"4 haplotypespecifc methylation in the FTO type 2 diabetes and obesity susceptibility locus, PLaS One’ 14040, 58. Bell, CG, Teschondorfl, AE., Rakyan, VK., Maxell, AP, Beck S,, and Savage, D.A. (2010), Genome-wide DNA methylation alysis for diabetic nephropathy in type 1 diabetes mellitus, BMC Med Genomics3,33, 59, Gu, , Pahammar, 1, Ga, 1, and Brismar, K. 2014). Epigenetic analyses ofthe insulr-fke growth factor binding poten | gene in ype | diabetes and diabesic nephropathy. Clin Epigenctics 610 60. Yang, XH. Cao, RP, Yu, ¥, Sui, M, Zhang, Xo, 3¥,and Wang XM. (2016). study on the correlation between MTHFR promoter ‘methylation andabeticnephropathy. Am) Transl Res, 4960-4967 61. Zhang, H, Cal, X. Yi, B., Huang, Wang, J, and Sun, J. (2014). Corelation of CTGF gene promoter methylation with CTGF expression in type 2dietes melts with or without nephropathy MolMedRep9, 2138-2144, 62, Fhnoyan, G., Lameive, N, Barsoum, R, Eckardt, KU. Levin, A. Levin, N, Local, , MacLeod, A. Vasholder, Walker Real (2008), The burden of kidney disease: rmproving global outcomes. Kidney In 65, 1310-1314 63. Por, FK., and Finoyan, G. (2004). The Dialysis Ouicomes and Practice Patterns Study (DOPPS) ad the Kidney Disease Outcomes Quality Intstive (K/DOQD: a cooperative inibative to improve ‘outcomes for hemodialysis patents worlwide, Am J Kidney Dis 44, 156 (4, Zak, A and Bonvonte JV. (2019). Recent advances in acute kidney injury and it consequences and impact an ebrone kidney disease Curr Opia Nephrol Hypertens 28, 397-405 65. Canaud, G, Brooks, CR, Kish, S, Taguchi, K, Nishimura, K Magassa, Sy Seoth A. Heino, LL, Ichimura, Ty Tez, Fy etal (2019) Cyclin GI and TASCC regulate kidney epithelial cll G2-M crest and boc maladaptverepsit So Teal Med 1 6. Zeisberg, M., and Kalli, R. (2008). Fibroblasts emerge via cpithelismessachymal transition in chronic kidney fibrosis, Fron Bros 13, 5991-599, 67. Zeisherg, EM, Potnta, SE, Sugimoto, H., Zeisbens, My and Kall, R. (2008), Fibroblasts in kidney fibrosis emerge via enadothslilto-mesenehymal snsiton J Am Soe Nephrol 19,2282 Der, (8. Zeisberg, M. Shab, A.A., and Kall, R (2005) Bone morphogenic protein? induces mesenchymal to epithelial rasiion in dul renal ‘broblats and acta egencration of injured kidney. JBol Chom 280, x088-8100 ENVIRONMENTAL 7 POLLUTANTS, CONNEXIN 43, STRA8 AND TESMIN AT THE CROSSROAD BETWEEN FERTILITY AND INFERTILITY J Raj Kumar Koiri'* and Aditi Mehrotra’ Department of Zaology Dr HarisinghGour Vishwavidyalaya, Sagar Madhya Pradesh ‘Department of Zoology, Banaras Hindu University ‘Varanasi, Uttar Pradesh E-mail: rkkolri@gmall.com Introduction Inmale,testes are one of the most susceptible organs towards stress induced by heat and agents of environmental pollution. The use of agents causing environmental ‘Translational Research in Roproductive Health pollution has increased considerably during the last few decades due to increase in agricultural and industrial activities [1]. In recent times there has been decline in male infertility with decreased sperm count, Notably exposure to environmental toxicants like cadmium, bisphenol A has bbeen the chief contributors. Further these environmental pollutants have been detected in food, drinking water and dairy products [2,3]. Just to revive the memory down the lane, environmental hazards to male reproductive funetion wwas discussed as early as more than 30 years ago, where contact with the nematocide 1,2-dibromo-3-chloropropanc (BCP), to workers in manufacturing plant and agricultural field resulted in severe impaired spermatogenesis resulting in infertility [4,5]. Since then a large number of pesticides and solvents has been reported as male reproductive toxicants [6] and the adverse effects include reduced sperm production, production of defective spermatozoa and abnormal level of androgen production. Non-invasive techniques which have been routinely used to assess male infertility involve assessment of reproductive hormones in blood, semen analysis and previous success rate in impregnatinga female partner. ‘Cyanotoxin Microeystin-LR Induced Infertility Apart from the above factors in recent times contamination of water bodies with cyanotoxins has assumed a great significance with respect to male infertility. Cyanobacteria have been reported throughout the world from fresh, brackish as well as marine water bodies with many species producing eyanotoxins. Among these, microcystins have received increasing worldwide concem due to their toxic effect especially on reproductive organs including tests [7- 9].Structure of microcystins have revealed that they are monocyclic heptapeptides composed of D-alanine at position 1, two variable L- amino acids at positions 2 and 4, ‘linked D-glutamic acid at position 6, and 3 unusual amino acids: b-linked D-erythro-b-methylaspartic acid (MeAsp) at position 3;(2S,38,88,9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyldeca-4,6-dienoic acid (Adda) at position 5; and N-methyl dehydroalanine (MDha) at position 7. So far in contaminated water bodies more than 90 microcystin isoforms have been reported with microcystin- leucine arginine (MC-LR) being the most abundant and toxic [7, 10]. MC-LR toxic potential is due to the fact that they can bioaccumulate in aquatic animals [11-13] and transferred along the food web to high trophic levels, including human beings via consumption of aquatic animals [11]. A quick survey of water bodies as the primary source of| drinking water has revealed that more and more water bodies are heavily contaminated with MC-LR pollution [14,15]. An important point to note about MC-LR is that it «gets concentrated by boiling and is also resistant to chemical hydrolysis or oxidation at near-neutral pH and is table even at very high temperature up to 300°C in laboratoryISSRF Newelatter © Issue 24 & September, 2019 conditions [7,16-19]. Both chronic and acute exposure of (MC-LR on the male reproductive system has shown to exert, toxic effect by inducing apoptosis in spermatogonia, leydig, cells, sertoli cells and also by adversely affecting the sperm ‘motility, morphology and hormone level [7] Status of Transporters and Blood Testis Barrier during Environmental Pollutant Induced Testicular Toxicity ‘Among the environmental pollutants testicular toxicity by heavy metals has been ably documented but the mechenism is still not fully delineated but their permeation through blood testis barrier (BTB) has been suggested as one of the fundamental mechanisms[20].BTB has been suggested to be crucial for spermatogenesis and fertility. Induction of high level of reactive oxygen species has been noted with redox heavy metal uptake, which in tum can cause DNA damage and induce apoptosis of spermatozoa vis-ievis, disruption of the BTB thereby impairing spermatogenesis [21]. Among heavy metals cadmium (Cé) has been «extensively studied and reported to induce testicular toxicity thereby impairing spermatogenesis, semen quality and endocrine function via severe damage to the structure of testis vascular endothelium resulting in testicular necrosis, impaired spermatogenesis and by compromising BIB integrity leads to the development of autoimmunity against ‘germ cells. Inflammation has also been noted inside tests, due to the modulation of calcium and cyclic AMP signaling pathways, inflammation mediators and provanti apoptotic factors. Direct disturbance of the hypothalamus-pituitary- gonadal axis has also been noted (22].Cadmium has been ‘observed to disrupt barrier function via the reduetion in the levels of tight jmction/J (e.g., occludin, zomula occludens+ 1) and basal ES (eg, N-cadherin, f-catenin) proteins, thereby resulting in the loss of germ cell loss from the seminiferous epithelium[23]. Further, CaCI2 was reported to disrupt interactions between the residual proteins present atthe BTB [e.g occludin/zonula occludens-1 (Z0-1)/focal adhesion kinase (FAK) and N-cadherin/f-catenin), which can further destabilized barvier function [24,25 Xenoestrogen bisphenol A (4,4" isopropylidenediphenol) with short half-life of <6 h is one of the world’s major environmental pollutant predominantly used in the ‘manufacture of polycarbonate plastics, epoxy resins which is used to line food and beverage cans, flame retardants, dental scalants and composites, coating of water pipe walls and compact dises. It has been reported to have anti- androgenic activity [26] and disrupt the BTB [27] Prolonged disruption of the BTB by environmental toxicants has been suggested to cause infertility or subfertlty [28,29]. Incase of cyanotoxin induced testicular toxicity, rganie anion transporting polypeptide superfamily (Oatps) transporters esp. five kind of Oatp subunits (Oatp1a5, -3al, -6b1, -6el and -641) have been suggested for the uptake of MC-LR into testis and their expression has ‘been noted in spermatogonia [30-32]. MC-LR has also been ‘observed to induce apoptosis in testis by covalently binding with protein phosphatases! and 2A (PP1/2A) and ‘modulating intracellular biochemical reactions [33,34] Further MC-LR has been reported to pass the blood testis, barrier and induce testicular damage as evidenced by blebbing of cell membrane, shrinkage of eytoplasm and swelling of mitochondria with deformed nucleus in rodent ‘animal models when treated with 10 ygikg b.w. of MC-LR, G5) Genetic Polymorphism as a Causative Factor for Male Infertility Certain genetic polymorphisms have been accounted responsible for increased susceptibility to some forms of ‘ale infertility. Polymorphicgenes that have been suggested to be associated with the human azoospermic populations are MEI, PRDM9 (MEISETZ), PARP-2, SPATAI7 and UBR2 causing azoospermia by meiotic arrest [36-40]. In addition to these some other genes are polymorphism of SEPTINI2, MTHFR, SHBG, Piwi, CYPI9A1, NER, GSTM1, BCL2, ESRI, ESR2, eNOS, TNP1, SOHLHI, EPPIN, GSTTI, TSSK6, TSSK2, MDR1, MSHS, MLH3, HOBFWT, PACRG, and FASLG. In addition to these environmental conditions have been suggested an important factor influencing genetic polymorphisms in human spermatogenesis [41], Connexin 43, Meiosis, Stra8 and Tesmin at the Interface of Testicular Toxicity and Infertility Connexin 43 (Cx43) which is one of the predominant connexin in testis is considered essential for spermatogenesis. Recent evidence suggests that ‘environmental toxicants ean alter testicular eonnexin 43 by ‘causing dysregulation of signaling pathways controlling its function. In fetal and nconatal testis expression of Cx43 is necessary during spermatogenesis and male fertility. Its impairment during critical period of development results in impaired germ cell survival and differentiation resulting in, infertility [42,43].Exposure to pollutants during these critical periods will result in a multitude of reproductive problem associated with reduced sperm counts, ‘ryptorchidism, hypospadias and testicular cancer and such type of impaired germ cell development has been classified as “testicular dysgenesis syndrome” [44]. This has been ably supported by similar results when laboratory animals were exposed to testicular toxicants and interestingly perinatal ‘exposure to pollutants altered the fertility of Fl as well as subsequent F2 and F3 generations [45,46]. Effect of environmental toxicants on male testicular funetion has been suggested to be mediated through Cx43 alteration and may occur at the level of hypothalamus/pituitary, thyroid and testis. In response to environmental and testicular toxicants like toxins, xenoestrogens, pesticides, herbicides"4 and heavy metals, expression of both gap junctions and (Cx43 has been observed to be altered, particularly during perinatal development; junctional proteins of sertli cells like adhesion, gap and tightjunctions has been reported tobe sensitive targets getting perturbed on exposure to BPA [4748], Decline in testicular expression of Cxd3 associated With germ cell sloughing andinfrility was reported during postnatal toxicant exposure via lactation and treatment of prepubertal animals [49]. Similarly, neonatal exposure to flutamide adversely affected spermatogenesis through alteration of Cx43 gap junction and also by causing permanent impairment of bath sertoli and leydig cell functions [49]. In eukaryotic cell division cycle meiosis, I isvery complex and failure to execute it properly may result in meiotic defects wich in tum can cause infertility and birth defects. Further these processes are differentially regulated in male spermatocytes and female oocytes and require tightly coordinated gene expression, Stra has been recognized asa promoter gene in the meiosis Sta8(Stimulated by retinoic acid gene 8) is a vertebrate-specific gene encoding cytoplasmic protein andits expressions induced by retinoic acid [50-55]. It has been reported to express postnatally in the mitotically active cells of spermatogonia and in preleptotene spermatocytes before meiotic prophase [54,56]. Sperm production has been reported to be hampered in male mice lacking Sta8; as apoptosis was observed in tajority of spermatogenie cells during the developmental, stage in which during normal condition should have progressed through meiotic prophase [57]. Stra8function has been reported to be a prerequisite for transition of spermatogenic cells from preleptotene to leptotene, and thereby helping to enter meiotic prophase BPA has been reported to detegulat the expresion of Stra8 gene that has been reported to be involved in important steps of premeiotic and first meiotic prophase [58]. Sra8 which is one ofthe most deregulated genes by BPA act as a positive regulator‘ the committed steps of spermatocytes tomeiosis and progression throughthe earl sages of meiotic prophase (59) Tesmin is a testis-specfic metallothionein-like, 30-kDa protein (tesmin-30) and is a member of CXC-hinge-CXC family, which has been reported fo be encoded by four mouse tesmin eDNAs [60]. However, after an immanoprecipitation reaction, it was revealed that tesmin- 30 is not full-length but is part of the C-terminal half of tesmin-60, During spermatogenesis it exhibits dynamic subcellular localization; before meiosis iis localized in the cyctoplasm of early to late spermatocytes but just before meiotic division, translocated into the nucleus [61]. However, after meiosis it has been observed in acrosomal vesicle of the spermatids and moves to the nuclear membrane and finally to the caudal end as spermatids ‘Translational Research in Roproductive Health elongate and next relocating into the cytoplasm [61]. Interestingly oxidative stress induced by cobalt chloride and diethylmaleate was observed to induce premature ‘translocation of tesmin from the cytoplasm to the nucleus ‘and induced apoptotic signals in spermatocytes, thereby suggesting the involvement of tesmin in multiple stages of spermatogenesis and spermiogenesis and also possibly