Reproductive Toxicity

Assessing reproductive toxicity based on zonagenetic assays of xenoestrogens

Effects of lindane on steroidogenesis and steroidogenic acute regulatory protein expression

Reduced Birthweight and Length in the Offspring of Females Exposed to PCDFs, PCP, and Lindane

Partition of the organochlorine insecticide lindane into the human sperm surface induces membrane depolarization and Ca2+ influx.

Multiple studies have reported that lindane exposure (as measured by body tissue level of lindane) is associated with premature labor and spontaneous abortions. The causal relationship has not been established for this action (ATSDR, 1994c); however, the reproductive system effects discussed in Section 5.3.9.4 (bio- chemical changes in uterine, cervical, and vaginal tissues and antiestrogenic effects) may be involved.

As noted above, lindane accumulates in body tissue; consequently, exposure occurring prior to pregnancy can contribute to the overall maternal body burden and result in exposure to the developing individual. As a result, it is necessary to reduce exposure to children and women with childbearing potential to reduce overall body burden. If exposure is reduced during pregnancy but has occurred prior to pregnancy, the pregnancy outcome may be affected, depending on the timing and extent of prior exposure. Two recent reproductive studies in rats found adverse effects on the male reproductive system. In a 7-wk study, decreased sperm counts were noted at 50 mg/kg-d and, in a 180-d study, seminiferous tubular degeneration was noted at 6 mg/kg-d with a NOAEL of 3 mg/kg-d. An older study had identified the same effects at 64.6 mg/kg-d in a 3-mo study. Experimental data indicate that the female reproductive system may also be altered by lindane exposure. A study of rats found uterine, cervical, and vaginal biochemical changes at 20 mg/kg-d in a 30-d study. Antiestrogenic effects were found at 20 mg/kg-d in female rats in a 15-wk study with a NOAEL of 5 mg/kg-d. This action was also found in two other recent studies (ATSDR, 1994c).

5.3.9.6    Mutagenicity

                In animals, ingestion of technical-grade hexachlorocyclohexane-induced dominant
                lethal mutations in mice. Studies found that lindane binds to mouse liver DNA at
                a low rate. Based on a review of genotoxicity studies, ATSDR concluded that
                lindane "has some genotoxic potential, but the evidence for this is not conclusive"
                (ATSDR, 1994c).

TOXICOLOGICAL PROFILE SUMMARIES FOR TARGET ANALYTES

Effects of lindane on steroidogenesis and steroidogenic acute regulatory protein expression.

Walsh LP, Stocco DM

Lindane, the gamma isomer of hexachlorocyclohexane (HCH), is one of the oldest synthetic pesticides still in use worldwide. Numerous reports have shown that this pesticide adversely affects reproductive function in animals. Although the pathogenesis of reproductive dysfunction is not yet fully understood, recent reports indicate that lindane can directly inhibit adrenal and gonadal steroidogenesis. Because Leydig cells play a pivotal role in male reproductive function through the production of testosterone, the mouse MA-10 Leydig tumor cell line was used to assess the potential effects of gamma-HCH and its isomers, alpha-HCH and delta-HCH, on steroid production, steroidogenic enzyme expression and activity, and steroidogenic acute regulatory (StAR) protein expression. StAR mediates the rate-limiting and acutely regulated step in hormone-stimulated steroidogenesis, the intramitochondrial transfer of cholesterol to the P450(scc) enzyme. Our studies demonstrate that alpha-, delta-, and gamma-HCH inhibited dibutyryl ([Bu](2)) cAMP-stimulated progesterone production in MA-10 cells in a dosage-dependent manner without affecting general protein synthesis; and protein kinase A or steroidogenic enzyme expression, activity, or both. In contrast, each of these isomers dramatically reduced (Bu)(2)cAMP-stimulated StAR protein levels. Therefore, our results are consistent with the hypothesis that alpha-, delta-, and gamma-HCH inhibited steroidogenesis by reducing StAR protein expression, an action that may contribute to the pathogenesis of lindane-induced reproductive dysfunction.

http://chem.sis.nlm.nih.gov/chemidplus/

Reduced Birthweight and Length in the Offspring of Females Exposed to PCDFs, PCP, and Lindane

Wilfried Karmaus¹ and Nicola Wolf²

(1)NORDIG Institute for Health Research and Prevention, 22529 Hamburg Germany
(2)Institute for Rehabilitation Science, Humboldt-University Berlin, 10098 Berlin, Germany

Abstract The objective of this study was to investigate a broad range of adverse health outcomes and their potential association to wood preservative used in daycare centers. This article focuses on reproductive effects. A sample of 221 exposed teachers was provided by the employer's liability insurers. A comparison group (n = 189) insured in the same two organizations was recruited from nonexposed daycare centers. In a face-to-face interview, job history and reproductive history of 398 female teachers were ascertained. Data on exposure were provided, including measurements on concentration of pentachlorophenol (PCP) and lindane in wood panels, and of PCP, lindane, polychlorinated dibenzo-p-dioxins and dibenzofurans in indoor air. An exposure matrix based on individual job history, independent exposure information from each center, and reproductive history was set up with regard to the vulnerable time windows for each pregnancy. Using this approach, 49 exposed and 507 nonexposed pregnancies were identified, including 32 exposed and 386 nonexposed live births. For subgroup analyses the observations were restricted to independent pregnancies, excluding multiple and consecutive births. The data were analyzed with linear regression techniques, taking confounders into account. The crude median difference between exposed and nonexposed was 175 g in birthweight and 2 cm in length. Controlling for confounders, the results show a significantly reduced birthweight (p = 0.04) and length (p = 0.02) in exposed pregnancies, even after restricting the data to independent pregnancies and pregnancies for which data could be validated from the mother's health cards. These differences were not explained by differences in gestational age, indicating that a toxic effect, which could cause small-for-date newborns, might have affected the fetus. Key words: birth length, birthweight, fetotoxic effects, lindane, PCDFs, PCDDs, pentachlorophenol, wood preservatives. Environ Health Perspect 103:1120-1125(1995)

http://ehpnet1.niehs.nih.gov/docs/1995/103-12/karmaus.html

Partition of the organochlorine insecticide lindane into the human sperm surface induces membrane depolarization and Ca2+ influx.

Silvestroni L, Fiorini R, Palleschi S

Dipartimento di Fisiopatologia Medica, Universita di Roma La Sapienza,Policlinico Umberto I, Rome, Italy.

The effects of the insecticide lindane (the gamma-isomer of 1,2,3,4,5,6-hexachlorocyclohexane) on membrane potential, cytosolic free Ca2+ concentration ([Ca2+]i) and surface biophysical properties were studied in human spermatozoa. The insecticide induces rapid, transient and reproducible membrane depolarization and opening of voltage-dependent Ca2+ channels leading to an increase in [Ca2+]i. In contrast with the effect in somatic cells, lindane did not affect gamma-aminobutyric acid receptor-linked Cl- currents. Ca2+ and K+ currents were found to drive lindane-induced membrane depolarization and repolarization respectively, whereas Na+ and Cl- fluxes appear not to have a role in the phenomenon. The insecticide was still able to produce membrane depolarization both in the combined absence of extracellular Ca2+ and Na+ and in high-K+ buffer, suggesting that lindane alters the membrane dipole potential. In agreement with this, Laurodan and Prodan fluorescence spectroscopy revealed that lindane partition into the sperm plasma membrane lowers water molecular dynamics in the uppermost region of the membrane external leaflet, probably as the result of reordering of water dipoles. We propose that the first effect of lindane partitioning into the sperm plasma membrane is a change in the membrane dipole potential, which results in the activation of membrane-located Ca2+-influx pathways.
PMID: 9032455, UI: 97184654