Sex-specific microRNA expression networks in an acute mouse model of ozone-induced lung inflammation

Abstract

BackgroundSex differences in the incidence and prognosis of respiratory diseases have been reported. Studies have shown that women are at increased risk of adverse health outcomes from air pollution than men, but sex-specific immune gene expression patterns and regulatory networks have not been well studied in the lung. MicroRNAs (miRNAs) are environmentally sensitive posttranscriptional regulators of gene expression that may mediate the damaging effects of inhaled pollutants in the lung, by altering the expression of innate immunity molecules.MethodsMale and female mice of the C57BL/6 background were exposed to 2 ppm of ozone or filtered air (control) for 3 h. Female mice were also exposed at different stages of the estrous cycle. Following exposure, lungs were harvested and total RNA was extracted. We used PCR arrays to study sex differences in the expression of 84 miRNAs predicted to target inflammatory and immune genes.ResultsWe identified differentially expressed miRNA signatures in the lungs of male vs. female exposed to ozone. In silico pathway analyses identified sex-specific biological networks affected by exposure to ozone that ranged from direct predicted gene targeting to complex interactions with multiple intermediates. We also identified differences in miRNA expression and predicted regulatory networks in females exposed to ozone at different estrous cycle stages.ConclusionOur results indicate that both sex and hormonal status can influence lung miRNA expression in response to ozone exposure, indicating that sex-specific miRNA regulation of inflammatory gene expression could mediate differential pollution-induced health outcomes in men and women.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0177-7) contains supplementary material, which is available to authorized users.

Modulation of the lung inflammatory response to ozone by the estrous cycle

“…; Fuentes et al. ). Here, we expanded our investigations to the study of the female lung, and specifically the influence of circulating sex hormone levels as well as other physiological changes occurring throughout the estrous cycle in lung inflammation.…”

“…; Fuentes et al. ). Furthermore, we reported differences in signaling cascades activated in female mice exposed to ozone in different estrous cycle stages (Mishra et al.…”

“…), only a few studies have addressed the mechanisms by which physiological hormonal fluctuations that occur in the female reproductive cycle affect the inflammatory response (Fuentes et al. ; Fuentes and Silveyra ).…”

“…By investigating females in a state of high or low levels of ovarian hormones related to the estrous cycle, researchers have demonstrated the existence of estrous cycle‐specific sex differences in tissues such as the brain and lung (Duclot and Kabbaj ; Fuentes et al. ; Fuentes and Silveyra ).…”

The role of sex in particle‐induced inflammation and injury

“…Epidemiological and clinical evidence has demonstrated that of the 1 billion people world‐wide suffering from acute or chronic lung disease, a disproportionate number of these individuals are women (Forum of International Respiratory Societies & European Respiratory Society, ; Fuentes & Silveyra, ). Lung diseases that present with increased incidence and/or severity in women include: non and cigarette‐mediated chronic obstructive pulmonary disease (COPD, particularly the chronic bronchitis form), autoimmune lung disease, pulmonary hypertension (Pinkerton et al, ), bronchiectasis (non and cystic fibrosis‐related; Vidaillac, Yong, Jaggi, Soh, & Chotirmall, ), chronic respiratory symptoms due to air pollution from ozone and particulate matter (Fuentes, Roy, Mishra, Cabello, & Silveyra, ; Yoshizaki et al, ), and adult asthma (Carey, Card, Voltz, Arbes Jr, ). However, there are also a number of lung diseases that affect men disproportionately, such as lung cancer and pulmonary fibrosis (Fuentes et al, ; Sathish & Prakish, 2016).…”