number of litters in albino mice. The analysis of the principal hormones involved in estrous cycle regulation showed that the plant extract altered gonadotropin release (LH, FSH and prolactin) and estradiol secretion. The results indicated the antifertility effect of Cissampelos pareira leaf extract in female albino mice. The oral LD50 of the extract was found to be 7.3 g/kg in mice.