{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T12:09:35Z","timestamp":1781093375120,"version":"3.54.1"},"reference-count":61,"publisher":"SAGE Publications","issue":"6-7","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Toxicol Ind Health"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:p>\u03b3-Hexachlorocyclohexane (\u03b3-HCH) is a persistent organochlorine pesticide widely used in agriculture and public health. While its neurotoxicity in humans and animals is well documented, its toxic effects on non-target organs, particularly the lungs, remain poorly understood. In the general population, diet is the primary route of \u03b3-HCH exposure; however, the long-term effects of dietary exposure on pulmonary immunity remain poorly understood. This study employed a two-hit murine model to determine whether prolonged oral exposure of \u03b3-HCH alters pulmonary immune responses to a secondary inflammatory challenge. Swiss albino male mice were administered \u03b3-HCH orally (0.12\u00a0mg\/kg body weight) for 60 or 90 days, followed by an acute intranasal lipopolysaccharide (LPS) challenge at the respective terminal time points. Systemic and local inflammatory responses were assessed by quantifying cytokine levels (IL-1\u03b2 and TNF\u03b1) in serum and bronchoalveolar lavage fluid using ELISA. Lung tissues were assessed for TLR4 and TNF\u03b1 expression by immunohistochemistry and examined ultrastructurally by transmission electron microscopy. Subchronic \u03b3-HCH exposure led to a significant increase in IL-1\u03b2 and TNF\u03b1 levels, accompanied by robust expression of these markers in pneumocytes, alveolar epithelial cells, and vascular endothelium. Upon LPS challenge, \u03b3-HCH-treated mice showed exacerbated pulmonary inflammation with histopathological changes. Interestingly, the inflammatory response in \u03b3-HCH + LPS groups was not consistently greater than that in the LPS-only group; in some cases, cytokine levels were moderately reduced. These findings suggest that subchronic dietary \u03b3-HCH exposure primes the immune system and alters pulmonary inflammatory responsiveness to a subsequent endotoxin challenge. This pattern is consistent with immune modulation rather than amplified protective immunity. While the observed responses are associated with activation of innate immune signaling pathways, including TLR4-linked mechanisms, further functional studies are required to establish causal relationships. Overall, this study underscores the importance of cumulative and sequential environmental exposures when assessing immunotoxic potential of persistent organic pollutants.<\/jats:p>","DOI":"10.1177\/07482337261453446","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:35:58Z","timestamp":1779806158000},"page":"258-273","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Subchronic \u03b3-hexachlorocyclohexane exposure is associated with altered TLR4-linked pulmonary immune responses following endotoxin challenge: Insights from a two-hit mouse model"],"prefix":"10.1177","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6331-1701","authenticated-orcid":false,"given":"Anita","family":"Tewari","sequence":"first","affiliation":[{"name":"Rewa (Nanaji Deshmukh Veterinary Science University, Jabalpur)"},{"name":"Guru Angad Dev Veterinary & Animal Science University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8568-0540","authenticated-orcid":false,"given":"Deepali","family":"Kalambhe","sequence":"additional","affiliation":[{"name":"Guru Angad Dev Veterinary & Animal Science University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0416-8946","authenticated-orcid":false,"given":"R.S.","family":"Sethi","sequence":"additional","affiliation":[{"name":"Guru Angad Dev Veterinary & Animal Science University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_3_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2008.01.056"},{"key":"e_1_3_7_3_1","volume-title":"Toxicological Profile for Hexachlorocyclohexane (HCH)","author":"Agency for Toxic Substances and Disease Registry (ATSDR)","year":"2024","unstructured":"Agency for Toxic Substances and Disease Registry (ATSDR) (2024) Toxicological Profile for Hexachlorocyclohexane (HCH). 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