Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility center

Abstract

Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer, was introduced commercially in 2002 as an alternative to ortho-phthalate esters because of its favorable toxicological profile. However, the potential health effects from DINCH exposure remain largely unknown. We explored the associations between urinary concentrations of metabolites of DINCH on markers of ovarian response among women undergoing in vitro fertilization (IVF) treatments. Between 2011 and 2015, 113 women enrolled a prospective cohort study at the Massachusetts General Hospital Fertility Center and provided up to two urine samples prior to oocyte retrieval. The urinary concentrations of two DINCH metabolites, cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH) and cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), were quantified by isotope dilution tandem mass spectrometry. We used generalized linear mixed models to evaluate the association between urinary metabolite concentrations and markers of ovarian response, accounting for multiple IVF cycles per woman via random intercepts. On average, women with detectable urinary MHiNCH concentrations, as compared to those below LOD, had a lower estradiol levels (−325 pmol/l, p=0.09) and number of retrieved oocytes (−1.8, p=0.08), with a stronger association among older women. However, urinary MHiNCH concentrations were unrelated to mature oocyte yield and endometrial wall thickness. In conclusion, we found suggestive negative associations between urinary MHiNCH concentrations and peak estradiol levels and number of total oocyte yields. This is the first study evaluating the effect of DINCH exposure on human reproductive health and raises the need for further experimental and epidemiological studies to better understand the potential effects of this chemical on health.

Female exposure to endocrine disrupting chemicals and fecundity: a review

“…Similarly, as research accumulates on the adverse health consequences of exposure to specific EDCs, substitute chemicals are introduced into the market such as bisphenol S and F, for BPA, and di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH), for high molecular weight phthalates. Thus, while exposure to certain EDCs such as BPA and DEHP may be declining, exposure to many others are on the rise [25, 49] and early studies suggest they may not be safer alternatives [50, 51]. Future research should focus on incorporating the assessment of these newer chemicals into ongoing studies to assess the potential effects that these chemicals could have on human fecundity.…”

Association of Parental Preconception Exposure to Phthalates and Phthalate Substitutes With Preterm Birth

“…[23][24][25] Human exposure to phthalates is ubiquitous in the United States, Europe, and elsewhere. [26][27][28] Regulation of some phthalates has prompted the use of plasticizer replacement chemicals such as 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Substitution of phthalates with DINCH warrants further screening in human populations 29 because its metabolites are biologically active and understudied.…”

Endocrine disrupting chemical exposure and maladaptive behavior during adolescence

“…di-2-ethylhexyl phthalate (DEHP) in children's toys] have been replaced by 1,2 cyclohexane dicarboxylic acid, diisononyl ester (DINCH) (Silva et al, 2013). Little is known about the potential human health effects of DINCH exposure but recent studies have reported that a metabolite of DINCH, cyclohexane-1,2-dicarboxylic acid monoisonyl ester (MHINCH), may interfere with the endocrine system in animal models (Campioli et al, 2015), and may alter female reproductive health in ways that are similar to DEHP (Minguez-Alarcon et al, 2016).…”