Abstract
In 2002, the plasticizer 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the European market as a substitute for endocrine-disrupting phthalates. We found that in utero exposure of rats to DINCH from gestational day 14 until parturition affected reproductive organ physiology and reduced circulating testosterone levels at post-natal day 60, indicating a long-term effect on Leydig cells of the testis. Metabolically, animals exhibited randomly increased serum glucose concentrations not associated with impaired glucose utilization. Analysis of liver markers in the serum showed a hepatic effect; e.g. reduced bilirubin levels and albumin/globulin ratio. At post-natal day 200, random appearance of testicular atrophy was noted in exposed offspring, and limited changes in other reproductive parameters were observed. In conclusion, DINCH exposure appears to directly affect Leydig cell function, likely causing premature aging of the testes and impaired liver metabolic capacity. These effects might be attenuated with physiologic aging.
Highlights
Since the first use of rubber around 1600 bc to model artifacts and other objects[1], humans have manipulated natural materials and developed complex synthetic polymers[2] in order to improve their quality of life
Based on previous studies of DEHP and testicular function, expression of the following genes was analyzed[25, 26]: steroidogenic pathway genes luteinizing hormone/choriogonadotropin receptor (Lhcgr), steroidogenic acute regulatory protein (Star), translocator protein (Tspo), cytochrome P450 11a1 (Cyp11a1), Leydig cell marker platelet-derived growth factor receptor 1a (Pdgfra), Leydig/Sertoli cell marker Nestin (Nes), Sertoli cell marker Wilms tumor protein (Wt1), global testicular marker androgen receptor (Ar), thyroid receptor expressed in the testes (Thra1), urogenital tract gene insulin like 3 (Insl3), proliferation marker proliferation cell nuclear antigen (Pcna), and germ cell markers heat shock protein 90 (Hsp90) and octamer-binding transcription factor 4 (Oct4)
Legend; A-b: testis A basal level, B-b: testis B basal level, A-NT: testis A not treated, B-NT: testis B treated with human chorionic gonadotropin (hCG), C: control animals, D: DINCH-treated animals. (C) Quantitative reverse transcription–polymerase chain reaction (qRT-PCR) analysis of expression levels of genes involved in the steroidogenic pathway (Lhcgr, Star, Tspo, Cyp11a1), cell- and function-specific genes, including a Leydig cell marker (Pdgfra), a Leydig/Sertoli cell marker (Nes), a Sertoli cell marker (Wt1), a global testicular marker (Ar), a thyroid receptor expressed in the testes (Thra1), a urogenital tract marker (Insl3), a cell proliferation marker (Pcna), and germ cell markers (Hsp[90], Oct4); n = 9–13
Summary
Since the first use of rubber around 1600 bc to model artifacts and other objects[1], humans have manipulated natural materials (e.g. rubber, nitrocellulose, cellophane, casein derivates) and developed complex synthetic polymers (e.g. bakelite, polyvinyl chloride [PVC], polystyrene, acrylate polymers, polyethylene, and formica laminates to cite some)[2] in order to improve their quality of life. Water and oil are not suitable for use in modern, mass-produced plastics In plastics such as PVC, plasticizers are only dispersed into the polymer due to the lack of covalent bonds[6]; they are readily released into the environment, which can lead to human and animal exposure through ingestion[6, 8], dermal contact[8], and/or inhalation[9]. Eljezi et al recently reported that both DINCH and DEHP were cytotoxic to L929 murine cells exposed to 0.1 mg/ml of either compound for 7 days[22]
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