[Formula: see text] Exposure of Mice during Spermatogenesis: A Role of Inhibitor [Formula: see text] Kinase 2 in Pro-Opiomelanocortin Neurons

BACKGROUND: Epidemiological studies have shown that exposure to ambient fine particulate matter with aerodynamic diameter less than or equal to 2.5 μm ([Formula: see text]) correlates with a decrease in sperm count, but the biological mechanism remains elusive. OBJECTIVES: This study tested whether hypothalamic inflammation, an emerging pathophysiological mediator, mediates the development of lower epididymal sperm count due to [Formula: see text] exposure. METHODS: Inhibitor [Formula: see text] kinase 2 (IKK2) was conditionally knocked out either in all neurons or subtypes of hypothalamic neurons of mice. Effects of concentrated ambient [Formula: see text] (CAP) exposure on hypothalamic inflammation, the hypothalamic–pituitary–gonadal (HPG) axis, and epididymal sperm count of these mouse models were then assessed. Furthermore, to test whether hypothalamic inflammation is sufficient to decrease sperm production, we overexpressed constitutively active IKK2 (IKK2ca) either in all neurons or subtypes of hypothalamic neurons and assessed hypothalamic inflammation, the HPG axis, and sperm production of these overexpression mouse models. RESULTS: CAP-exposed wild-type control mice vs. filtered air (FA)-exposed wild-type control mice had a higher expression of hypothalamic inflammatory markers, lower functional indexes of the HPG axis, and a lower epididymal sperm count. In contrast, all these measurements for CAP- vs. FA-exposed mice deficient of IKK2 in all neurons were comparable. We also found that overexpression of IKK2ca in either all neurons or pro-opiomelanocortin (POMC) neurons only, but not in Agouti-related protein (AgRP) neurons only, resulted in lower functional indexes of the HPG axis and a lower epididymal sperm count. Moreover, we showed that CAP- vs. FA-exposed mice deficient of IKK2 in POMC neurons had a comparable expression of hypothalamic inflammatory markers, comparable functional indexes of the HPG axis, and a comparable epididymal sperm count. DISCUSSION: This mouse model study shows a causal role of IKK2 of POMC neurons in the development of lower epididymal sperm count due to [Formula: see text] exposure, providing a mechanistic insight into this emerging pathogenesis. https://doi.org/10.1289/EHP8868