The role of parity status on cigarette smoke-induced modulation of anti-tumor immune mechanisms.

Epidemiologic studies indicate that women who smoke cigarettes are more likely to experience adverse reproductive and immunological health effects. Despite these facts, 20-30% of American women still smoke during their reproductive years. As little is known of the relationship between smoking and the immune response during pregnancy, an investigation was conducted using parous and non-parous (virgin) B6C3F1 mice to investigate what role (if any) parity status had on cigarette smoke (CS) induced effects on immune functions important in surveillance against developing tumors. Pregnant mice were exposed to CS for 5 d/wk ( 4 hr/d) from gestational day 4 to parturition; virgin mice were exposed for an equivalent amount of time. Smoke- and parity-associated alterations in pulmonary histology and lung inflammation, along with tumor cell host resistance, and cytotoxic T-lymphocyte (CTL) activity were examined either 24- 48 hr or 5 wk post-exposure/parturition; in the parous mice, gestational parameters were also evaluated. Exposure to CS significantly increased tumor susceptibility in virgin mice first injected with EL4 lymphoma cells at the 5 wk post-exposure timepoint; tumor incidence began to increase in smoke-exposed virgin mice as early as 24- 48 hr post-exposure. Pregnancy itself increased tumor incidence in mice injected with EL4 cells 24- 48 hr after birth, but this effect then dissipated over 5 wk to levels seen in virgin mice. When EL4 injections were first performed at either timepoint in CS-exposed parous mice, the tumor incidence was not significantly different from that in the air-exposed parity-matched controls. CTL activity in CS-exposed parous mice was significantly increased from both nulliparous groups as well as from the parous air control mice examined 5 wk post-exposure. Results suggest that exposure to CS throughout gestation could act in combination with pregnancy-associated changes to up-regulate immune responses, potentially compromising fetal tolerance.

The parity-related protection against breast cancer is compromised by cigarette smoke during rat pregnancy: observations on tumorigenesis and immunological defenses of the neonate.

Early pregnancy is a powerful negative risk factor for breast cancer (BCa) in women. Pregnancy also protects rats against induction of BCa by carcinogens such as N-methyl-N-nitrosourea (MNU), making the parous rat a useful model for studying this phenomenon. Smoking during early pregnancy may lead to an increased risk of BCa in later life, possibly attributable to carcinogens in cigarette smoke (CS), or to reversal of the parity-related protection against BCa. To investigate these possibilities, 50-day-old timed first-pregnancy rats were exposed to standardized mainstream CS (particle concentration = 50 mg/m3) or to filtered air (FA) 4 h/day, Day 2-20 of gestation. Age-matched virgin rats were similarly exposed to CS or FA. At age 100 days, the CS or FA-exposed, parous and virgin rats were injected s.c. with MNU (50 mg/kg body wt), or with MNU vehicle. Mammary tumors (MTs) first appeared in virgin rats 9 weeks post-MNU injection. While no MTs were detected in FA-exposed parous rats until 18 weeks post-MNU, MTs appeared in the CS-exposed parous rats as early as 10 wks (P < 0.02). As no MTs developed in CS-exposed rats not injected with MNU, CS did not act as a direct mammary carcinogen. Serum prolactin concentration on Day 19 of pregnancy in CS-exposed dams was reduced by 50% compared with FA-exposed dams (P < 0.005). CS exposure during a pregnancy may thus 'deprotect' rats, enhancing their vulnerability to MNU-induced BCa. Prenatal CS exposure had no detectable effect on the immune responses of the pups examined at 3, 8 or 19 weeks of age. However, prolactin concentration in stomach contents (milk) of 3-day-old pups suckled by CS-exposed dams was decreased when compared with that of FA-exposed dams (P < 0.032). As milk-borne prolactin modulates development of the central nervous and immune systems of neonatal rats, CS exposure of the dams could adversely affect later maturation of these systems by reducing milk prolactin.