Exposure to p,p′-DDE Alters Macrophage Reactivity and Increases Macrophage Numbers in Adipose Stromal Vascular Fraction

Abstract

Exposure to p,p'-DDE (DDE), the main bioaccumulative metabolite of the organochlorine insecticide p,p'-DDT, is associated with a higher prevalence of obesity, dyslipidemia, insulin resistance, metabolic syndrome, and immunomodulation. The present study was carried out to determine whether DDE perturbs adipose tissue homeostasis through modulation of macrophage function. Treatment with DDE or a cyclooxygenase-2 inhibitor prior to lipopolysaccharide exposure significantly decreased production of prostaglandins (PG) from J774a.1 macrophages in vitro. Similarly, J774A.1 cell lysates incubated with DDE or a specific cyclooxygenase-2 inhibitor (NS-398) produced significantly less PGE2 and PGF2α. Macrophage polarization studies revealed a pattern of DDE effects that were not fully consistent with a purely pro- or purely anti- M1 or M2 effect. However, DDE suppressed expression of two M1 markers (induced by an M1 stimulus) and enhanced expression of an M2 marker (induced by an M2 stimulus). Further studies including assessment of macrophage function are needed to fully characterize the effects of DDE on macrophage polarization. Obesity is characterized by an increase in the number of resident adipose tissue macrophages. To assess monocyte/macrophage recruitment to the adipose tissue in vivo, male C57Bl/6H mice were treated with 2 mg/kg DDE or corn oil vehicle for 5 days by gavage. Epididymal fat pads were digested and macrophage populations were analyzed by flow cytometry. In DDE-treated animals, there was a significant increase (37%) in F4/80(+)CD11b(+) macrophages/g of epididymal adipose over vehicle (P < .05). Together, these results suggest a role for DDE in the enhancement of adipose tissue macrophage recruitment and/or proliferation, as well as modulation of immune cell function that may contribute to the etiology of metabolic diseases associated with organochlorine exposure.

Endocrine Disruptors Leading to Obesity and Related Diseases

“…Dysregulation of the above-mentioned pathways leads to obesity. Adipose tissue macrophage accumulation is responsible for adipose TNF-α, NOS2 (nitric oxide synthase 2) and IL-6 expression [ 26 , 27 ]. A strong association has been reported among the extent of infiltrating adipose tissue macrophages, other pro-inflammatory immune cells and several pro-inflammatory mediators (TNF-α, IL-1β, and IL-6), which are enhanced in obesity [ 28 ].…”

Prediagnostic serum organochlorine insecticide concentrations and primary liver cancer: A case–control study nested within two prospective cohorts

“…One mechanism through which organochlorine insecticides could increase liver cancer risk is via immune perturbations, which have been observed in epidemiologic and animal studies . Evidence includes inverse associations between plasma p,p’ ‐DDE levels and IgG levels among farmers in the United States, inverse associations between blood hexachlorobenzene levels and interferon‐γ levels among occupationally exposed individuals, and increased risk of otitis media with increased prenatal exposure to p,p’ ‐DDE, hexachlorobenzene and dieldrin among Inuit infants .…”

“…Zhao et al 18 observed HBV infection to be synergistic with p,p'-DDT exposure, but antagonistic with p,p'-DDE exposure, although no such interactions were observed by McGlynn et al 17 One mechanism through which organochlorine insecticides could increase liver cancer risk is via immune perturbations, which have been observed in epidemiologic and animal studies. [36][37][38][39][40][41] Evidence includes inverse associations between plasma p,p'-DDE levels and IgG levels among farmers in the United States, 36 inverse associations between blood hexachlorobenzene levels and interferon-γ levels among occupationally exposed individuals, 41 and increased risk of otitis media with increased prenatal exposure to p,p'-DDE, hexachlorobenzene and dieldrin among Inuit infants. 37 Other evidence indicates suppression of humoral and cell-mediated immune response in rats treated with sub-toxic doses of DDT 40 and decreased cytotoxic function (e.g., ability to lyse tumor cells) of purified human natural killer cells by αand y-chlordane, oxychlordane, heptachlor and DDT in vitro.…”

Environmental toxin exposure in polycystic ovary syndrome women and possible ovarian neoplastic repercussion

“…Oxidative stress, a known carcinogenetic stimulus, is a by-product of chronic metainflammation mainly sustained by TNF-α and IL-6, powerful cytokines produced by adipose tissue and its residing macrophages 145,146 . TNF-α leads to lipolysis and subsequent IL-6 secretion.…”