{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:09:37Z","timestamp":1791360577895,"version":"4.3.1"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81372944"],"award-info":[{"award-number":["81372944"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81072262"],"award-info":[{"award-number":["81072262"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Di\u2010(2\u2010ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Pregnant wild\u2010type and muscle\u2010specific myostatin knockout (MSTN KO) C57BL\/6 mice were randomized to receive vehicle (corn oil) or 250\u00a0mg\/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono\u20102\u2010ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure\u2010induced muscle wasting in the offspring was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70\u00a0\u00b1\u00a00.1 vs. 3.38\u00a0\u00b1\u00a00.23, Gastroc: 2.29\u00a0\u00b1\u00a00.09 vs. 2.81\u00a0\u00b1\u00a00.14, Tibialis: 1.01\u00a0\u00b1\u00a00.07 vs. 1.25\u00a0\u00b1\u00a00.11, mg\/tibial length in mm, all <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01, <jats:italic>n<\/jats:italic>\u00a0=\u00a035). Maternal DEHP exposure significantly increased Myostatin expression (2.45\u00a0\u00b1\u00a00.41 vs. 0.03\u00a0\u00b1\u00a00.00 DEHP vs. controls, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), Atrogin\u20101(2.68\u00a0\u00b1\u00a00.65 vs. 0.63\u00a0\u00b1\u00a00.01, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), MuRF1 (1.56\u00a0\u00b1\u00a00.51 vs. 0.31\u00a0\u00b1\u00a00.01, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), and Smad2\/3 phosphorylation (4.12\u00a0\u00b1\u00a00.35 vs. 0.49\u00a0\u00b1\u00a00.18, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), and decreased MyoD (0.27\u00a0\u00b1\u00a00.01 vs. 1.52\u00a0\u00b1\u00a00.01, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), Myogenin (0.25\u00a0\u00b1\u00a00.03 vs. 1.95\u00a0\u00b1\u00a00.56, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), and AKT phosphorylation (4.12\u00a0\u00b1\u00a00.35 vs. 1.00\u00a0\u00b1\u00a00.06, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05), in skeletal muscle of the offspring in MSTN<jats:sup>flox\/flox<\/jats:sup>, but not in MSTN KO mice. Maternal DEHP exposure resulted in up\u2010regulation of CCAAT\/enhancer\u2010binding protein \u03b4 (C\/EBP\u03b4, 4.12\u00a0\u00b1\u00a00.35 vs. 1.00\u00a0\u00b1\u00a00.19, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05) in skeletal muscle of the offspring in MSTN<jats:sup>flox\/flox<\/jats:sup> and MSTN KO mice (4.12\u00a0\u00b1\u00a00.35 vs. 4.35\u00a0\u00b1\u00a00.28, <jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05, <jats:italic>n<\/jats:italic>\u00a0=\u00a05). In vitro, C\/EBP\u03b4 silencing abrogated the MEHP\u2010induced increases in Myostatin, MuRF\u20101, and Atrogin\u20101 and decreases in MyoD and Myogenin expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C\/EBP\u03b4\u2010myostatin pathway in mice.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13098","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T02:36:49Z","timestamp":1666233409000},"page":"2740-2751","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Maternal rodent exposure to di\u2010(2\u2010ethylhexyl) phthalate decreases muscle mass in the offspring by increasing myostatin"],"prefix":"10.1002","volume":"13","author":[{"given":"Fengju","family":"Li","sequence":"first","affiliation":[{"name":"Department of Health Education, College of Military 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