Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice

Abstract

Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant.

Environmentally-relevant exposure to diethylhexyl phthalate (DEHP) alters regulation of double-strand break formation and crossover designation leading to germline dysfunction in Caenorhabditis elegans

“…In female rodent studies, DEHP decreased 17β-estradiol levels, induced anovulation, disrupted estrous cyclicity and altered folliculogenesis in the ovaries [23,24]. Furthermore, reduced primordial follicular reserve, oocyte quality and embryonic developmental competence were observed in the first three generations of female offspring from exposed female mice, indicating a DEHP-induced transgenerational effect [25]. Moreover, an association between DEHP exposure and endometriosis or decreased gestational age has been described in women [26].…”

Reduced camptothecin sensitivity of estrogen receptor‐positive human breast cancer cells following exposure to di(2‐ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes

“…Recently, a growing number of genome‐wide epigenetic profiling studies have been conducted in search for disease‐specific hypermethylated CpG sites associated with DEHP exposure. The health problems connected to DEHP include a decrease in spermatogenesis activity, anogenital distance, ovarian disease, obesity, and development of liver cancer . In particular, heritable epigenetic changes, so‐called epimutations, resulting from in utero exposure to DEHP have been observed in a number of rodent models .…”

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy

“…3) CAR ligands [e.g., DDT (Kamata et al, 2018), permethrin (Kublbeck et al, 2011), chlordane (Kamata et al, 2018), dibutylphthalate (Wyde et al, 2005), dieldrin (Wei et al, 2002), methoxychlor (Kamata et al, 2018), pyren (Zhang et al, 2015a), and toxaphen (Wei et al, 2002)], which cross the placenta or are transferred via milk (Campoy et al, 2001;Skopp et al, 2002;Cok et al, 2012;Corcellas et al, 2012;Limon-Miro et al, 2017;Muller et al, 2017;Wang et al, 2017;Yasmeen et al, 2017). The lipophilic pollutants and CAR modulators BPA and DEHP (DeKeyser et al, 2011) exhibit not only multi-but even transgenerational (beyond F1) effects (Ziv-Gal et al, 2015;Pocar et al, 2017). The assessment of F1 effects could start with transcriptional profiling in appropriate animal models.…”