Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus

Abstract

This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner.

Epigenetic impacts of endocrine disruptors in the brain

“…In the AVPV, Ar expression was altered in females but not males by gestational A1221 (E16 and E18), with females displaying a male-typical expression pattern across development when assessed at four ages from P15 through P90 (Walker et al, 2014). This dosing paradigm did not alter Ar expression in the male rat MPN at these same developmental ages (Topper et al, 2015). Interestingly, altering the dosing paradigm slightly (A1221 administered on E16, E18 and E20, rather than just on E16 and E18) decreased Ar expression in the mPOA of adult males (~P100) but not females, suggesting that even slight changes in the window of exposure and/or age at analysis result in sex and/or region specific alterations on gene expression in adulthood (Bell et al, 2016a).…”

“…In the MPN, the most common expression pattern of miRNAs was a developmental increase, seen in both sexes for 7 of the 8 miRNAs. Interestingly, expression of 6 of the 8 miRNAs was increased on P30 specifically in the females, an effect found in both the A1221 and EB groups compared to the vehicle-exposed females (Topper et al, 2015). In the males, a completely different response pattern was seen, with expression of 6 of 8 miRNAs decreased by A1221, but not EB, at P90.…”

“…Similar sex differences and hormonal responses were observed in halibut (Bizuayehu et al, 2012). Additionally, these effects may be region- and age- specific as our lab has identified developmental sex differences (P15–P90) in miRNAs in the MPN but not VMH of rats, which are sensitive to perinatal estrogen exposure (Topper et al, 2015). Finally, there is evidence that miRNAs, specifically let-7 and lin-28, are necessary for the initiation of puberty in rats and monkeys and are altered by neonatal hormonal manipulation in a sex-specific manner (Sangiao-Alvarellos et al, 2013).…”

“…Using the model described earlier for effects of A1221 (1 mg/kg), estradiol benzoate (EB, 50 μg/kg), or vehicle (all administered on E16 and E18) on hypothalamic gene and protein expression, and on reproductive behaviors, developmental expression profiles of eight miRNAs ( mir-132, mir-219, mir-7, mir-9, mir-145, mir-124a, let-7a , and let-7b ) were profiled. Measurements were made in the MPN and VMN of male and female exposed offspring across postnatal development and puberty, on P15, 30 (peripubertal), 45 (late puberty) and P90 (adulthood) (Topper et al, 2015). In the MPN, the most common expression pattern of miRNAs was a developmental increase, seen in both sexes for 7 of the 8 miRNAs.…”

“…In that same study (Topper et al, 2015) we also measured the same 8 miRNAs in the VMN. While all of the measured miRNAs underwent developmental increases from P15 to P90, there were relatively few effects of treatment.…”