Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes

Abstract

The hypothalamus and hippocampus are sensitive to early exposure to endocrine disrupting chemicals (EDCs). Two EDCs that have raised particular concerns are bisphenol A (BPA), a widely prevalent chemical in many common household items, and genistein (GEN), a phyto-oestrogen present in soy and other plants. We hypothesised that early exposure to BPA or GEN may lead to permanent effects on gene expression profiles for both coding RNAs (mRNAs) and microRNAs (miRs), which can affect the translation of mRNAs. Such EDC-induced biomolecular changes may affect behavioural and metabolic patterns. California mice (Peromyscus californicus) male and female offspring were developmentally exposed via the maternal diet to BPA (5 mg kg -1 feed weight low dose [LD] and 50 mg kg -1 feed weight upper dose [UD]), GEN (250 mg kg -1 feed weight) or a phyto-oestrogen-free diet (AIN) control.Behavioural and metabolic tests were performed at 180 days of age. A quantitative polymerase chain reacttion analysis was performed for candidate mRNAs and miRs in the hypothalamus and hippocampus. LD BPA and GEN exposed California mice offspring showed socio-communication impairments. Hypothalamic Avp, Esr1, Kiss1 and Lepr were increased in LD BPA offspring. miR-153 was elevated but miR-181a was reduced in LD BPA offspring. miR-9 and miR-153 were increased in the hippocampi of LD BPA offspring, whereas GEN decreased hippocampal miR-7a and miR-153 expression. Correlation analyses revealed neural expression of miR-153 and miR-181a was associated with socio-communication deficits in LD BPA individuals.The findings reveal a cause for concern such that developmental exposure of BPA or GEN in California mice (and potentially by translation in humans) can lead to long standing neurobehavioural consequences. K E Y W O R D S bisphenol A, brain, cognition, communication, epigenetics, genistein, miRNA, non-coding RNA S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Butler MC, Long CN, Kinkade JA, et al. Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes. J Neuroendocrinol. 2020;32:e12847. https://doi.

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

“…Additionally, during organogenesis and tissue repair different cell types with different receptors interact to form organs, increasing the complexity of interactions and thus the likelihood of non-monotonic dose-response curves [231]. But, perhaps more importantly, we applied a rigorous mixOmics approach [21], as done in previous BPA studies performed in the Rosenfeld Laboratory [22][23][24], to ascertain whether the low dose of BPA simultaneously affected several endpoints in different laboratories. As such, if low-dose effects in the same animals are identified across multiple systems, it seems unlikely that these findings are not important.…”

“…To achieve these lofty goals, we used the mixOmics R package [21], as we have done in previous BPA studies performed in the Rosenfeld Laboratory [22][23][24]. In this case, we used the program to correlate data obtained by independent CLARITY-BPA investigators.…”

“…In this integrative correlation analyses section, we emphasize first those associations identified in males and females at the lowest dose and at 6 months of age, as evidence of such persistent or developmental origins of health and disease (DOHaD) effects would suggest that we need to rethink the lowest safe dose of BPA. Rosenfeld's laboratory has used this mixOmics analyses approach in previous BPA studies to integrate various 'omics and phenotypic data generated in her lab together [22][23][24]. However, to our knowledge, this is the first time such a program has been used to perform integrative correlation analyses with comprehensive datasets spanning different ages and dosages and generated in the laboratories of multiple investigators.…”

Molecular mechanisms underlying altered neurobehavioural development of female offspring of mothers with polycystic ovary syndrome: FOS-mediated regulation of neurotrophins in placenta

“…As hypothalamic and hippocampal gene expression changes lead to persistent neurobehavioural consequences in rodents [61] , we conducted a global analysis of transcriptomic data of F1 pubertal female rats. The top 20 GO terms and KEGG pathways were identified in brains of pubertal female offspring of PCOS model rats.…”

The influence of phytoestrogens on different physiological and pathological processes: An overview

“…Butler and collaborators using bisphenol A (BPA) and genistein, demonstrated the effects on behavioral and metabolic patterns in California mice ( Peromyscus californicus ). The results showed that early exposure to BPA or genistein could cause long‐term neurobehavioral and endocrine changes (Butler et al, 2020). Thus, these data indicate that early exposure to phytoestrogens may induce life‐long effects on the differentiation of brain structures, neuronal networks, endocrine secretion and behaviors and can influence the development of the reproductive and other systems, as mentioned above.…”