The Effects of Fetal Exposure to 1, 2-Dibromo-3-Chloropropane on Adult Male Reproductive Function1

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Abstract
Several drugs have been shown to cross the placental barrier and affect the fetal testis causing a reduction in testosterone with a resultant impairment of sexual differentiation and an ultimate problem in adult sexual function. In this study, pregnant female rats were treated with 25 mg/kg of the pesticide 1,2-dibromo-3-chloropropane (DBCP). Treatment began on Days 14.5, 16.5, or 18.5 and continued through Day 19.5 of gestation. Some animals were killed on Day 20.5 of intrauterine life and fetal intratesticular testosterone was measured. All other animals were allowed to deliver, and the males were raised to adulthood. At adulthood, body, testis, prostate glands and seminal vesicle weights were recorded. Intratesticular testosterone and luteinizing hormone (LH) receptors were measured. Male and female sexual behavior was quantified and the volume of the sexually dimorphic nucleus of the preoptic area of the hypothalamus was calculated. The histological appearance of the testis was also examined. Treatment for 6 days during fetal life with DBCP decreased intratesticular testosterone by 50% compared to controls at 20.5 days of gestation. At adulthood, all male rats treated during fetal life had a reduced body weight that was correlated with the duration of exposure. Adult testis weight was reduced to 75% of controls as a result of 2 days of fetal exposure to DBCP, whereas 4 and 6 days of exposure during fetal life reduced testis weight by greater than 90%. LH receptors and intratesticular testosterone, in the adults treated during fetal life, were also dramatically reduced. The volume of the sexually dimorphic nucleus of males treated for 6 days of fetal life was significantly less than that measured in untreated controls and not significantly different from the volume of normal females. The volume of the sexually dimorphic nucleus of animals treated for 4 days of fetal life was not significantly different from control male animals. Animals treated for 2 days during fetal life displayed normal male sexual behavior. Animals treated for 6 days during gestation all displayed the female lordosis response whereas none of the control males showed this behavior. One-third of the animals treated for 4 days displayed lordosis; however, none of this group showed mounting behavior (38% of control males showed mounting behavior). In this 4-day treatment group, those animals with the smallest volume of the sexually dimorphic nucleus were the animals that displayed lordosis behavior. Histologically, 7 of 9 animals treated for 6 days and 3 of 6 animals treated for 4 days were devoid of seminiferous tubules. The other animals in these two groups had a few tubules that contained only Sertoli cells. Animals treated for 2 days during gestation had testes with a histological appearance ranging from normal spermatogenesis to gonads composed of a few seminiferous tubules containing only Sertoli cells. We have concluded that DBCP produces a major effect on the fetal testis that includes both the interstitial and tubular compartments. Although androgen levels were decreased, androgen activity, as judged by the histological appearance of the prostate glands and seminal vesicles, was still apparent in the adult. In some animals with greatly decreased androgen levels during critical periods of fetal life, sexual differentiation of sexual behavior centers in the brain was permanently altered. The most novel effect was the complete absence of seminiferous tubules in many of the animals treated for 4 or 6 days of fetal life.