Developmental estrogen exposures and disruptions to maternal behavior and brain: Effects of ethinyl estradiol, a common positive control

Abstract

Due of its structural similarity to the endogenous estrogen 17β-estradiol (E2), the synthetic estrogen 17α-ethinyl estradiol (EE2) is widely used to study the effects of estrogenic substances on sensitive organs at multiple stages of development. Here, we investigated the effects of EE2 on maternal behavior and the maternal brain in females exposed during gestation and the perinatal period. We assessed several components of maternal behavior including nesting behavior and pup retrieval; characterized the expression of estrogen receptor (ER)α in the medial preoptic area (MPOA), a brain region critical for the display of maternal behavior; and measured expression of tyrosine hydroxylase, a marker for dopaminergic cells, in the ventral tegmental area (VTA), a brain region important in maternal motivation. We found that developmental exposure to EE2 induces subtle effects on several aspects of maternal behavior including time building the nest and time spent engaged in self-care. Developmental exposure to EE2 also altered ERα expression in the central MPOA during both early and late lactation and led to significantly reduced tyrosine hydroxylase immunoreactivity in the VTA. Our results demonstrate both dose- and postpartum stage-related effects of developmental exposure to EE2 on behavior and brain that manifest later in adulthood, during the maternal period. These findings provide further evidence for effects of exposure to exogenous estrogenic compounds during the critical periods of fetal and perinatal development.

The parental brain and behavior: A target for endocrine disruption

“…This work has mostly focused on evaluating the endocrine disrupting activities of estrogenic compounds including ethinyl estradiol (EE2), Bisphenol A and S (BPA, BPS), chlorpyrifos and lindane, an insecticide with both estrogenic and anti-estrogenic properties (Catanese et al, 2015). Low dose EE2 exposure only during perinatal development increased the time mice spent on self-care and nest building in adulthood, during the early postpartum period (Catanese & Vandenberg, 2018). Developmental BPA (Palanza et al, 2002a) and BPS exposure (Catanese & Vandenberg, 2017a) both decreased time spent on the nest once females reached adulthood; developmental BPS exposure also induced severe disruptions to maternal behavior including infanticide.…”

Low dose bisphenol S or ethinyl estradiol exposures during the perinatal period alter female mouse mammary gland development

“…Fish exposed to the mixture developed higher levels of ovarian follicle atresia compared to the EE2 exposed group. In our own studies, we have observed striking differences between the effects of BPS and EE2 on a range of maternal behavior and brain endpoints [41, 42, 53, 54]. For example, females exposed to BPS during early development spent significantly less time on the nest compared to untreated controls but this was not observed in EE2 treated females; in contrast, EE2 treated females displayed decreases in the number of dopaminergic neurons in the ventral tegmental area of the midbrain, but this was not observed in BPS treated females.…”

“…Post-weaning mortality was rare. One female developed hydrocephaly and had to be euthanized; see description in [54].…”