Impact of Long-Lasting Environmental Factors on Regulation Mediated by the miR-34 Family.

The present review focuses on the interactions of newly emerging environmental factors with miRNA-mediated regulation. In particular, we draw attention to the effects of phthalates, electromagnetic fields (EMFs) and a disrupted light/dark cycle. miRNAs are small non-coding RNA molecules with a tremendous regulatory impact, which is usually executed via gene expression inhibition. To address the capacity of environmental factors to influence miRNA-mediated regulation, the miR-34 family was selected for its well-described oncostatic and neuro-modulatory properties. The expression of miR-34 is in a tissue-dependent manner to some extent under the control of the circadian system. There is experimental evidence implicating that phthalates, EMFs and the circadian system interact with the miR-34 family, in both lines of its physiological functioning. The inhibition of miR-34 expression in response to phthalates, EMFs and light contamination has been described in cancer tissue and cell lines and was associated with a decline in oncostatic miR-34a signalling (decrease in p21 expression) and a promotion of tumorigenesis (increases in Noth1, cyclin D1 and cry1 expressions). The effects of miR-34 on neural functions have also been influenced by phthalates, EMFs and a disrupted light/dark cycle. Environmental factors shifted the effects of miR-34 from beneficial to the promotion of neurodegeneration and decreased cognition. Moreover, the apoptogenic capacity of miR-34 induced via phthalate administration in the testes has been shown to negatively influence germ cell proliferation. To conclude, as the oncostatic and positive neuromodulatory functions of the miR-34 family can be strongly influenced by environmental factors, their interactions should be taken into consideration in translational medicine.

Prenatal and perinatal phthalate exposure is associated with sex-dependent changes in hippocampal miR-15b-5p and miR-34a-5p expression and changes in testicular morphology in rat offspring.

MicroRNAs are a large group of non-coding nucleic acids, usually 20-22 nt long, which bind to regulatory sections of messenger RNA (mRNA) and inhibit gene expression. However, genome activity is also regulated by hormones. Endocrine disruptors such as those from the phthalate group imitate or block these hormonal effects, and our previous study showed a long-lasting decrease in plasma testosterone levels in rat offspring exposed to a mixture of three phthalates in utero and postnatally. These effects were also observed at the behavioural level. To shed more light on these findings, in this new study we compared testicular tissue morphology between control and phthalatetreated males and investigated possible persistent changes and sex differences in the expression of two hippocampal microRNAs - miR- 15b-5p and miR-34a-5p - participating in the transcription of steroidogenic genes. Histologically observed changes in testicular tissue morphology of phthalate-exposed males compared to control support testosterone drop observed in the previous study. At the microRNA level, we observed more significant changes in phthalate-treated females than in males. However, we are unable to relate these effects to the previously observed behavioural changes.

Effect of 17ß-estradiol on the daily pattern of ACE2, ADAM17, TMPRSS2 and estradiol receptor transcription in the lungs and colon of male rats.

Covid-19 progression shows sex-dependent features. It is hypothesized that a better Covid-19 survival rate in females can be attributed to the presence of higher 17ß-estradiol (E2) levels in women than in men. Virus SARS-CoV-2 is enabled to enter the cell with the use of angiotensin converting enzyme 2 (ACE2). The expression of several renin-angiotensin system components has been shown to exert a rhythmic pattern, and a role of the circadian system in their regulation has been implicated. Therefore, the aim of the study is to elucidate possible interference between E2 signalling and the circadian system in the regulation of the expression of ACE2 mRNA and functionally related molecules. E2 was administered at a dosage of 40 µg/kg/day for 7 days to male Wistar rats, and sampling of the lungs and colon was performed during a 24-h cycle. The daily pattern of expression of molecules facilitating SARS-CoV-2 entry into the cell, clock genes and E2 receptors was analysed. As a consequence of E2 administration, a rhythm in ACE2 and TMPRSS2 mRNA expression was observed in the lungs but not in the colon. ADAM17 mRNA expression showed a pronounced rhythmic pattern in both tissues that was not influenced by E2 treatment. ESR1 mRNA expression exerted a rhythmic pattern, which was diminished by E2 treatment. The influence of E2 administration on ESR2 and GPER1 mRNA expression was greater in the lungs than in the colon as a significant rhythm in ESR2 and GPER1 mRNA expression appeared only in the lungs after E2 treatment. E2 administration also increased the amplitude of bmal1 expression in the lungs, which implicates altered functioning of peripheral oscillators in response to E2 treatment. The daily pattern of components of the SARS-CoV-2 entrance pathway and their responsiveness to E2 should be considered in the timing of pharmacological therapy for Covid-19.